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Zuo Y, Li T, Yang S, Chen X, Tao X, Dong D, Liu F, Zhu Y. Contribution and expression of renal drug transporters in renal cell carcinoma. Front Pharmacol 2025; 15:1466877. [PMID: 40034145 PMCID: PMC11873565 DOI: 10.3389/fphar.2024.1466877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/23/2024] [Indexed: 03/05/2025] Open
Abstract
Renal cell carcinoma (RCC) is a common substantive tumor. According to incomplete statistics, RCC incidence accounts for approximately 90% of renal malignant tumors, and is the second most prevalent major malignant tumor in the genitourinary system, following bladder cancer. Only 10%-15% of chemotherapy regimens for metastatic renal cell carcinoma (mRCC) are effective, and mRCC has a high mortality. Drug transporters are proteins located on the cell membrane that are responsible for the absorption, distribution, and excretion of drugs. Lots of drug transporters are expressed in the kidneys. Changes in carrier function weaken balance, cause disease, or modify the effectiveness of drug treatment. The changes in expression of these transporters during cancer pathology results in multi-drug resistance to cancer chemotherapy. In the treatment of RCC, the study of drug transporters helps to optimize treatment regimens, improve therapeutic effects, and reduce drug side effects. In this review, we summarize advances in the role of renal drug transporters in the genesis, progression, and treatment of RCC.
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Affiliation(s)
- Yawen Zuo
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Tong Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xuyang Chen
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fang Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yanna Zhu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
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Ontawong A, Aida CJ, Vivithanaporn P, Amornlerdpison D, Vaddhanaphuti CS. Cladophora glomerata Kützing extract exhibits antioxidant, anti-inflammation, and anti-nitrosative stress against impairment of renal organic anion transport in an in vivo study. Nutr Res Pract 2024; 18:633-646. [PMID: 39398884 PMCID: PMC11464274 DOI: 10.4162/nrp.2024.18.5.633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/28/2024] [Accepted: 07/01/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND/OBJECTIVES Cladophora glomerata extract (CGE), rich in polyphenols, was reported to exhibit antidiabetic and renoprotective effects by modulating the functions of protein kinases-mediated organic anion transporter 1 (Oat1) and 3 (Oat3) in rats with type 2 diabetes mellitus (T2DM). Nevertheless, the antioxidant effects of CGE on such renoprotection have not been investigated. This study examined the mechanisms involved in the antioxidant effects of CGE on renal organic anion transport function in an in vivo study. MATERIALS/METHODS Diabetes was induced in the rats through a high-fat diet combined with a single dose of 40 mg/kg body weight (BW) streptozotocin. Subsequently, normal-diet rats were supplemented with a vehicle or 1,000 mg/kg BW of CGE, while T2DM rats were supplemented with a vehicle, CGE, or 200 mg/kg BW of vitamin C for 12 weeks. The study evaluated the general characteristics of T2DM and renal oxidative stress markers. The renal organic transport function was assessed by measuring the para-aminohippurate (PAH) uptake using renal cortical slices and renal inflammatory cytokine expression in the normal diet (ND) and ND + CGE treated groups. RESULTS CGE supplementation significantly reduced hyperglycemia, hypertriglyceridemia, insulin resistance, and renal lipid peroxidation in T2DM rats. This was accompanied by the normalization of high expressions of renal glutathione peroxidase and nuclear factor kappa B by CGE and vitamin C. The renal anti-inflammation of CGE was evidenced by the reduction of tumor necrosis factor-1α and interleukin-1β. CGE directly blunted sodium nitroprusside-induced renal oxidative/nitrosative stresses and mediated the PAH uptake in the normally treated CGE in rats was particularly noteworthy. These data also correlated with reduced nitric oxide production, highlighting the potential of CGE as a therapeutic agent for managing T2DM-related renal complications. CONCLUSION These findings suggest that CGE has antidiabetic effects and directly prevents diabetic nephropathy through oxidative/nitrosative stress pathways.
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Affiliation(s)
- Atcharaporn Ontawong
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Chaliya J. Aida
- Office of Educational Affairs, Faculty of Abhaibhubejhr Thai Traditional Medicine, Burapha University, Chon Buri 20131, Thailand
| | - Pornpun Vivithanaporn
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan 10540, Thailand
| | - Doungporn Amornlerdpison
- Center of Excellence in Agricultural Innovation for Graduate Entrepreneurs and Faculty of Fisheries Technology and Aquatic Resources, Maejo University, Chiang Mai 50290, Thailand
| | - Chutima S. Vaddhanaphuti
- Innovative Research Unit of Epithelial Transport and Regulation (iETR), Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
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Rox K, Kühne A, Herrmann J, Jansen R, Hüttel S, Bernecker S, Hagos Y, Brönstrup M, Stadler M, Hesterkamp T, Müller R. Interaction of the Atypical Tetracyclines Chelocardin and Amidochelocardin with Renal Drug Transporters. ACS Pharmacol Transl Sci 2024; 7:2093-2109. [PMID: 39022358 PMCID: PMC11249637 DOI: 10.1021/acsptsci.4c00183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Antimicrobial resistance is expected to increase mortality rates by up to several million deaths per year by 2050 without new treatment options at hand. Recently, we characterized the pharmacokinetic (PK) and pharmacodynamic properties of two atypical tetracyclines, chelocardin (CHD) and amidochelocardin (CDCHD) that exhibit no cross-resistance with clinically used antibacterials. Both compounds were preferentially renally cleared and demonstrated pronounced effects in an ascending urinary tract infection model against E. coli. Renal drug transporters are known to influence clearance into the urine. In particular, inhibition of apical transporters in renal tubular epithelial cells can lead to intracellular accumulation and potential cell toxicity, whereas inhibition of basolateral transporters can cause a higher systemic exposure. Here, selected murine and human organic cation (Oct), organic anion (Oat), and efflux transporters were studied to elucidate interactions with CHD and CDCHD underlying their PK behavior. CHD exhibited stronger inhibitory effects on mOat1 and mOat3 and their human homologues hOAT1 and hOAT3 compared to CDCHD. While CHD was a substrate of mOat3 and mOct1, CDCHD was not. By contrast, no inhibitory effect was observed on Octs. CDCHD rather appeared to foster enhanced substrate transport on mOct1. CHD and CDCHD inhibited the efflux transporter hMRP2 on the apical side. In summary, the substrate nature of CHD in conjunction with its autoinhibition toward mOat3 rationalizes the distinct urine concentration profile compared to CDCHD that was previously observed in vivo. Further studies are needed to investigate the accumulation in renal tubular cells and the nephrotoxicity risk.
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Affiliation(s)
- Katharina Rox
- Department
of Chemical Biology, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
| | - Annett Kühne
- PortaCellTec
Biosciences GmbH, 37079 Göttingen, Germany
| | - Jennifer Herrmann
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
- Department
of Microbial Natural Products, Helmholtz
Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre
for Infection Research (HZI) and Department of Pharmacy, Saarland
University, 66123 Saarbrücken, Germany
| | - Rolf Jansen
- Department
of Microbial Drugs, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
| | - Stephan Hüttel
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
- Department
of Microbial Drugs, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
| | - Steffen Bernecker
- Department
of Microbial Drugs, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
| | | | - Mark Brönstrup
- Department
of Chemical Biology, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
| | - Marc Stadler
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
- Department
of Microbial Drugs, Helmholtz Centre for
Infection Research (HZI), 38124 Braunschweig, Germany
| | - Thomas Hesterkamp
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
- Translational
Product Management Office, German Center
for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
| | - Rolf Müller
- German
Center for Infection Research (DZIF), partner site Braunschweig-Hannover, 38124 Braunschweig, Germany
- Department
of Microbial Natural Products, Helmholtz
Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre
for Infection Research (HZI) and Department of Pharmacy, Saarland
University, 66123 Saarbrücken, Germany
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Löscher W, Gramer M, Römermann K. Heterogeneous brain distribution of bumetanide following systemic administration in rats. Biopharm Drug Dispos 2024; 45:138-148. [PMID: 38823029 DOI: 10.1002/bdd.2390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/19/2024] [Accepted: 05/16/2024] [Indexed: 06/03/2024]
Abstract
Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood-brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.
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Affiliation(s)
- Wolfgang Löscher
- Translational Neuropharmacology Laboratory, NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
- Center for Systems Neuroscience Hannover, Hannover, Germany
| | - Martina Gramer
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Kerstin Römermann
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany
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Wang FH, Tan HX, Hu JH, Duan XY, Bai WT, Wang XB, Wang BL, Su Y, Hu JP. Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:353-371. [PMID: 37589480 DOI: 10.1080/10286020.2023.2240722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/20/2023] [Indexed: 08/18/2023]
Abstract
The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.
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Affiliation(s)
- Feng-He Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Hui-Xin Tan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Jia-Huan Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Department of Health Management and Service, Cangzhou Medical College, Cangzhou 061001, China
| | - Xiao-Yan Duan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Wan-Ting Bai
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Xin-Bo Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Bao-Lian Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yan Su
- Department of Health Management and Service, Cangzhou Medical College, Cangzhou 061001, China
| | - Jin-Ping Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
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6
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Niu S, Cao Y, Chen R, Bedi M, Sanders AP, Ducatman A, Ng C. A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:76002. [PMID: 37418334 DOI: 10.1289/ehp11885] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/09/2023]
Abstract
BACKGROUND Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and have been shown to cause various adverse health impacts. In animals, sex- and species-specific differences in PFAS elimination half-lives have been linked to the activity of kidney transporters. However, PFAS molecular interactions with kidney transporters are still not fully understood. Moreover, the impact of kidney disease on PFAS elimination remains unclear. OBJECTIVES This state-of-the-science review integrated current knowledge to assess how changes in kidney function and transporter expression from health to disease could affect PFAS toxicokinetics and identified priority research gaps that should be addressed to advance knowledge. METHODS We searched for studies that measured PFAS uptake by kidney transporters, quantified transporter-level changes associated with kidney disease status, and developed PFAS pharmacokinetic models. We then used two databases to identify untested kidney transporters that have the potential for PFAS transport based on their endogenous substrates. Finally, we used an existing pharmacokinetic model for perfluorooctanoic acid (PFOA) in male rats to explore the influence of transporter expression levels, glomerular filtration rate (GFR), and serum albumin on serum half-lives. RESULTS The literature search identified nine human and eight rat kidney transporters that were previously investigated for their ability to transport PFAS, as well as seven human and three rat transporters that were confirmed to transport specific PFAS. We proposed a candidate list of seven untested kidney transporters with the potential for PFAS transport. Model results indicated PFOA toxicokinetics were more influenced by changes in GFR than in transporter expression. DISCUSSION Studies on additional transporters, particularly efflux transporters, and on more PFAS, especially current-use PFAS, are needed to better cover the role of transporters across the PFAS class. Remaining research gaps in transporter expression changes in specific kidney disease states could limit the effectiveness of risk assessment and prevent identification of vulnerable populations. https://doi.org/10.1289/EHP11885.
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Affiliation(s)
- Shan Niu
- Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yuexin Cao
- Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ruiwen Chen
- Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Megha Bedi
- Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alison P Sanders
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alan Ducatman
- Department of Occupational and Environmental Health Sciences, West Virginia University, Morgantown, West Virginia, USA
| | - Carla Ng
- Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Janaszkiewicz A, Tóth Á, Faucher Q, Arnion H, Védrenne N, Barin-Le Guellec C, Marquet P, Di Meo F. Substrate binding and lipid-mediated allostery in the human organic anion transporter 1 at the atomic-scale. Biomed Pharmacother 2023; 160:114342. [PMID: 36739760 DOI: 10.1016/j.biopha.2023.114342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 01/23/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
The Organic Anion Transporter 1 is a membrane transporter known for its central role in drug elimination by the kidney. hOAT1 is an antiporter translocating substrate in exchange for a-ketoglutarate. The understanding of hOAT1 structure and function remains limited due to the absence of resolved structure of hOAT1. Benefiting from conserved structural and functional patterns shared with other Major Facilitator Superfamily transporters, the present study intended to investigate fragments of hOAT1 transport function and modulation of its activity in order to make a step forward the understanding of its transport cycle. μs-long molecular dynamics simulation of hOAT1 were carried out suggesting two plausible binding sites for a typical substrate, adefovir, in line with experimental observations. The well-known B-like motif binding site was observed in line with previous studies. However, we here propose a new inner binding cavity which is expected to be involved in substrate translocation event. Binding modes of hOAT1 co-substrate α-ketoglutarate were also investigated suggesting that it may bind to highly conserved intracellular motifs. We here hypothesise that α-ketoglutarate may disrupt the pseudo-symmetrical intracellular charge-relay system which in turn may participate to the destabilisation of OF conformation. Investigations regarding allosteric communications along hOAT1 also suggest that substrate binding event might modulate the dynamics of intracellular charge relay system, assisted by surrounding lipids as active partners. We here proposed a structural rationalisation of transport impairments observed for two single nucleotide polymorphisms, p.Arg50His and p.Arg454Gln suggesting that the present model may be used to transport dysfunctions arising from hOAT1 mutations.
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Affiliation(s)
| | - Ágota Tóth
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France
| | - Quentin Faucher
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utre-cht University, 3584 CG Utrecht, The Netherlands
| | - Hélène Arnion
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France
| | - Nicolas Védrenne
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France
| | - Chantal Barin-Le Guellec
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France; CHU de Tours, 2 Boulevard Tonnellé, 37044 Tours, France
| | - Pierre Marquet
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France; Department of Pharmacology and Toxicology, CHU Limoges, F-87000 Limoges, France
| | - Florent Di Meo
- Inserm U1248 Pharmacology & Transplantation, Univ. Limoges, 87000 Limoges, France.
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Susa K, Kobayashi K, Galichon P, Matsumoto T, Tamura A, Hiratsuka K, Gupta NR, Yazdi IK, Bonventre JV, Morizane R. ATP/ADP biosensor organoids for drug nephrotoxicity assessment. Front Cell Dev Biol 2023; 11:1138504. [PMID: 36936695 PMCID: PMC10017499 DOI: 10.3389/fcell.2023.1138504] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Drug nephrotoxicity is a common healthcare problem in hospitalized patients and a major limitation during drug development. Multi-segmented kidney organoids derived from human pluripotent stem cells may complement traditional cell culture and animal experiments for nephrotoxicity assessment. Here we evaluate the capability of kidney organoids to investigate drug toxicity in vitro. Kidney organoids express renal drug transporters, OAT1, OAT3, and OCT2, while a human proximal tubular cell line shows the absence of OAT1 and OAT3. Tenofovir and aristolochic acid (AA) induce proximal tubular injury in organoids which is ameliorated by an OAT inhibitor, probenecid, without damage to podocytes. Similarly, cisplatin causes proximal tubular damage that can be relieved by an OCT inhibitor, cimetidine, collectively suggesting the presence of functional OATs and OCTs in organoid proximal tubules. Puromycin aminonucleoside (PAN) induced segment-specific injury in glomerular podocytes in kidney organoids in the absence of tubular injury. Reporter organoids were generated with an ATP/ADP biosensor, which may be applicable to high-throughput screening in the future. In conclusion, the kidney organoid is a useful tool for toxicity assessment in the multicellular context and may contribute to nephrotoxicity assessment during drug development.
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Affiliation(s)
- Koichiro Susa
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenichi Kobayashi
- Harvard Medical School, Boston, MA, United States
- Massachusetts General Hospital, Boston, MA, United States
| | - Pierre Galichon
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Takuya Matsumoto
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
| | - Akitoshi Tamura
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
| | - Ken Hiratsuka
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Massachusetts General Hospital, Boston, MA, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
| | - Navin R. Gupta
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Massachusetts General Hospital, Boston, MA, United States
| | - Iman K. Yazdi
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Joseph V. Bonventre
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard-MIT Division of Health Sciences &Technology, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Ryuji Morizane
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Massachusetts General Hospital, Boston, MA, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
- Harvard Stem Cell Institute, Cambridge, MA, United States
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Torres-Vergara P, Rivera R, Escudero C, Penny J. Maternal and Fetal Expression of ATP-Binding Cassette and Solute Carrier Transporters Involved in the Brain Disposition of Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1428:149-177. [PMID: 37466773 DOI: 10.1007/978-3-031-32554-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Evidence from preclinical and clinical studies demonstrate that pregnancy is a physiological state capable of modifying drug disposition. Factors including increased hepatic metabolism and renal excretion are responsible for impacting disposition, and the role of membrane transporters expressed in biological barriers, including the placental- and blood-brain barriers, has received considerable attention. In this regard, the brain disposition of drugs in the mother and fetus has been the subject of studies attempting to characterize the mechanisms by which pregnancy could alter the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters. This chapter will summarize findings of the influence of pregnancy on the maternal and fetal expression of ABC and SLC transporters in the brain and the consequences of such changes on the disposition of therapeutic drugs.
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Affiliation(s)
- Pablo Torres-Vergara
- Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
- Grupo de Investigación Vascular (GRIVAS), Universidad del Bio-Bio, Chillán, Chile.
| | - Robin Rivera
- Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
| | - Carlos Escudero
- Grupo de Investigación Vascular (GRIVAS), Universidad del Bio-Bio, Chillán, Chile
- Laboratorio de Fisiología Vascular, Facultad de Ciencias Básicas, Universidad del Bio Bio, Chillán, Chile
| | - Jeffrey Penny
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Health and Medicine, The University of Manchester, Manchester, UK
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10
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Gou X, Ran F, Yang J, Ma Y, Wu X. Construction and Evaluation of a Novel Organic Anion Transporter 1/3 CRISPR/Cas9 Double-Knockout Rat Model. Pharmaceutics 2022; 14:2307. [PMID: 36365126 PMCID: PMC9697873 DOI: 10.3390/pharmaceutics14112307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/13/2022] [Accepted: 10/25/2022] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Organic anion transporter 1 (OAT1) and OAT3 have an overlapping spectrum of substrates such that one can exert a compensatory effect when the other is dysfunctional. As a result, the knockout of either OAT1 or OAT3 is not reflected in a change in the excretion of organic anionic substrates. To date, only the mOAT1 and mOAT3 individual knockout mouse models have been available. METHODS In this study, we successfully generated a Slc22a6/Slc22a8 double-knockout (KO) rat model using CRISPR/Cas9 technology and evaluated its biological properties. RESULTS The double-knockout rat model did not expression mRNA for rOAT1 or rOAT3 in the kidneys. Consistently, the renal excretion of p-aminohippuric acid (PAH), the classical substrate of OAT1/OAT3, was substantially decreased in the Slc22a6/Slc22a8 double-knockout rats. The relative mRNA level of Slco4c1 was up-regulated in KO rats. No renal pathological phenotype was evident. The renal elimination of the organic anionic drug furosemide was nearly abolished in the Slc22a6/Slc22a8 knockout rats, but elimination of the organic cationic drug metformin was hardly affected. CONCLUSIONS These results demonstrate that this rat model is a useful tool for investigating the functions of OAT1/OAT3 in metabolic diseases, drug metabolism and pharmacokinetics, and OATs-mediated drug interactions.
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Affiliation(s)
- Xueyan Gou
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730013, China
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Fenglin Ran
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Jinru Yang
- School of First Clinical Medicine, Lanzhou University, Lanzhou 730000, China
| | - Yanrong Ma
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730013, China
| | - Xin’an Wu
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730013, China
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11
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Serrano-Contreras JI, Meléndez-Camargo ME, Márquez-Flores YK, Soria-Serrano MP, Campos-Aldrete ME. Exploratory toxicology studies of 2,3-substituted imidazo[1,2- a]pyridines with antiparasitic and anti-inflammatory properties. Toxicol Res (Camb) 2022; 11:730-742. [PMID: 36337253 PMCID: PMC9618103 DOI: 10.1093/toxres/tfac046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/23/2022] [Accepted: 07/04/2022] [Indexed: 09/08/2024] Open
Abstract
Background Trichomoniasis and amoebiasis are neglected diseases and still remain as a global health burden not only for developing countries, from where are endemic, but also for the developed world. Previously, we tested the antiparasitic activity of a number of imidazo[1,2-a]pyridine derivatives (IMPYs) on metronidazole-resistant strains of Entamoeba Hystolitica (HM1:IMSS), and Trichomonas Vaginalis (GT3). Their anti-inflammatory activity was also evaluated. Objective The present work is a part of a project whose aim is to find new alternatives to standard treatments for these maladies, and to address the current concern of emerging resistant parasite strains. Here we report a non-clinical study focused on exploratory toxicology assays of seven IMPYs that showed the best antiparasitic and/or anti-inflammatory properties. Methods Acute, and subacute toxicity tests were carried out. After 14-day oral treatment, liver and kidney functionality assays in combination with chemometric methods were implemented to detect hepatic and/or kidney damage. Results Some compounds produced off-target effects. Vehicle effects were also detected. However, no signs of hepatic or renal toxicity were observed for any IMPY. Conclusion These compounds can continue non-clinical evaluations, and if possible, clinical trials as new candidates to treat trichomoniasis and amoebiasis, and inflammatory diseases. Further studies are also needed to fully elucidate a proposed dual effect that may exert these molecules against trichomoniasis and amoebiasis, which may also signify a novel mechanism of action to treat these infections.
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Affiliation(s)
- José Iván Serrano-Contreras
- Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Col. Santo Tomas, C.P. 11340, Delegación Miguel Hidalgo, Ciudad de México, México
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu 399, Unidad Profesional Adolfo López Mateos, Col. Nueva Industrial Vallejo, C.P. 07738, Delegación Gustavo A. Madero, Ciudad de México, México
| | - María Estela Meléndez-Camargo
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu 399, Unidad Profesional Adolfo López Mateos, Col. Nueva Industrial Vallejo, C.P. 07738, Delegación Gustavo A. Madero, Ciudad de México, México
| | - Yazmín Karina Márquez-Flores
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu 399, Unidad Profesional Adolfo López Mateos, Col. Nueva Industrial Vallejo, C.P. 07738, Delegación Gustavo A. Madero, Ciudad de México, México
| | - Martha Patricia Soria-Serrano
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu 399, Unidad Profesional Adolfo López Mateos, Col. Nueva Industrial Vallejo, C.P. 07738, Delegación Gustavo A. Madero, Ciudad de México, México
| | - María Elena Campos-Aldrete
- Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Col. Santo Tomas, C.P. 11340, Delegación Miguel Hidalgo, Ciudad de México, México
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12
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Yang L, Wang B, Ma L, Fu P. Traditional Chinese herbs and natural products in hyperuricemia-induced chronic kidney disease. Front Pharmacol 2022; 13:971032. [PMID: 36016570 PMCID: PMC9395578 DOI: 10.3389/fphar.2022.971032] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/06/2022] [Indexed: 11/20/2022] Open
Abstract
Hyperuricemia is a common biochemical disorder, which resulted from both excessive uric acid (UA) production and/or absolute or relative impairment of urinary UA excretion. Growing evidence has indicated that hyperuricemia is an independent risk factor for the development and progression of chronic kidney disease (CKD), causing hyperuricemia-induced CKD (hyperuricemic nephropathy, HN). The therapeutic strategy of HN is managing hyperuricemia and protecting kidney function. Adverse effects of commercial drugs make persistent treatment of HN challenging. Traditional Chinese medicine (TCM) has exact efficacy in lowering serum UA without serious adverse effects. In addition, TCM is widely applied for the treatment of CKD. This review aimed to provide an overview of efficacy and mechanisms of traditional Chinese herbs and natural products in hyperuricemia-induced CKD.
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Affiliation(s)
| | | | - Liang Ma
- *Correspondence: Liang Ma, ; Ping Fu,
| | - Ping Fu
- *Correspondence: Liang Ma, ; Ping Fu,
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13
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Gledhill A, Bowen R, Bartels M, Bond A, Chung G, Brown CDA, Pye K, Vora T. The chlorophenoxy herbicide MCPA: A mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs. Xenobiotica 2022; 52:498-510. [PMID: 35822285 DOI: 10.1080/00498254.2022.2100842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
1. Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50-67% dose in rat, ∼40% in human and 2-27% in dog. No dog specific metabolite is apparent.2. In rat and human, MCPA and metabolites are rapidly eliminated in urine (65-70% within 24 hours) but in dog, excretion is via urine and faeces (20-30% within 24 hours), with renal excretion saturating between 5 and 100 mg.kg bw.3. The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15-17 hour) but higher in dog (47 hour). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing.4. The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.
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Affiliation(s)
| | | | | | | | - Git Chung
- Newcells Biotech, Newcastle upon Tyne, UK
| | | | - Keith Pye
- Newcells Biotech, Newcastle upon Tyne, UK
| | - Tarang Vora
- Simulations Plus, Lancaster, California, USA
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14
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Torres A, Pedersen B, Cobo I, Ai R, Coras R, Murillo-Saich J, Nygaard G, Sanchez-Lopez E, Murphy A, Wang W, Firestein GS, Guma M. Epigenetic Regulation of Nutrient Transporters in Rheumatoid Arthritis Fibroblast-like Synoviocytes. Arthritis Rheumatol 2022; 74:1159-1171. [PMID: 35128827 PMCID: PMC9246826 DOI: 10.1002/art.42077] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 11/21/2021] [Accepted: 01/25/2022] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Since previous studies indicate that metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), we undertook this study to determine if changes in the genome-wide chromatin and DNA states in genes associated with nutrient transporters could help to identify activated metabolic pathways in RA FLS. METHODS Data from a previous comprehensive epigenomic study in FLS were analyzed to identify differences in genome-wide states and gene transcription between RA and osteoarthritis. We utilized the single nearest genes to regions of interest for pathway analyses. Homer promoter analysis was used to identify enriched motifs for transcription factors. The role of solute carrier transporters and glutamine metabolism dependence in RA FLS was determined by small interfacing RNA knockdown, functional assays, and incubation with CB-839, a glutaminase inhibitor. We performed 1 H nuclear magnetic resonance to quantify metabolites. RESULTS The unbiased pathway analysis demonstrated that solute carrier-mediated transmembrane transport was one pathway associated with differences in at least 4 genome-wide states or gene transcription. Thirty-four transporters of amino acids and other nutrients were associated with a change in at least 4 epigenetic marks. Functional assays revealed that solute carrier family 4 member 4 (SLC4A4) was critical for invasion, and glutamine was sufficient as an alternate source of energy to glucose. Experiments with CB-839 demonstrated decreased RA FLS invasion and proliferation. Finally, we found enrichment of motifs for c-Myc in several nutrient transporters. CONCLUSION Our findings demonstrate that changes in the epigenetic landscape of genes are related to nutrient transporters, and metabolic pathways can be used to identify RA-specific targets, including critical solute carrier transporters, enzymes, and transcription factors, to develop novel therapeutic agents.
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Affiliation(s)
- Alyssa Torres
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
| | - Brian Pedersen
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
| | - Isidoro Cobo
- Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, CA 92093, USA
| | - Rizi Ai
- Department of Chemistry and Biochemistry, Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Roxana Coras
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain
| | - Jessica Murillo-Saich
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
| | - Gyrid Nygaard
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
| | | | | | - Wei Wang
- Department of Chemistry and Biochemistry, Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Gary S Firestein
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
| | - Monica Guma
- Division of Rheumatology, Allergy and Immunology and, School of Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain
- VA Medical Center, San Diego, California
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15
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Huttunen J, Adla SK, Markowicz-Piasecka M, Huttunen KM. Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs). Pharmaceutics 2022; 14:pharmaceutics14061234. [PMID: 35745806 PMCID: PMC9228667 DOI: 10.3390/pharmaceutics14061234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 02/04/2023] Open
Abstract
Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future.
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Affiliation(s)
- Johanna Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; (J.H.); (S.K.A.)
| | - Santosh Kumar Adla
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; (J.H.); (S.K.A.)
- Institute of Organic Chemistry and Biochemistry (IOCB), Czech Academy of Sciences, Flemingovo Namesti 542/2, 160 00 Prague, Czech Republic
| | - Magdalena Markowicz-Piasecka
- Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland;
| | - Kristiina M. Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; (J.H.); (S.K.A.)
- Correspondence:
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16
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Schicker K, Farr CV, Boytsov D, Freissmuth M, Sandtner W. Optimizing the Substrate Uptake Rate of Solute Carriers. Front Physiol 2022; 13:817886. [PMID: 35185619 PMCID: PMC8850955 DOI: 10.3389/fphys.2022.817886] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/10/2022] [Indexed: 11/16/2022] Open
Abstract
The diversity in solute carriers arose from evolutionary pressure. Here, we surmised that the adaptive search for optimizing the rate of substrate translocation was also shaped by the ambient extracellular and intracellular concentrations of substrate and co-substrate(s). We explored possible solutions by employing kinetic models, which were based on analytical expressions of the substrate uptake rate, that is, as a function of the microscopic rate constants used to parameterize the transport cycle. We obtained the defining terms for five reaction schemes with identical transport stoichiometry (i.e., Na+: substrate = 2:1). We then utilized an optimization algorithm to find the set of numeric values for the microscopic rate constants, which provided the largest value for the substrate uptake rate: The same optimized rate was achieved by different sets of numerical values for the microscopic rate constants. An in-depth analysis of these sets provided the following insights: (i) In the presence of a low extracellular substrate concentration, a transporter can only cycle at a high rate, if it has low values for both, the Michaelis-Menten constant (KM) for substrate and the maximal substrate uptake rate (Vmax). (ii) The opposite is true for a transporter operating at high extracellular substrate concentrations. (iii) Random order of substrate and co-substrate binding is superior to sequential order, if a transporter is to maintain a high rate of substrate uptake in the presence of accumulating intracellular substrate. Our kinetic models provide a framework to understand how and why the transport cycles of closely related transporters differ.
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Affiliation(s)
| | | | | | | | - Walter Sandtner
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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17
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Yu Z, Liu C, Zhang J, Liang Z, You G. Protein kinase C regulates organic anion transporter 1 through phosphorylating ubiquitin ligase Nedd4-2. BMC Mol Cell Biol 2021; 22:53. [PMID: 34663225 PMCID: PMC8524912 DOI: 10.1186/s12860-021-00393-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 10/08/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Organic anion transporter 1 (OAT1) is a drug transporter expressed on the basolateral membrane of the proximal tubule cells in kidneys. It plays an essential role in the disposition of numerous clinical therapeutics, impacting their pharmacological and toxicological properties. The activation of protein kinase C (PKC) is shown to facilitate OAT1 internalization from cell surface to intracellular compartments and thereby reducing cell surface expression and transport activity of the transporter. The PKC-regulated OAT1 internalization occurs through ubiquitination, a process catalyzed by a E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2). Nedd4-2 directly interacts with OAT1 and affects ubiquitination, expression and stability of the transporter. However, whether Nedd4-2 is a direct substrate for PKC-induced phosphorylation is unknown. RESULTS In this study, we investigated the role of Nedd4-2 phosphorylation in the PKC regulation of OAT1. The results showed that PKC activation enhanced the phosphorylation of Nedd4-2 and increased the OAT1 ubiquitination, which was accompanied by a decreased OAT1 cell surface expression and transport function. And the effects of PKC could be reversed by PKC-specific inhibitor staurosporine. We further discovered that the quadruple mutant (T197A/S221A/S354A/S420A) of Nedd4-2 partially blocked the effects of PKC on Nedd4-2 phosphorylation and on OAT1 transport activity. CONCLUSIONS Our investigation demonstrates that PKC regulates OAT1 likely through direct phosphorylation of Nedd4-2. And four phosphorylation sites (T197, S221, S354, and S420) of Nedd4-2 in combination play an important role in this regulatory process.
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Affiliation(s)
- Zhou Yu
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA
| | - Chenchang Liu
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA
| | - Jinghui Zhang
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA
| | - Zhengxuan Liang
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
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18
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Pou Casellas C, Jansen K, Rookmaaker MB, Clevers H, Verhaar MC, Masereeuw R. Regulation of Solute Carriers OCT2 and OAT1/3 in the Kidney: A Phylogenetic, Ontogenetic and Cell Dynamic Perspective. Physiol Rev 2021; 102:993-1024. [PMID: 34486394 DOI: 10.1152/physrev.00009.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the course of more than 500 million years, the kidneys have undergone a remarkable evolution from primitive nephric tubes to intricate filtration-reabsorption systems that maintain homeostasis and remove metabolic end products from the body. The evolutionarily conserved solute carriers Organic Cation Transporter 2 (OCT2), and Organic Anion Transporters 1 and 3 (OAT1/3) coordinate the active secretion of a broad range of endogenous and exogenous substances, many of which accumulate in the blood of patients with kidney failure despite dialysis. Harnessing OCT2 and OAT1/3 through functional preservation or regeneration could alleviate the progression of kidney disease. Additionally, it would improve current in vitro test models that lose their expression in culture. With this review, we explore OCT2 and OAT1/3 regulation using different perspectives: phylogenetic, ontogenetic and cell dynamic. Our aim is to identify possible molecular targets to both help prevent or compensate for the loss of transport activity in patients with kidney disease, and to enable endogenous OCT2 and OAT1/3 induction in vitro in order to develop better models for drug development.
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Affiliation(s)
- Carla Pou Casellas
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands.,Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
| | - Katja Jansen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Maarten B Rookmaaker
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - Hans Clevers
- Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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19
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Zou F, Zhao X, Wang F. A review on the fruit components affecting uric acid level and their underlying mechanisms. J Food Biochem 2021; 45:e13911. [PMID: 34426969 DOI: 10.1111/jfbc.13911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/12/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022]
Abstract
Uric acid (UA) is produced in the liver and excreted through the kidneys and intestines. If UA is overproduced or its excretion reduces, the concentration of UA increases, leading to hyperuricemia and gout. The high concentration of UA is also related to cardiovascular disease, hypertension, obesity, and other diseases. Fruits are healthy foods. However, fruits contain fructose and small amounts of purine, and the product of their metabolism is UA. Therefore, theoretically, eating fruits will increase the concentration of serum UA. Fruit components are numerous, and their effects on serum UA are complex. According to the current research, fructose, purine, polyphenols, vitamin C, dietary fiber, and minerals present in fruits influence serum UA concentrations. In addition to the UA synthesized by fructose and purine metabolism, the mechanisms by which other components affect the concentration of serum UA can be summarized as follows: (a) inhibiting xanthine oxidase; (b) reducing reabsorption of UA; and (c) improving the excretion of UA. In this review, we comprehensively discussed the fruit components that affect serum UA concentrations, and explained their mechanisms for the first time, which references for patients with hyperuricemia to take fruits. PRACTICAL APPLICATIONS: With the rising prevalence, hyperuricemia and gout have become public health problems that endanger our daily life. The key to the treatment of hyperuricemia is to control the level of serum UA within the normal range. Fruits are healthy foods. However, fruit components are numerous, and their effects on serum UA are complex. According to the current research, fructose, purine, polyphenols, vitamin C, dietary fiber, and minerals present in fruits influence serum UA concentrations. In this review, we comprehensively discussed the fruit components that affect serum UA concentrations. We also explained their mechanisms, which references for patients with hyperuricemia to take fruits.
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Affiliation(s)
- Fengmao Zou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Xu Zhao
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Fuqi Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
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20
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Nethathe B, Chipangura J, Hassan IZ, Duncan N, Adawaren EO, Havenga L, Naidoo V. Diclofenac toxicity in susceptible bird species results from a combination of reduced glomerular filtration and plasma flow with subsequent renal tubular necrosis. PeerJ 2021; 9:e12002. [PMID: 34513332 PMCID: PMC8388555 DOI: 10.7717/peerj.12002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 07/27/2021] [Indexed: 01/13/2023] Open
Abstract
Diclofenac caused the death of millions of vultures on the Asian subcontinent. Other non-steroidal anti-inflammatory drugs (NSAIDs) have since also been shown to be toxic to vultures with the exception of meloxicam. For this study, we evaluated the effect of diclofenac on renal uric acid transport and glomerulus filtration in an acute toxicity model. In a two-phase study with the same birds, healthy chickens (a validated model species) were treated intravenously with para-amino hippuric acid (PAH) and iohexol (IOH) in combination in phase 1. In phase 2, the same PAH and IOH combination was then combined with diclofenac (10 mg/kg). In both phases, blood and faeces were sequentially collected. In phase 1, the birds showed no signs of ill health. Moreover, PAH, IOH and uric acid clearance was rapid. In phase 2, two chickens showed early signs of hyperuricemia 8 hours after exposure and died approximately 24h later. Necropsy showed classic signs of renal damage and gout. Diclofenac had a rapid plasma half-life of elimination of less than 2 hours indicating that toxicity was likely due to an irreversible destruction of a physiological process. All the birds in phase 2 had decreased uric acid, PAH and IOH clearance in comparison to phase 1. The decrease in PAH clearance was variable between the birds (average of 71%) but was near 98% reduced in the two birds that died. It is concluded that diclofenac alters both renal perfusion and renal plasma flow, with death associated with tubular secretion being reduced to negligible functionality for a prolonged period. This would support previous in vitro findings of early cell death from ROS accumulation. However, further evaluation is needed to elucidate this final step.
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Affiliation(s)
- Bono Nethathe
- Department of Paraclinical Science, University of Pretoria, Onderstepoort, Pretoria, South Africa
- Department of Food Science and Technology, University of Venda for Science and Technology, Thohoyandou, Limpopo, South Africa
| | - John Chipangura
- Department of Paraclinical Science, University of Pretoria, Onderstepoort, Pretoria, South Africa
| | - Ibrahim Zubairu Hassan
- Department of Paraclinical Science, University of Pretoria, Onderstepoort, Pretoria, South Africa
| | - Neil Duncan
- Department of Pathology, University of Pretoria, Onderstepoort, Pretoria, South Africa
| | | | - Lauren Havenga
- Department of Anatomy and Physiology, University of Pretoria, Onderstepoort, Pretoria, South Africa
| | - Vinny Naidoo
- Department of Paraclinical Science, University of Pretoria, Onderstepoort, Pretoria, South Africa
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21
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Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, Platt FM, Galione A. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep 2021; 11:15812. [PMID: 34349180 PMCID: PMC8338929 DOI: 10.1038/s41598-021-95255-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two-carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. N-acetyl-D,L-leucine is approved in France for vertigo and its L-enantiomer is being developed as a drug for rare and common neurological disorders. However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the L-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N-acetyl-L-leucine. MCT1-mediated uptake of a N-acetyl-L-leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR. Converting an amino acid into an anion through acetylation reveals a way for the rational design of drugs to target anion transporters.
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Affiliation(s)
- Grant C Churchill
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
| | - Michael Strupp
- Department of Neurology and German Center for Vertigo and Balance Disorders, Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Cailley Factor
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Tatiana Bremova-Ertl
- Department of Neurology, University Hospital Inselspital, Bern, BE, Switzerland
- Center for Rare Diseases, University Hospital Inselspital Bern, Bern, BE, Switzerland
| | - Mallory Factor
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Marc C Patterson
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Frances M Platt
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Antony Galione
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
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22
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Nethathe B, Phaswane R, Abera A, Naidoo V. Molecular characterization of Gyps africanus (African white-backed vulture) organic anion transporter 1 and 2 expressed in the kidney. PLoS One 2021; 16:e0250408. [PMID: 33945567 PMCID: PMC8096082 DOI: 10.1371/journal.pone.0250408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/06/2021] [Indexed: 11/19/2022] Open
Abstract
Gyps species have been previously shown to be highly sensitive to the toxic effects of diclofenac, when present in their food sources as drug residues following use as a veterinary medicine. Vultures exposed to diclofenac soon become depressed and die with signs of severe visceral gout and renal damage on necropsy. The molecular mechanism behind toxicity and renal excretion of uric acid is still poorly understood. With the clinical pictures suggesting renal uric acid excretion as the target site for toxicity, as a first step the following study was undertaken to determine the uric acid excretory pathways present in the African white-backed vulture (Gyps africanus) (AWB), one of the species susceptible to toxicity. Using transcriptome analysis, immunohistochemistry and functional predictions, we demonstrated that AWB makes use of the organic anion transporter 2 (OAT2) for their uric acid excretion. RT-qPCR analysis subsequently demonstrated relatively similar expression of the OAT2 transporter in the vulture and chicken. Lastly docking analysis, predicted that the non-steroidal drugs induce their toxicity through an allosteric binding.
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Affiliation(s)
- Bono Nethathe
- Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
- Department of Food Science and Technology, School of Agriculture, University of Venda, Limpopo, South Africa
| | - Rephima Phaswane
- Department of Pathology, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Aron Abera
- Inqaba Biotechnology, Pretoria, South Africa
| | - Vinny Naidoo
- Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
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23
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Intracellular prostaglandin E2 contributes to hypoxia-induced proximal tubular cell death. Sci Rep 2021; 11:7047. [PMID: 33782420 PMCID: PMC8007803 DOI: 10.1038/s41598-021-86219-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/22/2021] [Indexed: 12/23/2022] Open
Abstract
Proximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E2 (PGE2), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O2)-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE2 (iPGE2) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE2 contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE2). Thus, iPGE2 is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.
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24
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Zhang J, You G. Peptide Hormone Insulin Regulates Function, Expression, and SUMOylation of Organic Anion Transporter 3. AAPS JOURNAL 2021; 23:41. [PMID: 33709304 DOI: 10.1208/s12248-021-00575-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/17/2021] [Indexed: 11/30/2022]
Abstract
Organic anion transporter 3 (OAT3) plays an important role in the disposition of various anionic drugs which impacts the pharmacokinetics and pharmacodynamics of the therapeutics, thus influencing the pharmacological effects and toxicity of the drugs. In this study, we investigated the effect of insulin on the regulation of OAT3 function, expression, and SUMOylation. We demonstrated that insulin induced an increase in OAT3 transport activity through a dose- and time-dependent manner in COS-7 cells. The insulin-induced elevation in OAT3 function was blocked by PKA inhibitor H89, which correlated well with OAT3 protein expression. Moreover, both PKA activator Bt2-cAMP-induced increase and insulin-induced increase in OAT3 function were blocked by PKB inhibitor AKTi1/2. To further investigate the involvement of SUMOylation, we treated OAT3-expressing cells with insulin in presence or absence of H89 or AKTi1/2 followed by examining OAT3 SUMOylation. We showed that insulin enhanced OAT3 SUMOylation, and such enhancement was abrogated by H89 and AKTi1/2. Lastly, insulin increased OAT3 function and SUMOylation in rat kidney slice. In conclusion, our investigations demonstrated that insulin regulated OAT3 function, expression, and SUMOylation through PKA/PKB signaling pathway. Graphical abstract.
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Affiliation(s)
- Jinghui Zhang
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.
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25
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Auxtero MD, Chalante S, Abade MR, Jorge R, Fernandes AI. Potential Herb-Drug Interactions in the Management of Age-Related Cognitive Dysfunction. Pharmaceutics 2021; 13:124. [PMID: 33478035 PMCID: PMC7835864 DOI: 10.3390/pharmaceutics13010124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/25/2022] Open
Abstract
Late-life mild cognitive impairment and dementia represent a significant burden on healthcare systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treatment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmacological interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration. A literature review was conducted to identify mutual targets affected (inhibition/induction/substrate), the frequency of which was taken as a measure of potential interaction. Although a limited number of drugs were studied, from this work, interaction with other drugs affecting the same targets may be anticipated and prevented, constituting a valuable tool for healthcare professionals in clinical practice.
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Affiliation(s)
- Maria D. Auxtero
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Susana Chalante
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Mário R. Abade
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Rui Jorge
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
- Polytechnic Institute of Santarém, School of Agriculture, Quinta do Galinheiro, 2001-904 Santarém, Portugal
- CIEQV, Life Quality Research Centre, IPSantarém/IPLeiria, Avenida Dr. Mário Soares, 110, 2040-413 Rio Maior, Portugal
| | - Ana I. Fernandes
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
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26
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Betterton RD, Davis TP, Ronaldson PT. Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery. Handb Exp Pharmacol 2021; 266:301-328. [PMID: 33674914 PMCID: PMC8603467 DOI: 10.1007/164_2021_448] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Therapeutic delivery to the central nervous system (CNS) continues to be a considerable challenge in the pharmacological treatment and management of neurological disorders. This is primarily due to the physiological and biochemical characteristics of brain barrier sites (i.e., blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB)). Drug uptake into brain tissue is highly restricted by expression of tight junction protein complexes and adherens junctions between brain microvascular endothelial cells and choroid plexus epithelial cells. Additionally, efflux transport proteins expressed at the plasma membrane of these same endothelial and epithelial cells act to limit CNS concentrations of centrally acting drugs. In contrast, facilitated diffusion via transporter proteins allows for substrate-specific flux of molecules across the plasma membrane, directing drug uptake into the CNS. Organic Cation Transporters (OCTs) and Novel Organic Cation Transporters (OCTNs) are two subfamilies of the solute carrier 22 (SLC22) family of proteins that have significant potential to mediate delivery of positively charged, zwitterionic, and uncharged therapeutics. While expression of these transporters has been well characterized in peripheral tissues, the functional expression of OCT and OCTN transporters at CNS barrier sites and their role in delivery of therapeutic drugs to molecular targets in the brain require more detailed analysis. In this chapter, we will review current knowledge on localization, function, and regulation of OCT and OCTN isoforms at the BBB and BCSFB with a particular emphasis on how these transporters can be utilized for CNS delivery of therapeutic agents.
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Affiliation(s)
- Robert D Betterton
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Thomas P Davis
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Patrick T Ronaldson
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
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27
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Nethathe B, Abera A, Naidoo V. Expression and phylogeny of multidrug resistance protein 2 and 4 in African white backed vulture (Gyps africanus). PeerJ 2020; 8:e10422. [PMID: 33344079 PMCID: PMC7718797 DOI: 10.7717/peerj.10422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/02/2020] [Indexed: 11/20/2022] Open
Abstract
Diclofenac toxicity in old world vultures is well described in the literature by both the severity of the toxicity induced and the speed of death. While the mechanism of toxicity remains unknown at present, the necropsy signs of gout suggests primary renal involvement at the level of the uric acid excretory pathways. From information in the chicken and man, uric acid excretion is known to be a complex process that involves a combination of glomerular filtration and active tubular excretion. For the proximal convoluted tubules excretion occurs as a two-step process with the basolateral cell membrane using the organic anion transporters and the apical membrane using the multidrug resistant protein to transport uric acid from the blood into the tubular fluid. With uric acid excretion seemingly inhibited by diclofenac, it becomes important to characterize these transporter mechanism at the species level. With no information being available on the molecular characterization/expression of MRPs of Gyps africanus, for this study we used next generation sequencing, and Sanger sequencing on the renal tissue of African white backed vulture (AWB), as the first step to establish if the MRPs gene are expressed in AWB. In silico analysis was conducted using different software to ascertain the function of the latter genes. The sequencing results revealed that the MRP2 and MRP4 are expressed in AWB vultures. Phylogeny of avian MRPs genes confirms that vultures and eagles are closely related, which could be attributed to having the same ancestral genes and foraging behavior. In silico analysis confirmed the transcribed proteins would transports anionic compounds and glucose.
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Affiliation(s)
- Bono Nethathe
- Department of Paraclinical Science, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, Pretoria, South Africa.,Department of Food Science and Technology, University of Venda, Thohoyandou, Limpopo, South Africa
| | - Aron Abera
- Inqaba Biotechnology, Sunnyside, Pretoria, South Africa
| | - Vinny Naidoo
- Department of Paraclinical Science, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, Pretoria, South Africa
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28
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Hai Y, Zhang Y, Liang Y, Ma X, Qi X, Xiao J, Xue W, Luo Y, Yue T. Advance on the absorption, metabolism, and efficacy exertion of quercetin and its important derivatives. FOOD FRONTIERS 2020. [DOI: 10.1002/fft2.50] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Yu Hai
- College of Food Science and Technology Northwest University Xi'an Shaanxi P. R. China
| | - Yuanxiao Zhang
- School of Chemical Engineering Northwest University Xi'an Shaanxi P. R. China
| | - Yingzhi Liang
- College of Food Science and Technology Northwest University Xi'an Shaanxi P. R. China
| | - Xiaoyu Ma
- College of Life Science Northwest University Xi'an Shaanxi P. R. China
| | - Xiao Qi
- College of Food Science and Technology Northwest University Xi'an Shaanxi P. R. China
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology University of Vigo ‐ Ourense Campus Ourense E‐32004 Spain
| | - Weiming Xue
- School of Chemical Engineering Northwest University Xi'an Shaanxi P. R. China
| | - Yane Luo
- College of Food Science and Technology Northwest University Xi'an Shaanxi P. R. China
| | - Tianli Yue
- College of Food Science and Technology Northwest University Xi'an Shaanxi P. R. China
- Laboratory of Quality and Safety Risk Assessment for Agro‐products (Yangling) Ministry of Agriculture Beijing P. R. China
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29
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van Nuland M, Rosing H, Huitema ADR, Beijnen JH. Predictive Value of Microdose Pharmacokinetics. Clin Pharmacokinet 2020; 58:1221-1236. [PMID: 31030372 DOI: 10.1007/s40262-019-00769-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Phase 0 microdose trials are exploratory studies to early assess human pharmacokinetics of new chemical entities, while limiting drug exposure and risks for participants. The microdose concept is based on the assumption that microdose pharmacokinetics can be extrapolated to pharmacokinetics of a therapeutic dose. However, it is unknown whether microdose pharmacokinetics are actually indicative of the pharmacokinetics at therapeutic dose. The aim of this review is to investigate the predictive value of microdose pharmacokinetics and to identify drug characteristics that may influence the scalability of these parameters. The predictive value of microdose pharmacokinetics was determined for 46 compounds and showed adequate predictability for 28 of 41 orally administered drugs (68%) and 15 of 16 intravenously administered drugs (94%). Microdose pharmacokinetics were considered predictive if the mean observed values of the microdose and the therapeutic dose were within twofold. Nonlinearity may be caused by saturation of enzyme and transporter systems, such as intestinal and hepatic efflux and uptake transporters. The high degree of success regarding linear pharmacokinetics shows that phase 0 microdose trials can be used as an early human model for determination of drug pharmacokinetics.
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Affiliation(s)
- Merel van Nuland
- Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. .,Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Hilde Rosing
- Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.,Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.,Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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30
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Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination. Pharmacol Ther 2020; 217:107647. [PMID: 32758646 DOI: 10.1016/j.pharmthera.2020.107647] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/27/2020] [Indexed: 12/24/2022]
Abstract
The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.
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31
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Nigam SK, Bush KT, Bhatnagar V, Poloyac SM, Momper JD. The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology. Clin Pharmacol Ther 2020; 108:40-53. [PMID: 32119114 PMCID: PMC7292762 DOI: 10.1002/cpt.1818] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/12/2020] [Indexed: 12/19/2022]
Abstract
Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME) of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies—including systems biology analyses of “omics” data as well as metabolomics studies—indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME proteins in a large multiorgan remote sensing and signaling network. We use the Remote Sensing and Signaling Theory (RSST) to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST‐based view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME proteins with key pathways in metabolism and signaling. The RSST‐based view should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.
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Affiliation(s)
- Sanjay K Nigam
- Departments of Pediatrics and Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Kevin T Bush
- Departments of Pediatrics and Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Vibha Bhatnagar
- Department of Family Medicine and Public Health, School of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Samuel M Poloyac
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jeremiah D Momper
- Division of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
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32
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Kumar R, Adiga A, Novack J, Etinger A, Chinitz L, Slater J, de Loor H, Meijers B, Holzman RS, Lowenstein J. The renal transport of hippurate and protein-bound solutes. Physiol Rep 2020; 8:e14349. [PMID: 32097533 PMCID: PMC7041931 DOI: 10.14814/phy2.14349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Measurement of the concentration of hippurate in the inferior vena cava and renal blood samples performed in 13 subjects with normal or near-normal serum creatinine concentrations confirmed the prediction that endogenous hippurate was cleared on a single pass through the kidney with the same avidity as that reported for infused para-amino hippurate. This suggests that a timed urine collection without infusion would provide a measure of effective renal plasma flow. Comparison of the arteriovenous concentration differences for a panel of protein-bound solutes identified solutes that were secreted by the renal tubule and solutes that were subjected to tubular reabsorption.
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Affiliation(s)
| | | | | | | | | | | | - Henriette de Loor
- Nephrology and Renal Transplantation Research GroupDepartment of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium
| | - Bjorn Meijers
- Nephrology and Renal Transplantation Research GroupDepartment of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium
- Department of Nephrology and Renal TransplantationUniversity Hospitals LeuvenLeuvenBelgium
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Nigam AK, Li JG, Lall K, Shi D, Bush KT, Bhatnagar V, Abagyan R, Nigam SK. Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning. J Biol Chem 2020; 295:1829-1842. [PMID: 31896576 DOI: 10.1074/jbc.ra119.010729] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/30/2019] [Indexed: 01/04/2023] Open
Abstract
The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.
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Affiliation(s)
- Anisha K Nigam
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0693
| | - Julia G Li
- Department of Biology, University of California San Diego, La Jolla, California 92093-0693
| | - Kaustubh Lall
- Department of Computer Engineering, University of California San Diego, La Jolla, California 92093-0693
| | - Da Shi
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0693
| | - Kevin T Bush
- Department of Pediatrics, University of California San Diego, La Jolla, California 92093-0693
| | - Vibha Bhatnagar
- Department of Family and Preventative Medicine, University of California San Diego, La Jolla, California 92093-0693
| | - Ruben Abagyan
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0693.
| | - Sanjay K Nigam
- Department of Pediatrics, University of California San Diego, La Jolla, California 92093-0693; Department of Medicine, University of California San Diego, La Jolla, California 92093-0693.
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Anderson JT, Huang KM, Lustberg MB, Sparreboom A, Hu S. Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions. Rev Physiol Biochem Pharmacol 2020; 183:177-215. [PMID: 32761456 DOI: 10.1007/112_2020_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics. These proteins are highly expressed in the gastrointestinal tract and eliminating organs such as the liver and kidney, and are considered to be of particular importance in governing drug absorption and elimination. Many of the same transporters are also expressed in a wide variety of organs targeted by clinically important anticancer drugs, directly affect cellular sensitivity to these agents, and indirectly influence treatment-related side effects. Furthermore, targeted intervention strategies involving the use of transport inhibitors have been recently developed, and have provided promising lead candidates for combinatorial therapies associated with decreased toxicity. Gaining a better understanding of the complex interplay between transporter-mediated on-target and off-target drug disposition will help guide the further development of these novel treatment strategies to prevent drug accumulation in toxicity-associated organs, and improve the safety of currently available treatment modalities. In this report, we provide an update on this rapidly emerging field with particular emphasis on anticancer drugs belonging to the classes of taxanes, platinum derivatives, nucleoside analogs, and anthracyclines.
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Affiliation(s)
- Jason T Anderson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Maryam B Lustberg
- Department of Medical Oncology, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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Zhang J, Yu Z, You G. Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway. Acta Pharm Sin B 2020; 10:186-194. [PMID: 31993315 PMCID: PMC6977015 DOI: 10.1016/j.apsb.2019.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/10/2019] [Accepted: 05/09/2019] [Indexed: 12/18/2022] Open
Abstract
Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. In the current study, we investigated the role of insulin-like growth factor 1 (IGF-1) in the regulation of OAT3. We showed that IGF-1 induced a dose- and time-dependent increase in OAT3 transport activity, which correlated well with an increase in OAT3 expression. The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A (PKA) inhibitor H89. Moreover, IGF-1 induced an increase in OAT3 phosphorylation, which was also blocked by H89. These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway. To further confirm the involvement of PKA, we treated OAT3-expressing cells with PKA activator Bt2-cAMP, followed by examining OAT activity and phosphorylation. We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells. Finally, linsitinib, an anticancer drug that blocks the IGF-1 receptor, abrogated IGF-1-stimulated OAT3 transport activity. In conclusion, our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway, possibly by phosphorylating the transporter.
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36
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Abedi F, Razavi BM, Hosseinzadeh H. A review on gentisic acid as a plant derived phenolic acid and metabolite of aspirin: Comprehensive pharmacology, toxicology, and some pharmaceutical aspects. Phytother Res 2019; 34:729-741. [PMID: 31825145 DOI: 10.1002/ptr.6573] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 10/24/2019] [Accepted: 11/12/2019] [Indexed: 12/29/2022]
Abstract
Beneficial therapeutic effects of phenolic acids have been proven in various research projects including in vivo and in vitro studies. Gentisic acid (GA) is a phenolic acid that has been associated with useful effects on human health, such as antiinflammatory, antigenotoxic, hepatoprotective, neuroprotective, antimicrobial, and especially antioxidant activities. It is an important metabolite of aspirin and also widely distributed in plants as a secondary plant product such as Gentiana spp., Citrus spp., Vitis vinifera, Pterocarpus santalinus, Helianthus tuberosus, Hibiscus rosa-sinensis, Olea europaea, and Sesamum indicum and in fruits such as avocados, batoko plum, kiwi fruits, apple, bitter melon, black berries, pears, and some mushrooms. This study was undertaken to review the pharmacological effects, pharmacokinetic properties as well as toxicity and pharmaceutical applications of GA.
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Affiliation(s)
- Farshad Abedi
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Li TT, An JX, Xu JY, Tuo BG. Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver. World J Clin Cases 2019; 7:3915-3933. [PMID: 31832394 PMCID: PMC6906560 DOI: 10.12998/wjcc.v7.i23.3915] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 02/05/2023] Open
Abstract
Organic anion transporters (OATs) and organic anion transporter polypeptides (OATPs) are classified within two SLC superfamilies, namely, the SLC22A superfamily and the SLCO superfamily (formerly the SLC21A family), respectively. They are expressed in many tissues, such as the liver and kidney, and mediate the absorption and excretion of many endogenous and exogenous substances, including various drugs. Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm. OATs and OATPs are abundantly expressed in the liver, where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs. However, differences in the locations of glycosylation sites, phosphorylation sites, and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver, which ultimately results in their different roles in the liver. To date, few articles have addressed these aspects of OAT and OATP structures, and we study further the similarities and differences in their structures, tissue distribution, substrates, and roles in liver diseases.
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Affiliation(s)
- Ting-Ting Li
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jia-Xing An
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Bi-Guang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
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Euteneuer AM, Seeger‐Nukpezah T, Nolte H, Henjakovic M. Estrogen receptor α (ERα) indirectly induces transcription of human renal organic anion transporter 1 (OAT1). Physiol Rep 2019; 7:e14229. [PMID: 31724834 PMCID: PMC6854606 DOI: 10.14814/phy2.14229] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 08/20/2019] [Indexed: 01/05/2023] Open
Abstract
Organic anion transporter 1 (OAT1) is a polyspecific transport protein located in the basolateral membrane of renal proximal tubule cells. OAT1 plays a pivotal role in drug clearance. Adverse drug reactions (ADR) are observed more frequently in women than in men, especially ADR are higher in women for drugs which are known interactors of OAT1. Sex-dependent expression of Oat1 has been observed in rodents with a tendency to male-dominant expression. This study aims at elucidating the transcriptional regulation of human OAT1 and tests the effect of estrogen receptor α (ERα). Promoter activation of OAT1 was assessed by luciferase assays carried out by Opossum kidney (OK) cells, transiently transfected with promoter constructs of human OAT1 and expression vectors for ERα and exposed to 100 nmol/L 17β-estradiol. Furthermore, a transcription factor array and proteomic analysis was performed to identify estrogen-induced transcription factors. Human OAT1 was significantly activated by ligand activated ERα. However, activation occurred without a direct interaction of ERα with the OAT1 promoter. Our data rather show an activation of the transcription factors CCAAT-box-binding transcription factor (CBF) and heterogeneous nuclear ribonucleoprotein K (HNRNPK) by ERα, which in turn bind and initiate OAT1 promoter activity. Herewith, we provide novel evidence of estrogen-dependent, transcriptional regulation of polyspecific drug transporters including the estrogen-induced transcription factors CBF and HNRNPK.
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Affiliation(s)
- Anna M. Euteneuer
- Department I of Internal Medicine and Center for Integrated OncologyUniversity of CologneCologneGermany
| | - Tamina Seeger‐Nukpezah
- Department I of Internal Medicine and Center for Integrated OncologyUniversity of CologneCologneGermany
| | - Hendrik Nolte
- Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD)University of CologneCologneGermany
| | - Maja Henjakovic
- Department I of Internal Medicine and Center for Integrated OncologyUniversity of CologneCologneGermany
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Xing X, Ma P, Huang Q, Qi X, Zou B, Wei J, Tao L, Li L, Zhou G, Song Q. Predicting Pharmacokinetics Variation of Faropenem Using a Pharmacometabonomic Approach. J Proteome Res 2019; 19:119-128. [PMID: 31617722 DOI: 10.1021/acs.jproteome.9b00436] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Xiaoqing Xing
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Pengcheng Ma
- Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Qing Huang
- Jiangsu Institute for Food and Drug Control, Nanjing 210008, China
| | - Xiemin Qi
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Bingjie Zou
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Jun Wei
- Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Lei Tao
- Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Lingjun Li
- Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Guohua Zhou
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Qinxin Song
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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40
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Wang H, You G. The SUMO-Specific Protease Senp2 Regulates SUMOylation, Expression and Function of Human Organic Anion Transporter 3. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2019; 1861:1293-1301. [PMID: 31054272 DOI: 10.1016/j.bbamem.2019.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 01/17/2023]
Abstract
Organic anion transporter 3 (OAT3) plays a vital role in removing a broad array of anionic drugs from kidney, thereby avoiding their possibly toxic side effects in the body. We earlier demonstrated that OAT3 is subjected to a specific type of post-translational modification called SUMOylation. SUMOylation is a dynamic event, where de-SUMOylation is catalyzed by a class of SUMO-specific proteases. In the present investigation, we assessed the role of SUMO-specific protease Senp2 in OAT3 SUMOylation, expression and function. We report here that overexpression of Senp2 in COS-7 cells led to a reduced OAT3 SUMOylation, which correlated well with a decreased OAT3 expression and transport activity. Such phenomenon was not observed in cells overexpressing an inactive mutant of Senp2. Furthermore, transfection of cells with Senp2-specific siRNA to knockdown the endogenous Senp2 resulted in an increased OAT3 SUMOylation, which correlated well with an enhanced OAT3 expression and transport activity. Coimmunoprecipitation experiments showed that Senp2 directly interacted with OAT3 in the kidneys of rats. Together these results provided first demonstration that Senp2 is a significant regulator for OAT3-mediated organic anion/drug transport.
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Affiliation(s)
- Haoxun Wang
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
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Nigam SK. The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease. Annu Rev Pharmacol Toxicol 2019; 58:663-687. [PMID: 29309257 DOI: 10.1146/annurev-pharmtox-010617-052713] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters-such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)-are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor-cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.
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Affiliation(s)
- Sanjay K Nigam
- Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, California 92093, USA;
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Nigam SK, Bush KT. Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling. Nat Rev Nephrol 2019; 15:301-316. [PMID: 30728454 PMCID: PMC6619437 DOI: 10.1038/s41581-019-0111-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Uraemic syndrome (also known as uremic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uraemic solutes and uraemic toxins (also known as uremic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uraemic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host-microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signalling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signalling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uraemic syndrome. Pathways considered central to drug ADME might be particularly important for the body's attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uraemic solutes and toxins. This Review discusses how the remote sensing and signalling hypothesis helps to provide a systems-level understanding of aspects of uraemia that could lead to novel approaches to its treatment.
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Affiliation(s)
- Sanjay K Nigam
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
| | - Kevin T Bush
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
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Wang H, Zhang J, You G. Activation of Protein Kinase A Stimulates SUMOylation, Expression, and Transport Activity of Organic Anion Transporter 3. AAPS JOURNAL 2019; 21:30. [PMID: 30761470 DOI: 10.1208/s12248-019-0303-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/22/2019] [Indexed: 12/13/2022]
Abstract
Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. We earlier established that activation of protein kinase C (PKC) enhances OAT3 ubiquitination, which promotes OAT3 internalization from the cell plasma membrane to intracellular endosomes and consequent degradation. As a result, OAT3 expression and transport activity are reduced. In the current study, we discovered that protein kinase A (PKA) had an opposite effect to PKC on the regulation of OAT3. We showed that activation of PKA by Bt2-cAMP stimulated OAT3 transport activity, which was largely caused by an enhanced plasma membrane expression of the transporter, kinetically reflected as an augmented maximal transport velocity Vmax without notable alteration in substrate-binding affinity Km. Additionally, we showed that PKA activation accelerated the rate of OAT3 recycling from intracellular compartments to the plasma membrane and decelerated the rate of OAT3 degradation. We further showed that OAT3 is subjected to post-translational modification by SUMO-2 and SUMO-3 not by SUMO-1. PKA activation enhanced OAT3 SUMOylation, which was accompanied by a reduced OAT3 ubiquitination. Finally, insulin-like growth factor 1 significantly stimulated OAT3 transport activity and SUMOylation through PKA signaling pathway. In conclusion, this is the first demonstration that PKA stimulated OAT3 expression and transport activity by altering the trafficking kinetics of OAT3 possibly through the crosstalk between SUMOylation and ubiquitination. Our studies are consistent with a remote sensing and signaling model for transporters (Wu et al. in Mol Pharmacol. 79(5):795-805, 2011).
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Affiliation(s)
- Haoxun Wang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Jinghui Zhang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.
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Wang H, Zhang J, You G. The mechanistic links between insulin and human organic anion transporter 4. Int J Pharm 2019; 555:165-174. [PMID: 30453017 DOI: 10.1016/j.ijpharm.2018.11.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 11/10/2018] [Accepted: 11/15/2018] [Indexed: 11/18/2022]
Abstract
Human organic anion transporter 4 (hOAT4) belongs to a class of organic anion transporters that exert critical function in the secretion, absorption, and distribution of numerous drugs in the body, such as anti-viral drugs, anti-cancer therapeutics, antibiotics, antihypertensive medicine, and anti-inflammatory drugs. hOAT4 is richly existent in the kidney and placenta. We previously established that serum- and glucocorticoid-inducible kinases (sgk) stimulate hOAT4 expression and transport activity by abrogating the inhibitory effect of a ubiquitin ligase Nedd4-2. Insulin is one of the upstream signaling molecules for sgk. We therefore investigated the effect of insulin on hOAT4 function. We showed that insulin stimulated hOAT4 expression and transport activity, and the action of insulin was abolished in cells overexpressing Nedd4-2-specific siRNA to knockdown the endogenous Nedd4-2. We further showed that insulin phosphorylated serine 327 on Nedd4-2 and weakened the interaction between hOAT4 and Nedd4-2. Interestingly, in cells overexpressing sgk2, the stimulatory effect of insulin on hOAT4 was diminished. In addition, the stimulatory effect of insulin on hOAT4 was blocked by wortmannin and buparlisib, two PI3K inhibitors. In conclusion, our study demonstrated that insulin stimulates hOAT4 expression and transport activity by abrogating the inhibition effect of Nedd4-2 on the transporter. Moreover, insulin regulates hOAT4 by competing with sgk2 rather than through sgk2.
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Affiliation(s)
- Haoxun Wang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Jinghui Zhang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Guofeng You
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
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Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways. Toxins (Basel) 2018; 10:toxins10070280. [PMID: 29976888 PMCID: PMC6071035 DOI: 10.3390/toxins10070280] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/29/2018] [Accepted: 07/02/2018] [Indexed: 02/08/2023] Open
Abstract
It is hypothesized that the uremic toxin indoxyl sulfate (IS) plays a role in the pathogenesis of renal anemia. To further explore that hypothesis, we examined the effects of IS on reactive oxygen species (ROS) production, levels of reduced glutathione (GSH), and erythrocyte death (eryptosis) in red blood cells (RBC) from healthy controls (CON-RBC) and hemodialyzed patients (HD-RBC), respectively. RBC were incubated either in either TRIS-Glc-BSA buffer or IS at concentrations of 0.01, 0.09, and 0.17 mM, respectively. We measured ROS generation (expressed as % of DCFH-DA positive RBC), eryptosis (expressed as % of annexin-V positive RBC), and GSH levels after 6, 12, and 24 h. When incubated in buffer, ROS production was approximately seven-fold higher at all time points HD-RBC when compared to CON-RBC. Incubation with IS increased ROS production in CON-RBS dose-dependently up to 10-fold. Eryptosis in buffer-incubated HD-RBC was up to seven-fold higher as compared to COB-RBC. Incubation of CON-RBC with IS increased the eryptosis rate dose-dependently up to 6-fold. Pretreatment of CON-RBC with the organic anion transporter 2 (OAT2) specific inhibitor ketoprofen or with NADPH oxidase inhibitor diphenyleneiodonium-Cl blunted the IS effect on both ROS production and eryptosis induction. While GSH levels in HD-RBC were reduced when compared to CON-RBC, they were not affected by IS incubation. In summary, IS increases ROS generation and eryptosis in CON-RBC by an activity dependent of the IS influx through OAT2, and NADPH oxidase activity-dependent, and a GSH-independent mechanism. These findings lend support to a putative role of IS in the pathogenesis of renal anemia.
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Sun CY, Wu MS, Lee CC, Chen SH, Lo KC, Chen YH. A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease. Sci Rep 2018; 8:8085. [PMID: 29795395 PMCID: PMC5967335 DOI: 10.1038/s41598-018-26460-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/09/2018] [Indexed: 11/10/2022] Open
Abstract
We aimed to analyze the associations of single nucleotide polymorphisms (SNP) in the 5′ regulatory region of the human organic anion transporter 1 (OAT1) gene with chronic kidney disease (CKD). A case-control study including age- and sex-matched groups of normal subjects and patients with CKD (n = 162 each) was designed. Direct sequencing of the 5′ regulatory region (+88 to −1196 region) showed that patients with CKD had a higher frequency of the −475 SNP (T > T/G) than normal subjects (14/162 vs. 2/162). The luciferase activity assay results indicated that the −475G SNP had a higher promoter efficiency than the −475T SNP. Chromatin immunoprecipitation (ChIP) and LC/MS/MS analyses showed that the −475G SNP up-regulated 26 proteins and down-regulated 74 proteins. The Southwestern blot assay results revealed that the −475G SNP decreased the binding of Hepatoma-derived growth factor (HDGF), a transcription repressor, compared to the −475T SNP. Overexpression of HDGF significantly down-regulated OAT1 in renal tubular cells. Moreover, a zebrafish animal model showed that HDGF-knockdown zebrafish embryos had higher rates of kidney malformation than wild-type controls [18/78 (23.1%) vs. 1/30 (3.3%)]. In conclusion, our results suggest that an OAT1 SNP might be clinically associated with CKD. Renal tubular cells with the −475 SNP had increased OAT1 expression, which resulted in increased transportation of organic anion toxins into cells. Cellular accumulation of organic anion toxins caused cytotoxicity and resulted in CKD.
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Affiliation(s)
- Chiao-Yin Sun
- Department of Nephrology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Mai-Szu Wu
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chin-Chan Lee
- Department of Nephrology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shu-Hong Chen
- Department of Nephrology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Medical Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Kang-Chieh Lo
- Department of Chemistry, Tamkang University, Tamsui, New Taipei City, Taiwan
| | - Yau-Hung Chen
- Department of Chemistry, Tamkang University, Tamsui, New Taipei City, Taiwan.
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47
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Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition. J Pers Med 2018; 8:jpm8020014. [PMID: 29659532 PMCID: PMC6023491 DOI: 10.3390/jpm8020014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.
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48
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Schiffer L, Arlt W, Storbeck KH. Intracrine androgen biosynthesis, metabolism and action revisited. Mol Cell Endocrinol 2018; 465:4-26. [PMID: 28865807 PMCID: PMC6565845 DOI: 10.1016/j.mce.2017.08.016] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/28/2017] [Accepted: 08/28/2017] [Indexed: 12/19/2022]
Abstract
Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone. However, the intracellular or intracrine activation of C19 androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C19 steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed.
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Affiliation(s)
- Lina Schiffer
- Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Wiebke Arlt
- Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
| | - Karl-Heinz Storbeck
- Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South Africa
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49
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Liu N, Xu L, Shi Y, Fang L, Gu H, Wang H, Ding X, Zhuang S. Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats. Oncotarget 2018; 8:33807-33826. [PMID: 28442634 PMCID: PMC5464913 DOI: 10.18632/oncotarget.16995] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 02/20/2017] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis of hyperuricemia-induced chronic kidney disease is largely unknown. In this study, we investigated whether extracellular signal–regulated kinases1/2 (ERK1/2) would contribute to the development of hyperuricemic nephropathy (HN). In a rat model of HN induced by feeding mixture of adenine and potassium oxonate, increased ERK1/2 phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, in parallel with diminished levels of renal function and increased urine microalbumin excretion. Administration of U0126, which is a selective inhibitor of the ERK1/2 pathway, improved renal function, decreased urine microalbumin and inhibited activation of renal interstitial fibroblasts as well as accumulation of extracellular proteins. U0126 also inhibited hyperuricemia-induced expression of multiple profibrogenic cytokines/chemokines and infiltration of macrophages in the kidney. Furthermore, U0126 treatment suppressed xanthine oxidase, which mediates uric acid production. It also reduced expression of the urate anion exchanger 1, which promotes reabsorption of uric acid, and preserved expression of organic anion transporters 1 and 3, which accelerate uric acid excretion in the kidney of hyperuricemic rats. Finally, U0126 inhibited phosphorylation of Smad3, a key mediator in transforming growth factor (TGF-β) signaling. In cultured renal interstitial fibroblasts, inhibition of ERK1/2 activation by siRNA suppressed uric acid-induced activation of renal interstitial fibroblasts. Collectively, pharmacologic targeting of ERK1/2 can alleviate HN by suppressing TGF-β signaling, reducing inflammation responses, and inhibiting the molecular processes associated with elevation of blood uric acid levels in the body. Thus, ERK1/2 inhibition may be a potential approach for the prevention and treatment of hyperuricemic nephropathy.
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Affiliation(s)
- Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Liuqing Xu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yingfeng Shi
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Lu Fang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Hongwei Gu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Hongrui Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiaoqiang Ding
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.,Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA
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50
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Edmonds DJ, Kung DW, Kalgutkar AS, Filipski KJ, Ebner DC, Cabral S, Smith AC, Aspnes GE, Bhattacharya SK, Borzilleri KA, Brown JA, Calabrese MF, Caspers NL, Cokorinos EC, Conn EL, Dowling MS, Eng H, Feng B, Fernando DP, Genung NE, Herr M, Kurumbail RG, Lavergne SY, Lee ECY, Li Q, Mathialagan S, Miller RA, Panteleev J, Polivkova J, Rajamohan F, Reyes AR, Salatto CT, Shavnya A, Thuma BA, Tu M, Ward J, Withka JM, Xiao J, Cameron KO. Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK). J Med Chem 2018; 61:2372-2383. [DOI: 10.1021/acs.jmedchem.7b01641] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- David J. Edmonds
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Daniel W. Kung
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Amit S. Kalgutkar
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Kevin J. Filipski
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - David C. Ebner
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Shawn Cabral
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Aaron C. Smith
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Gary E. Aspnes
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Samit K. Bhattacharya
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Kris A. Borzilleri
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Janice A. Brown
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Matthew F. Calabrese
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Nicole L. Caspers
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Emily C. Cokorinos
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Edward L. Conn
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Matthew S. Dowling
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Heather Eng
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Bo Feng
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Dilinie P. Fernando
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Nathan E. Genung
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Michael Herr
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Ravi G. Kurumbail
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Sophie Y. Lavergne
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Esther C.-Y. Lee
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Qifang Li
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Sumathy Mathialagan
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Russell A. Miller
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Jane Panteleev
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jana Polivkova
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Francis Rajamohan
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Allan R. Reyes
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Christopher T. Salatto
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Andre Shavnya
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Benjamin A. Thuma
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Meihua Tu
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Jessica Ward
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
| | - Jane M. Withka
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jun Xiao
- Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Kimberly O. Cameron
- Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
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