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Marques AVL, Ruginsk BE, Prado LDO, de Lima DE, Daniel IW, Moure VR, Valdameri G. The association of ABC proteins with multidrug resistance in cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119878. [PMID: 39571941 DOI: 10.1016/j.bbamcr.2024.119878] [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: 08/26/2024] [Revised: 11/07/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024]
Abstract
Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both in vitro and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1-3, ABCA7, ABCB1-2, ABCB4-6, ABCC1-5, ABCC10-11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.
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Affiliation(s)
- Andrezza Viviany Lourenço Marques
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Bruna Estelita Ruginsk
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Larissa de Oliveira Prado
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Diogo Eugênio de Lima
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Isabelle Watanabe Daniel
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil
| | - Vivian Rotuno Moure
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil.
| | - Glaucio Valdameri
- Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, Paraná, Brazil.
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Garg M, Gandhi K, Gera P, Jadhav SM, Mohanty B, Gurjar M, Sandupatla B, Gala R, Chaudhari P, Prasad M, Chinnaswamy G, Gota V. Implications of chronic moderate protein-deficiency malnutrition on doxorubicin pharmacokinetics and cardiotoxicity in early post-weaning stage. Life Sci 2024; 350:122765. [PMID: 38830506 DOI: 10.1016/j.lfs.2024.122765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/14/2024] [Accepted: 05/29/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND Malnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AIMS In this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. MATERIALS AND METHODS We developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. KEY FINDINGS Here we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SIGNIFICANCE Our findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.
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Affiliation(s)
- Megha Garg
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India
| | - Khushboo Gandhi
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Poonam Gera
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India; Biorepository, Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Shraddha Mahesh Jadhav
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Bhabani Mohanty
- Department of Comparative Oncology and Small Animal Imaging Facility, ACTREC, Tata Memorial Center, Kharghar, Navi-Mumbai, Maharashtra 410210, India
| | - Murari Gurjar
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India; Department of Clinical Pharmacology, Mahamana Pandit Madan Mohan Malviya Cancer Centre, Banaras Hindu University Campus, Varanasi, Uttar Pradesh 221005, India
| | | | - Rajul Gala
- Paediatric Oncology, Tata Memorial Hospital, Mumbai, India
| | - Pradip Chaudhari
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India; Department of Comparative Oncology and Small Animal Imaging Facility, ACTREC, Tata Memorial Center, Kharghar, Navi-Mumbai, Maharashtra 410210, India
| | - Maya Prasad
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India; Paediatric Oncology, Tata Memorial Hospital, Mumbai, India
| | - Girish Chinnaswamy
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India; Paediatric Oncology, Tata Memorial Hospital, Mumbai, India
| | - Vikram Gota
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400094, India.
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Mao YX, Chen ZP, Wang L, Wang J, Zhou CZ, Hou WT, Chen Y. Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain. Nat Commun 2024; 15:1061. [PMID: 38316776 PMCID: PMC10844203 DOI: 10.1038/s41467-024-45337-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/19/2024] [Indexed: 02/07/2024] Open
Abstract
Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.
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Affiliation(s)
- Yao-Xu Mao
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Zhi-Peng Chen
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Liang Wang
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Jie Wang
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Cong-Zhao Zhou
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, 230027, China.
| | - Wen-Tao Hou
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, 230027, China.
| | - Yuxing Chen
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, 230027, China.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Wada M. Role of ABC Transporters in Cancer Development and Malignant Alteration. YAKUGAKU ZASSHI 2022; 142:1201-1225. [DOI: 10.1248/yakushi.22-00108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Vansell NR. Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats. Drug Metab Dispos 2022; 50:508-517. [PMID: 35046065 DOI: 10.1124/dmd.121.000498] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 12/23/2021] [Indexed: 02/13/2025] Open
Abstract
Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and, in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of thyroxine (T4) glucuronidation by UDP-glycosyltransferase (UGT) enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in thyroid-stimulating hormone. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (e.g., organic anion transporter polypeptides) and efflux (e.g., multidrug resistance proteins) transporters, data exist that support transporters as additional target sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (triiodothyronine more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals have contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also require further study. SIGNIFICANCE STATEMENT: Key advances in understanding the target sites for altered disposition of thyroid hormones have occurred in the last 2 decades to better inform potential sites of action of inducing chemicals. Ultimately, the knowledge of inducible thyroid hormone transport into and out of liver, beyond induction of glucuronidation, should be considered and applied to screening and risk assessment paradigms when assessing an inducer's potential to alter thyroid homeostasis in nonclinical species and humans.
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Khunweeraphong N, Kuchler K. Multidrug Resistance in Mammals and Fungi-From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms. Int J Mol Sci 2021; 22:4806. [PMID: 33946618 PMCID: PMC8124828 DOI: 10.3390/ijms22094806] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/19/2022] Open
Abstract
Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure-function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.
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Affiliation(s)
| | - Karl Kuchler
- Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Medical University of Vienna, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria;
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Wu H, Zhao XK, Zhu JJ. Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: A case report and review of the literature. World J Clin Cases 2021; 9:878-885. [PMID: 33585635 PMCID: PMC7852649 DOI: 10.12998/wjcc.v9.i4.878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dubin-Johnson syndrome (DJS) is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene. It is characterized by chronic or intermittent conjugated hyperbilirubinemia, with chronic idiopathic jaundice as the main clinical manifestation. Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS; however, the causative ABCC2 point mutation in Chinese patients remains unknown. Research on ABCC2 mutations in Chinese DJS patients is extremely rare, and the diagnosis of DJS remains limited. The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS. Here, we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient. This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.
CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses. ABCC2 mutations were identified by next-generation sequencing (NGS). The patient showed intermittent jaundice and conjugated hyper-bilirubinemia. Histopathological examinations were consistent with the typical phenotype of DJS. Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant, namely c.2443C>T (p.Arg815*), which has not been reported previously in the domestic or foreign literature.
CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS, especially in patients with atypical presentations. Currently, NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.
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Affiliation(s)
- Huan Wu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Xue-Ke Zhao
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Juan-Juan Zhu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
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9
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Ziemian S, Green C, Sourbron S, Jost G, Schütz G, Hines CD. Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T. NMR IN BIOMEDICINE 2021; 34:e4401. [PMID: 32851735 PMCID: PMC7757196 DOI: 10.1002/nbm.4401] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 06/11/2023]
Abstract
Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol-1 s-1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.
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Affiliation(s)
| | - Claudia Green
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
| | - Steven Sourbron
- Department of Infection, Immunity and Cardiovascular DiseaseUniversity of SheffieldSheffieldUK
| | - Gregor Jost
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
| | - Gunnar Schütz
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
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Huang J, Wang Q, Chen M, Bi Y, Shi H, Zhou K. Effects of psoralen on hepatic bile acid transporters in rats. Hum Exp Toxicol 2020; 40:1012-1021. [PMID: 33317360 DOI: 10.1177/0960327120979346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Fructus Psoraleae (FP), widely used in traditional medicine, is increasingly reported to cause serious hepatotoxicity in recent years. However, the main toxic constituents responsible for hepatotoxicity and the underlying mechanisms are poorly understood. In the present study, psoralen, a main and quality-control constituent of FP, was intragastrically administered to Sprague-Dawley rats at a dose of 60 mg/kg for 1, 3 and 7 days. Blood and selected tissue samples were collected and analyzed for biochemistry and histopathology to evaluate hepatotoxicity. The results showed that psoralen could induce hepatotoxicity by enhanced liver-to-body weight ratio and alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total cholesterol after administration for 3 days. In addition, histopathological examinations also indicated the hepatotoxicity induced by psoralen. Furthermore, the mRNA and protein levels of hepatic bile acid transporters were significantly changed, in which MRP4, ABCG5 and ABCG8 were repressed, while the protein level of NTCP tended to increase in the rat liver. Taken together, psoralen caused liver injury possibly through affecting bile acid transporters, leading to the disorder of bile acid transport and accumulation in hepatocytes.
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Affiliation(s)
- Juyang Huang
- School of Integrative Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qin Wang
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mengying Chen
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanan Bi
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hong Shi
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Chinese medicine Pharmacology, Tianjin, China
| | - Kun Zhou
- Institute of Traditional Chinese Medicine, 58301Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Key Laboratory of Chinese medicine Pharmacology, Tianjin, China
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Reduced Mrp2 surface availability as PI3Kγ-mediated hepatocytic dysfunction reflecting a hallmark of cholestasis in sepsis. Sci Rep 2020; 10:13110. [PMID: 32753644 PMCID: PMC7403153 DOI: 10.1038/s41598-020-69901-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 06/30/2020] [Indexed: 12/14/2022] Open
Abstract
Sepsis-associated liver dysfunction manifesting as cholestasis is common during multiple organ failure. Three hepatocytic dysfunctions are considered as major hallmarks of cholestasis in sepsis: impairments of microvilli covering canalicular membranes, disruptions of tight junctions sealing bile-collecting canaliculae and disruptions of Mrp2-mediated hepatobiliary transport. PI3Kγ loss-of-function was suggested as beneficial in early sepsis. Yet, the PI3Kγ-regulated cellular processes in hepatocytes remained largely unclear. We analysed all three sepsis hallmarks for responsiveness to massive PI3K/Akt signalling and PI3Kγ loss-of-function, respectively. Surprisingly, neither microvilli nor tight junctions were strongly modulated, as shown by electron microscopical studies of mouse liver samples. Instead, quantitative electron microscopy proved that solely Mrp2 surface availability, i.e. the third hallmark, responded strongly to PI3K/Akt signalling. Mrp2 plasma membrane levels were massively reduced upon PI3K/Akt signalling. Importantly, Mrp2 levels at the plasma membrane of PI3Kγ KO hepatocytes remained unaffected upon PI3K/Akt signalling stimulation. The effect explicitly relied on PI3Kγ's enzymatic ability, as shown by PI3Kγ kinase-dead mice. Keeping the surface availability of the biliary transporter Mrp2 therefore is a cell biological process that may underlie the observation that PI3Kγ loss-of-function protects from hepatic excretory dysfunction during early sepsis and Mrp2 should thus take center stage in pharmacological interventions.
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Szpirer C. Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes. J Biomed Sci 2020; 27:84. [PMID: 32741357 PMCID: PMC7395987 DOI: 10.1186/s12929-020-00673-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades. The availability of these resources has stimulated numerous studies aimed at discovering causal disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.
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Affiliation(s)
- Claude Szpirer
- Université Libre de Bruxelles, B-6041, Gosselies, Belgium.
- , Waterloo, Belgium.
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Gupta SK, Singh P, Ali V, Verma M. Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy. Oncol Rev 2020; 14:448. [PMID: 32676170 PMCID: PMC7358983 DOI: 10.4081/oncol.2020.448] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
One of the major problems being faced by researchers and clinicians in leukemic treatment is the development of multidrug resistance (MDR) which restrict the action of several tyrosine kinase inhibitors (TKIs). MDR is a major obstacle to the success of cancer chemotherapy. The mechanism of MDR involves active drug efflux transport of ABC superfamily of proteins such as Pglycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that weaken the effectiveness of chemotherapeutics and negative impact on the future of anticancer therapy. In this review, the authors aim to provide an overview of various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR. Extensive studies have been carried out since last several years to enhance the efficacy of chemotherapy by defeating these MDR mechanisms with the use of novel anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanotechnology, and RNA interference (RNAi) therapy.
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Affiliation(s)
- Sonu Kumar Gupta
- Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Punjab, India
| | - Priyanka Singh
- Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Punjab, India
| | - Villayat Ali
- Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Punjab, India
| | - Malkhey Verma
- Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Punjab, India
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14
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Liu DM, Yang D, Zhou CY, Wu JS, Zhang GL, Wang P, Wang F, Meng XL. Aloe-emodin induces hepatotoxicity by the inhibition of multidrug resistance protein 2. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 68:153148. [PMID: 32028185 DOI: 10.1016/j.phymed.2019.153148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/05/2019] [Accepted: 12/07/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Aloe-emodin (AE) is among the primary bioactive anthraquinones present in traditional Chinese medicinal plants such as Rheum palmatum L. Multidrug resistance protein 2 (ABCC2/ MRP2) is an important efflux transporter of substances associated with cellular oxidative stress. However, the effects of traditional Chinese medicine on this protein remain unclear. PURPOSE The aim of this research is to study the role of ABCC2 in AE-induced hepatotoxicity. METHODS The expression of ABCC2 protein and mRNA levels were analyzed by Western-Blotting and qRT-PCR, respectively. The intracellular oxidative stress caused by AE was evaluated by quantifying the levels of intracellular reactive oxygen species, malondialdehyde, glutathione reduced and oxidized glutathione. The levels of adenosine triphosphate, mitochondrial membrane potential and mitochondrial DNA were explored to evaluate the effects of AE on mitochondrial function. The effects of AE on cell apoptosis and cell cycle were detected by flow cytometry. To further clarify the key role of ABCC2 in AE induced cytotoxicity, we used pCI-neo-ABCC2 plasmid to over express ABCC2 protein, and small interfering RNA was used to knockdown ABCC2 in HepG2 cells. Additionally, we investigated the impact of AE on ABCC2 degradation pathway and the hepatotoxic effects of AE in mice. RESULTS AE was found to inhibit ABCC2 transport activity, downregulate ABCC2 expression and altered intracellular redox balance. Induction of oxidative stress resulted in depletion of intracellular glutathione reduced, mitochondria dysfunction and activation of apoptosis. ABCC2 overexpression significantly reduced AE-induced intracellular oxidative stress and cell death, which was enhanced by ABCC2 knockdown. Furthermore, AE was observed to promote ABCC2 degradation through induction of autophagy and hepatotoxicity was induced in mice by promoting ABCC2 degradation. CONCLUSIONS The inhibition of ABCC2 is a novel effect of AE that triggers oxidative stress and apoptosis. These findings are helpful in understanding the toxicological effects of AE-containing medicinal plants.
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Affiliation(s)
- De-Ming Liu
- College Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610037, China; Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, China
| | - Dong Yang
- College Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610037, China
| | - Chun-Yan Zhou
- Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400011, China
| | - Jia-Si Wu
- College Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610037, China
| | - Guo-Lin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Ping Wang
- College Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610037, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
| | - Xian-Li Meng
- College Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610037, China.
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15
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Penman SL, Sharma P, Aerts H, Park BK, Weaver RJ, Chadwick AE. Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells. Toxicol In Vitro 2019; 61:104595. [PMID: 31288073 PMCID: PMC6853172 DOI: 10.1016/j.tiv.2019.104595] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/05/2019] [Accepted: 07/05/2019] [Indexed: 12/19/2022]
Abstract
Bile acids (BAs) are recognised as the causative agents of toxicity in drug-induced cholestasis (DIC). Research in isolated mitochondria and HepG2 cells have demonstrated BA-mediated mitochondrial dysfunction as a key mechanism of toxicity in DIC. However, HepG2 cells are of limited suitability for DIC studies as they do not express the necessary physiological characteristics. In this study, the mitotoxic potentials of BA mixtures were assessed in isolated mitochondria and a better-suited hepatic model, HepaRG cells. BAs induced structural alterations and a loss of mitochondrial membrane potential (MMP) in isolated mitochondria however, this toxicity did not translate to HepaRG cells. There were no changes in oxygen consumption rate, MMP or ATP levels in glucose and galactose media, indicating that there was no direct mitochondrial toxicity mediated via electron transport chain dysfunction in HepaRG cells. Assessment of key biliary transporters revealed that there was a time-dependent reduction in the expression and activity of multi-drug resistance protein 2 (MRP2), which was consistent with the induction of cytotoxicity in HepaRG cells. Overall, the findings from this study have demonstrated that mitochondrial dysfunction is not a mechanism of BA-induced toxicity in HepaRG cells.
HepaRG cells are a better suited in vitro model for cholestatic studies than HepG2 cell. Bile acids cause mitochondrial toxicity in isolated mitochondria but not in HepaRG cells. Time-dependent alterations in biliary transporters are consistent with the cytotoxicity of bile acid mixtures. There are important mechanistic differences when bile acids interact at the organelle level versus the whole cell.
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Affiliation(s)
- Sophie L Penman
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK
| | - Parveen Sharma
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK
| | - Hélène Aerts
- Biologie Servier, 905 Rue de Saran, 45520 Gidy, France
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK
| | - Richard J Weaver
- Institute de Recherches Internationales Servier, Biopharmacy, rue Carnot, 92284 Suresnes, France
| | - Amy E Chadwick
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK.
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16
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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17
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Oliveira C, Joshee L, Bridges CC. MRP2 and the Transport Kinetics of Cysteine Conjugates of Inorganic Mercury. Biol Trace Elem Res 2018; 184:279-286. [PMID: 28980184 PMCID: PMC5882609 DOI: 10.1007/s12011-017-1163-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/21/2017] [Indexed: 12/18/2022]
Abstract
Human exposure to mercuric species occurs regularly throughout the world. Mercuric ions may accumulate in target cells and subsequently lead to cellular intoxication and death. Therefore, it is important to have a thorough understanding of how transportable species of mercury are handled by specific membrane transporters. The purpose of the current study was to characterize the transport kinetics of cysteine (Cys)-S-conjugates of inorganic mercury (Cys-S-Hg-S-Cys) at the site of the multidrug resistance-associated transporter 2 (MRP2). In order to estimate the maximum velocity (V max) and Michaelis constant (K m) for the uptake of Cys-S-Hg-S-Cys mediated by MRP2, in vitro studies were carried out using radioactive Cys-S-Hg-S-Cys (5 μM) and inside-out membrane vesicles made from Sf9 cells transfected with MRP2. The V max was estimated to be 74.3 ± 10.1 nmol mg protein-1 30 s-1 while the K m was calculated to be 63.4 ± 27.3 μM. In addition, in vivo studies were utilized to measure the disposition of inorganic mercury (administered dose 0.5 μmol kg-1 in 2 mL normal saline) over time in Wistar and TR¯ (Mrp2-deficient) rats. These studies measured the disposition of mercuric ions in the kidney, liver, and blood. In general, the data suggest that the initial uptake of mercuric conjugates into select target cells is rapid followed by a period of slower uptake and accumulation. Overall, the data indicate that MRP2 transports Cys-S-Hg-S-Cys in a manner that is similar to that of other MRP2 substrates.
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Affiliation(s)
- Cláudia Oliveira
- Department of Biomedical Sciences, Mercer University School of Medicine, 1501 College St., Macon, GA, 31207, USA
- Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Lucy Joshee
- Department of Biomedical Sciences, Mercer University School of Medicine, 1501 College St., Macon, GA, 31207, USA
| | - Christy C Bridges
- Department of Biomedical Sciences, Mercer University School of Medicine, 1501 College St., Macon, GA, 31207, USA.
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18
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Crawford RR, Potukuchi PK, Schuetz EG, Schuetz JD. Beyond Competitive Inhibition: Regulation of ABC Transporters by Kinases and Protein-Protein Interactions as Potential Mechanisms of Drug-Drug Interactions. Drug Metab Dispos 2018; 46:567-580. [PMID: 29514827 PMCID: PMC5896366 DOI: 10.1124/dmd.118.080663] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 03/02/2018] [Indexed: 12/14/2022] Open
Abstract
ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs. The ABC transporters are also recognized as important contributors to pharmacokinetics, especially in drug-drug interactions and adverse drug effects. Drugs and xenobiotics, as well as pathologic conditions, can influence the transcription of ABC transporters, or modify their activity or intracellular localization. Kinases can affect the aforementioned processes for ABC transporters as do protein interactions. In this review, we focus on the ABC transporters ABCB1, ABCB11, ABCC1, ABCC4, and ABCG2 and illustrate how kinases and protein-protein interactions affect these transporters. The clinical relevance of these factors is currently unknown; however, these examples suggest that our understanding of drug-drug interactions will benefit from further knowledge of how kinases and protein-protein interactions affect ABC transporters.
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Affiliation(s)
- Rebecca R Crawford
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Praveen K Potukuchi
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Erin G Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - John D Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
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19
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Karasik A, Ledwitch KV, Arányi T, Váradi A, Roberts A, Szeri F. Boosted coupling of ATP hydrolysis to substrate transport upon cooperative estradiol-17-β-D-glucuronide binding in a Drosophila ATP binding cassette type-C transporter. FASEB J 2018; 32:669-680. [PMID: 28939593 DOI: 10.1096/fj.201700606r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
ATP binding cassette type-C (ABCC) transporters move molecules across cell membranes upon hydrolysis of ATP; however, their coupling of ATP hydrolysis to substrate transport remains elusive. Drosophila multidrug resistance-associated protein (DMRP) is the functional ortholog of human long ABCC transporters, with similar substrate and inhibitor specificity, but higher activity. Exploiting its high activity, we kinetically dissected the catalytic mechanism of DMRP by using E2-d-glucuronide (E2G), the physiologic substrate of human ABCC. We examined the DMRP-mediated interdependence of ATP and E2G in biochemical assays. We observed E2G-dependent ATPase activity to be biphasic at subsaturating ATP concentrations, which implies at least 2 E2G binding sites on DMRP. Furthermore, transport measurements indicated strong nonreciprocal cooperativity between ATP and E2G. In addition to confirming these findings, our kinetic modeling with the Complex Pathway Simulator indicated a 10-fold decrease in the E2G-mediated activation of ATP hydrolysis upon saturation of the second E2G binding site. Surprisingly, the binding of the second E2G allowed for substrate transport with a constant rate, which tightly coupled ATP hydrolysis to transport. In summary, we show that the second E2G binding-similar to human ABCC2-allosterically stimulates transport activity of DMRP. Our data suggest that this is achieved by a significant increase in the coupling of ATP hydrolysis to transport.-Karasik, A., Ledwitch, K. V., Arányi, T., Váradi, A., Roberts, A., Szeri, F. Boosted coupling of ATP hydrolysis to substrate transport upon cooperative estradiol-17-β-D-glucuronide binding in a Drosophila ATP binding cassette type-C transporter.
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Affiliation(s)
- Agnes Karasik
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | | | - Tamás Arányi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - András Váradi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Arthur Roberts
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, USA
| | - Flóra Szeri
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
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20
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Choudhuri S, Patton GW, Chanderbhan RF, Mattia A, Klaassen CD. From Classical Toxicology to Tox21: Some Critical Conceptual and Technological Advances in the Molecular Understanding of the Toxic Response Beginning From the Last Quarter of the 20th Century. Toxicol Sci 2018; 161:5-22. [PMID: 28973688 PMCID: PMC5837539 DOI: 10.1093/toxsci/kfx186] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too. The development of transgenic and knockout mice provided valuable animal models to investigate the role of specific genes in producing toxic effects of chemicals or protecting the organism from the toxic effects of chemicals. Further developments in toxicology came from the incorporation of the tools of "omics" (genomics, proteomics, metabolomics, interactomics), epigenetics, systems biology, computational biology, and in vitro biology. Collectively, the advances in toxicology made during the last 30-40 years are expected to provide more innovative and efficient approaches to risk assessment. A goal of experimental toxicology going forward is to reduce animal use and yet be able to conduct appropriate risk assessments and make sound regulatory decisions using alternative methods of toxicity testing. In that respect, Tox21 has provided a big picture framework for the future. Currently, regulatory decisions involving drugs, biologics, food additives, and similar compounds still utilize data from animal testing and human clinical trials. In contrast, the prioritization of environmental chemicals for further study can be made using in vitro screening and computational tools.
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Affiliation(s)
- Supratim Choudhuri
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland
| | - Geoffrey W Patton
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington
| | - Ronald F Chanderbhan
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland
| | - Antonia Mattia
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland
| | - Curtis D Klaassen
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington
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21
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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22
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van Dijk R, Aronson SJ, de Waart DR, van de Graaf SF, Duijst S, Seppen J, Elferink RO, Beuers U, Bosma PJ. Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo. Sci Rep 2017; 7:1646. [PMID: 28490767 PMCID: PMC5431759 DOI: 10.1038/s41598-017-01602-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/30/2017] [Indexed: 12/31/2022] Open
Abstract
We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity and 26 compounds were identified as BVRA inhibitors. Montelukast and Disulfiram were selected as potentially clinically applicable drugs and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for chronic unconjugated hyperbilirubinemia. Oral administration of Disulfiram was toxic in the Ugt1a1-deficient rat (weight loss, transaminase elevation). Oral Montelukast administration led to low serum concentrations and did not alter serum UCB levels. Intraperitoneal injections of Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/L in the liver. Still, serum UCB levels remained unaltered. This first study on biliverdin reductase inhibition as a novel concept for treatment of unconjugated hyperbilirubinemia identified putative in vitro BVRA inhibitors. Montelukast, the clinically most suitable inhibitor, did not result in reduction of serum UCB in the Ugt1a1-deficient rat. The proposed treatment strategy will not result in amelioration of severe unconjugated hyperbilirubinemia in humans without the identification or development of more potent BVRA inhibitors.
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Affiliation(s)
- Remco van Dijk
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Sem J Aronson
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stan F van de Graaf
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jurgen Seppen
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald Oude Elferink
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Piter J Bosma
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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23
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Bugde P, Biswas R, Merien F, Lu J, Liu DX, Chen M, Zhou S, Li Y. The therapeutic potential of targeting ABC transporters to combat multi-drug resistance. Expert Opin Ther Targets 2017; 21:511-530. [DOI: 10.1080/14728222.2017.1310841] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Piyush Bugde
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Riya Biswas
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Fabrice Merien
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Science, AUT Roche Diagnostic Laboratory, Auckland University of Technology, Auckland, New Zealand
| | - Jun Lu
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| | - Dong-Xu Liu
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Mingwei Chen
- Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shufeng Zhou
- Department of Biotechnology and Bioengineering, College of Chemical Engineering, Huaqiao University, Xiamen, China
| | - Yan Li
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
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24
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Oliveira C, Joshee L, George H, Nijhara S, Bridges C. Oral exposure of pregnant rats to toxic doses of methylmercury alters fetal accumulation. Reprod Toxicol 2017; 69:265-275. [PMID: 28341569 DOI: 10.1016/j.reprotox.2017.03.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 01/30/2017] [Accepted: 03/20/2017] [Indexed: 12/23/2022]
Abstract
Methylmercury (CH3Hg+) is an environmental toxicant that may lead to significant pathologies in exposed individuals. The current study assessed the disposition and toxicological effects of 2.5 or 7.5mgkg-1 CH3Hg+, conjugated to cysteine (Cys; Cys-S-CH3Hg) and administered orally to pregnant and non-pregnant Wistar and TR- rats. Rats were euthanized on gestational day 20 and the content of mercury in each fetus, amniotic sac, and placenta was determined. The brain, liver, and kidneys were removed from each fetus for estimation of mercury content. From the dams, a sample of blood, kidneys, liver, and brain were removed at the time of euthanasia. The findings from this study indicate that pregnancy leads to significant changes in the handling of mercuric ions, particularly in the liver. Furthermore, there are significant differences in the handling of non-nephrotoxic and nephrotoxic doses of Cys-S-CH3Hg by maternal and fetal organs.
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Affiliation(s)
- Cláudia Oliveira
- Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Lucy Joshee
- Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Hannah George
- Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Sanya Nijhara
- Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Christy Bridges
- Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA.
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25
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van der Mark VA, Rudi de Waart D, Shevchenko V, Elferink RPJO, Chamuleau RAFM, Hoekstra R. Stable Overexpression of the Constitutive Androstane Receptor Reduces the Requirement for Culture with Dimethyl Sulfoxide for High Drug Metabolism in HepaRG Cells. Drug Metab Dispos 2017; 45:56-67. [PMID: 27780834 DOI: 10.1124/dmd.116.072603] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/24/2016] [Indexed: 01/08/2023] Open
Abstract
Dimethylsulfoxide (DMSO) induces cellular differentiation and expression of drug metabolic enzymes in the human liver cell line HepaRG; however, DMSO also induces cell death and interferes with cellular activities. The aim of this study was to examine whether overexpression of the constitutive androstane receptor (CAR, NR1I3), the nuclear receptor controlling various drug metabolism genes, would sufficiently promote differentiation and drug metabolism in HepaRG cells, optionally without using DMSO. By stable lentiviral overexpression of CAR, HepaRG cultures were less affected by DMSO in total protein content and obtained increased resistance to acetaminophen- and amiodarone-induced cell death. Transcript levels of CAR target genes were significantly increased in HepaRG-CAR cultures without DMSO, resulting in increased activities of cytochrome P450 (P450) enzymes and bilirubin conjugation to levels equal or surpassing those of HepaRG cells cultured with DMSO. Unexpectedly, CAR overexpression also increased the activities of non-CAR target P450s, as well as albumin production. In combination with DMSO treatment, CAR overexpression further increased transcript levels and activities of CAR targets. Induction of CYP1A2 and CYP2B6 remained unchanged, whereas CYP3A4 was reduced. Moreover, the metabolism of low-clearance compounds warfarin and prednisolone was increased. In conclusion, CAR overexpression creates a more physiologically relevant environment for studies on hepatic (drug) metabolism and differentiation in HepaRG cells without the utilization of DMSO. DMSO still may be applied to accomplish higher drug metabolism, required for sensitive assays, such as low-clearance studies and identification of (rare) metabolites, whereas reduced total protein content after DMSO culture is diminished by CAR overexpression.
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Affiliation(s)
- Vincent A van der Mark
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
| | - D Rudi de Waart
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
| | - Valery Shevchenko
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
| | - Ronald P J Oude Elferink
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
| | - Robert A F M Chamuleau
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
| | - Ruurdtje Hoekstra
- Department of Experimental Surgery (V.A.M., R.A.F.M.C., R.H.), and the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center (V.A.M., D.R.W., R.P.J.O.E., R.A.F.M.C., R.H.), Amsterdam, the Netherlands; and Biopredic International, Saint-Grégoire, France (V.S.)
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van der Woerd WL, Wichers CGK, Vestergaard AL, Andersen JP, Paulusma CC, Houwen RHJ, van de Graaf SFJ. Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. J Hepatol 2016; 64:1339-47. [PMID: 26879107 DOI: 10.1016/j.jhep.2016.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 01/25/2016] [Accepted: 02/01/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS ATP8B1 deficiency is an autosomal recessive liver disease characterized by intrahepatic cholestasis. ATP8B1 mutation p.I661T, the most frequent mutation in European patients, results in protein misfolding and impaired targeting to the plasma membrane. Similarly, mutations in cystic fibrosis transmembrane conductance regulator (CFTR), associated with cystic fibrosis, impair protein folding and trafficking. The aim of this study was to investigate whether compounds that rescue CFTR F508del trafficking are capable of improving p.I661T-ATP8B1 plasma membrane expression. METHODS The effect of CFTR corrector compounds on plasma membrane expression of p.I661T-ATP8B1 was evaluated by cell surface biotinylation and immunofluorescence. ATPase activity was evaluated of a purified analogue protein carrying a mutation at the matching position (p.L622T-ATP8A2). RESULTS The clinically used compounds, 4-phenylbutyric acid (4-PBA), suberoylanilide hydroxamic acid (SAHA) and N-butyldeoxynojirimycin (NB-DNJ) improved p.I661T-ATP8B1 plasma membrane targeting. Compounds C4, C5, C13 and C17 also significantly increased plasma membrane expression of p.I661T-ATP8B1. SAHA and compound C17 upregulated ATP8B1 transcription. p.I661T-ATP8B1 was partly targeted to the canalicular membrane in polarized cells, which became more evident upon treatment with SAHA and/or C4. p.L622T-ATP8A2 showed phospholipid-induced ATPase activity, suggesting that mutations at a matching position in ATP8B1 do not block functionality. Combination therapy of SAHA and compound C4 resulted in an additional improvement of ATP8B1 cell surface abundance. CONCLUSIONS This study shows that several CFTR correctors can improve trafficking of p.I661T-ATP8B1 to the plasma membrane in vitro. Hence, these compounds may be suitable to be part of a future therapy for ATP8B1 deficiency and other genetic disorders associated with protein misfolding. LAY SUMMARY Compounds that improve the cellular machinery dealing with protein homeostasis (proteostasis) and allow for proper folding of proteins with (mild) missense mutations are called proteostasis regulators (Balch, Science 2008). Such compounds are potentially of high therapeutic value for many (liver) diseases. In this manuscript, we investigated whether compounds identified in screens as CFTR folding correctors are actually proteostasis regulators and thus have a broader application in other protein folding diseases. Using these compounds, we could indeed show improved trafficking to the (apical) plasma membrane of a mutated ATP8B1 protein, carrying the p.I661T missense mutation. This is the most frequently identified mutation in this rare cholestatic disorder. Importantly, ATP8B1 shows no similarity to CFTR. These data are important in providing support for the concept that rare, genetic liver diseases can potentially be treated using a generalized strategy.
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Affiliation(s)
- Wendy L van der Woerd
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands; Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Catharina G K Wichers
- Department of Molecular Cancer Research, Section of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | - Coen C Paulusma
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Roderick H J Houwen
- Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MGK, Mackey JR, Godbout R, Curtis JM, McMullen TPW, Brindley DN. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 2016; 6:21164. [PMID: 26883574 PMCID: PMC4756695 DOI: 10.1038/srep21164] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 01/14/2016] [Indexed: 02/07/2023] Open
Abstract
Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.
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Affiliation(s)
- Raie T Bekele
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Ganesh Venkatraman
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Rong-Zong Liu
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Si Mi
- Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada
| | - Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - John R Mackey
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Roseline Godbout
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Jonathan M Curtis
- Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada
| | - Todd P W McMullen
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.,Department of Surgery, Walter C Mackenzie Health Science Centre, University of Alberta, Edmonton, T6G 2R7, Alberta, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
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Chai J, Cai SY, Liu X, Lian W, Chen S, Zhang L, Feng X, Cheng Y, He X, He Y, Chen L, Wang R, Wang H, Boyer JL, Chen W. Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. J Hepatol 2015; 63. [PMID: 26212029 PMCID: PMC4686151 DOI: 10.1016/j.jhep.2015.07.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Multidrug resistance-associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis. METHODS We assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells. RESULTS Western blot detected that liver MRP2 protein expression in obstructive cholestatic patients (n=30) was significantly reduced to 25% of the non-cholestatic controls (n=23). Immunoprecipitation identified Ezrin but not Radixin associating with MRP2 in human livers, and the increased amount of phospho-Ezrin Thr567 was positively correlated with the amount of co-precipitated MRP2 in cholestatic livers, whereas Ezrin and Radixin total protein levels were unchanged in cholestasis. Further detailed studies indicate that Ezrin Thr567 phosphorylation plays an important role in MRP2 internalization in HepG2 cells. Since increased expression of PKCα, δ and ε were detected in these cholestatic livers, we further confirmed that these PKCs stimulated Ezrin phosphorylation and reduced MRP2 membrane expression in HepG2 cells. Finally, we identified GP78 as the key ubiquitin ligase E3 involved in MRP2 proteasome degradation. CONCLUSIONS Activation of liver PKCs during cholestasis leads to Ezrin Thr567 phosphorylation resulting in MRP2 internalization and degradation where ubiquitin ligase E3 GP78 is involved. This process provides a mechanistic explanation for jaundice seen in patients with obstructive cholestasis.
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Affiliation(s)
- Jin Chai
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Shi-Ying Cai
- Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xiaocong Liu
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Wei Lian
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Sheng Chen
- Department of Pediatrics, Third Military Medical University, Chongqing 400038, P.R. China
| | - Liangjun Zhang
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Xinchan Feng
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Ying Cheng
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Xiaochong He
- School of Nursing, Third Military Medical University, Chongqing 400038, P.R. China
| | - Yu He
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Lei Chen
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Rongquan Wang
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, P.R. China
| | - Huaizhi Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
| | - James L. Boyer
- Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Wensheng Chen
- Department of Gastroenterology, Third Military Medical University, Chongqing 400038, PR China.
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Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol 2015; 63:1023-37. [PMID: 26116792 PMCID: PMC4582071 DOI: 10.1016/j.jhep.2015.06.015] [Citation(s) in RCA: 188] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 06/14/2015] [Accepted: 06/15/2015] [Indexed: 02/08/2023]
Abstract
Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.
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Affiliation(s)
- Paul Gissen
- MRC Laboratory for Molecular Cell Biology, University College London, London, UK; UCL Institute of Child Health, London, UK; Great Ormond Street Hospital, London, UK.
| | - Irwin M Arias
- Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States
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Niu X, de Graaf IAM, van de Vegte D, Langelaar-Makkinje M, Sekine S, Groothuis GMM. Consequences of Mrp2 deficiency for diclofenac toxicity in the rat intestine ex vivo. Toxicol In Vitro 2015; 29:168-75. [PMID: 25450747 DOI: 10.1016/j.tiv.2014.10.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 10/01/2014] [Accepted: 10/06/2014] [Indexed: 02/07/2023]
Abstract
The non-steroidal anti-inflammatory drug diclofenac (DCF) has a high prevalence of intestinal side effects in humans and rats. It has been reported that Mrp2 transporter deficient rats (Mrp2) are more resistant to DCF induced intestinal toxicity. This was explained in vivo by impaired Mrp2-dependent biliary transport of DCF-acylglucuronide (DAG), leading to decreased intestinal exposure to DAG and DCF. However, it is not known to what extent adaptive changes in the Mrp2 intestine itself influence its sensitivity to DCF toxicity without the influence of liver metabolites. To investigate this, DCF toxicity and disposition were studied ex vivo by precision-cut intestinal slices and Ussing chamber using intestines from wild type(WT) and Mrp2 rats. The results show that adaptive changes due to Mrp2 deficiency concerning Mrp2, Mrp3 and BCRP gene expression, GSH content and DAG formation were different between liver and intestine. Furthermore, Mrp2 intestine was intrinsically more resistant to DCF toxicity than its WT counterpart ex vivo. This can at least partly be explained by a reduced DCF uptake by the Mrp2 intestine, but isnot related to the other adaptive changes in the intestine. The extrapolation of this data to humans with MRP2 deficiency is uncertain due to species differences in activity and regulation of transporters.
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Affiliation(s)
- Xiaoyu Niu
- Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, The Netherlands
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van der Schoor LWE, Verkade HJ, Kuipers F, Jonker JW. New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition. Expert Opin Drug Metab Toxicol 2014; 11:273-93. [PMID: 25380746 DOI: 10.1517/17425255.2015.981152] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION For the elimination of environmental chemicals and metabolic waste products, the body is equipped with a range of broad specificity transporters that are present in excretory organs as well as in several epithelial blood-tissue barriers. AREAS COVERED ABCC2 and ABCC3 (also known as MRP2 and MRP3) mediate the transport of various conjugated organic anions, including many drugs, toxicants and endogenous compounds. This review focuses on the physiology of these transporters, their roles in drug disposition and how they affect drug sensitivity and toxicity. It also examines how ABCC2 and ABCC3 are coordinately regulated at the transcriptional level by members of the nuclear receptor (NR) family of ligand-modulated transcription factors and how this can be therapeutically exploited. EXPERT OPINION Mutations in both ABCC2 and ABCC3 have been associated with changes in drug disposition, sensitivity and toxicity. A defect in ABCC2 is associated with Dubin-Johnson syndrome, a recessively inherited disorder characterized by conjugated hyperbilirubinemia. Pharmacological manipulation of the activity of these transporters can potentially improve the pharmacokinetics and thus therapeutic activity of substrate drugs but also affect the physiological function of these transporters and consequently ameliorate associated disease states.
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Affiliation(s)
- Lori W E van der Schoor
- University of Groningen, University Medical Center Groningen, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics , Hanzeplein 1, 9713 GZ Groningen , The Netherlands
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Dietrich CG, Geier A. Effect of drug transporter pharmacogenetics on cholestasis. Expert Opin Drug Metab Toxicol 2014; 10:1533-51. [PMID: 25260651 DOI: 10.1517/17425255.2014.963553] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood. AREAS COVERED Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis. EXPERT OPINION Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.
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van der Mark VA, de Waart DR, Ho-Mok KS, Tabbers MM, Voogt HW, Oude Elferink RPJ, Knisely AS, Paulusma CC. The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. Biochim Biophys Acta Mol Basis Dis 2014; 1842:2378-86. [PMID: 25239307 DOI: 10.1016/j.bbadis.2014.09.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/04/2014] [Accepted: 09/05/2014] [Indexed: 12/12/2022]
Abstract
Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1-CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
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Affiliation(s)
- Vincent A van der Mark
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
| | - D Rudi de Waart
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Kam S Ho-Mok
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Merit M Tabbers
- Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands
| | - Heleen W Voogt
- Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald P J Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - A S Knisely
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Coen C Paulusma
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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Gaikwad VL, Bhatia MS. Polymers influencing transportability profile of drug. Saudi Pharm J 2014; 21:327-35. [PMID: 24227951 DOI: 10.1016/j.jsps.2012.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 10/26/2012] [Indexed: 11/28/2022] Open
Abstract
Drug release from various polymers is generally governed by the type of polymer/s incorporated in the formulation and mechanism of drug release from polymer/s. A single polymer may show one or more mechanisms of drug release out of which one mechanism is majorly followed for drug release. Some of the common mechanisms of drug release from polymers were, diffusion, swelling, matrix release, leaching of drug, etc. Mechanism or rate of drug release from a polymer or a combination of polymers can be predicted by using different computational methods or models. These models were capable of predicting drug release from its dosage form in advance without actual formulation and testing of drug release from dosage form. Quantitative structure-property relationship (QSPR) is an important tool used in the prediction of various physicochemical properties of actives as well as inactives. Since last several decades QSPR has been applied in new drug development for reducing the total number of drugs to be synthesized, as it involves a selection of the most desirable compound of interest. This technique was also applied in predicting in vivo performance of drug/s for various parameters. QSPR serves as a predictive tool to correlate structural descriptors of molecules with biological as well as physicochemical properties. Several researchers have contributed at different extents in this area to modify various properties of pharmaceuticals. The present review is focused on a study of different polymers that influence the transportability profiles of drugs along with the application of QSPR either to study different properties of polymers that regulate drug release or in predicting drug transportability from different polymer systems used in formulations.
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Affiliation(s)
- Vinod L Gaikwad
- Department of Pharmaceutics, P.E. Society's Modern College of Pharmacy, Nigdi, Pune-411044, Maharashtra State, India
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Germano D, Uteng M, Pognan F, Chibout SD, Wolf A. Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment. Toxicol In Vitro 2014; 30:79-94. [PMID: 24933330 DOI: 10.1016/j.tiv.2014.05.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 05/13/2014] [Accepted: 05/19/2014] [Indexed: 12/26/2022]
Abstract
DILI is a major safety issue during drug development and one of the leading causes for market withdrawal. Despite many efforts made in the past, the prediction of DILI using in vitro models remains very unreliable. In the present study, the well-established hepatocyte Collagen I-Matrigel™ sandwich culture was used, mimicking chronic drug treatment after multiple incubations for 14 days. Ten drugs associated with different types of specific preclinical and clinical liver injury were evaluated at non-cytotoxic concentrations. Mrp2-mediated transport, intracellular accumulation of neutral lipids and phospholipids were selected as functional endpoints by using Cellomics™ Arrayscan® technology and assessed at five timepoints (day 1, 3, 7, 10, 14). Liver specific functional impairments after drug treatment were enhanced over time and could be monitored by HCI already after few days and before cytotoxicity. Phospholipidosis-inducing drugs Chlorpromazine and Amiodarone displayed the same response as in vivo. Cyclosporin A, Chlorpromazine, and Troglitazone inhibited Mrp2-mediated biliary transport, correlating with in vivo findings. Steatosis remained difficult to be reproduced under the current in vitro testing conditions, resulting into false negative and positive responses. The present results suggest that the repeated long-term treatment of rat hepatocytes in the Collagen I-Matrigel™ sandwich configuration might be a suitable tool for safety profiling of the potential to induce phospholipidosis and impair Mrp2-mediated transport processes, but not to predict steatosis.
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Affiliation(s)
- Davide Germano
- Discovery and Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland
| | - Marianne Uteng
- Discovery and Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland
| | - Francois Pognan
- Discovery and Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland
| | - Salah-Dine Chibout
- Discovery and Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland
| | - Armin Wolf
- Discovery and Investigative Safety, Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland.
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38
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Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology 2014; 146:1625-38. [PMID: 24704527 DOI: 10.1053/j.gastro.2014.03.047] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 03/12/2014] [Accepted: 03/23/2014] [Indexed: 12/11/2022]
Abstract
Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler-Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin-Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
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Affiliation(s)
| | | | - Daniel Dhumeaux
- Henri Mondor Hospital, Créteil, University of Paris-Est, Créteil, France
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39
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Cuperus FJC, Claudel T, Gautherot J, Halilbasic E, Trauner M. The role of canalicular ABC transporters in cholestasis. Drug Metab Dispos 2014; 42:546-60. [PMID: 24474736 DOI: 10.1124/dmd.113.056358] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.
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Affiliation(s)
- Frans J C Cuperus
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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40
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Döring B, Petzinger E. Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism. Drug Metab Rev 2014; 46:261-82. [PMID: 24483608 DOI: 10.3109/03602532.2014.882353] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination.
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Affiliation(s)
- Barbara Döring
- Institute of Pharmacology and Toxicology, Biomedical Research Center Seltersberg, Justus-Liebig-University Giessen , Giessen , Germany
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41
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Kappelmayer J, Simon A, Kiss F, Hevessy Z. Progress in defining multidrug resistance in leukemia. Expert Rev Mol Diagn 2014; 4:209-17. [PMID: 14995907 DOI: 10.1586/14737159.4.2.209] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Multidrug resistance (MDR) is a naturally occurring defense phenomenon by which cells battle against chemically foreign substances (xenobiotics), including some cytotoxic drugs. Membrane transporter hyperactivity is a major contributor to MDR and is the primary target of both diagnostic and therapeutic interventions. Multi-xenobiotic resistance can be exploited as several fluorescent indicator probes are extruded by the same drug transporters, making it possible to quantitatively measure MDR activity in cell lines and clinical samples by flow cytometry. The literature on MDR is reported in a number of different formats, making it difficult to compare data from various groups. This article will briefly review the pathomechanism, then focus upon the diagnostic approach, the interpretation of results from clinical samples and correlations with other variables. The authors believe that a standardized MDR assay, as well as a suitable monitoring test, may become a prognostic marker in several types of leukemia.
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Affiliation(s)
- János Kappelmayer
- Department of Clinical Biochemistry and Molecular Pathology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary H-4032.
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42
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Reshetnyak VI. Physiological and molecular biochemical mechanisms of bile formation. World J Gastroenterol 2013; 19:7341-7360. [PMID: 24259965 PMCID: PMC3831216 DOI: 10.3748/wjg.v19.i42.7341] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/17/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract.
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43
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Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol 2013; 19:6398-6407. [PMID: 24151358 PMCID: PMC3801310 DOI: 10.3748/wjg.v19.i38.6398] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 07/18/2013] [Accepted: 08/09/2013] [Indexed: 02/06/2023] Open
Abstract
Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
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44
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Ulloa JL, Stahl S, Yates J, Woodhouse N, Kenna JG, Jones HB, Waterton JC, Hockings PD. Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition. NMR IN BIOMEDICINE 2013; 26:1258-1270. [PMID: 23564602 PMCID: PMC3817526 DOI: 10.1002/nbm.2946] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 02/14/2013] [Accepted: 02/18/2013] [Indexed: 06/02/2023]
Abstract
Drug-induced liver injury (DILI) is a clinically important adverse drug reaction, which prevents the development of many otherwise safe and effective new drugs. Currently, there is a lack of sensitive and specific biomarkers that can be used to predict, assess and manage this toxicity. The aim of this work was to evaluate gadoxetate-enhanced MRI as a potential novel biomarker of hepatobiliary transporter inhibition in the rat. Initially, the volume fraction of extracellular space in the liver was determined using gadopentetate to enable an estimation of the gadoxetate concentration in hepatocytes. Using this information, a compartmental model was developed to characterise the pharmacokinetics of hepatic uptake and biliary excretion of gadoxetate. Subsequently, we explored the impact of an investigational hepatobiliary transporter inhibitor on the parameters of the model in vivo in rats. The investigational hepatobiliary transporter inhibitor reduced both the rate of uptake of gadoxetate into the hepatocyte, k1 , and the Michaelis-Menten constant, Vmax , characterising its excretion into bile, whereas KM values for biliary efflux were increased. These effects were dose dependent and correlated with effects on plasma chemistry markers of liver dysfunction, in particular bilirubin and bile acids. These results indicate that gadoxetate-enhanced MRI provides a novel functional biomarker of inhibition of transporter-mediated hepatic uptake and clearance in the rat. Since gadoxetate is used clinically, the technology has the potential to provide a translatable biomarker of drug-induced perturbation of hepatic transporters that may also be useful in humans to explore deleterious functional alterations caused by transporter inhibition.
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Affiliation(s)
- Jose L Ulloa
- Science and Validation, Personalised Healthcare and BiomarkersAstraZeneca, Macclesfield, UK
| | - Simone Stahl
- Molecular Toxicology, Safety Assessment UKAstraZeneca, Macclesfield, UK
| | - James Yates
- DMPK, Oncology iMedAstraZeneca, Macclesfield, UK
| | - Neil Woodhouse
- Science and Validation, Personalised Healthcare and BiomarkersAstraZeneca, Macclesfield, UK
| | - J Gerry Kenna
- Molecular Toxicology, Safety Assessment UKAstraZeneca, Macclesfield, UK
| | - Huw B Jones
- Pathology, Safety Assessment UKAstraZeneca, Macclesfield, UK
| | - John C Waterton
- Science and Validation, Personalised Healthcare and BiomarkersAstraZeneca, Macclesfield, UK
| | - Paul D Hockings
- Science and Validation, Personalised Healthcare and BiomarkersAstraZeneca, Mölndal, Sweden
- MedTech West, Chalmers University of TechnologyGothenburg, Sweden
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45
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Yamashita M, Yamashita Y, Suzuki T, Kani Y, Mizusawa N, Imamura S, Takemoto K, Hara T, Hossain MA, Yabu T, Touhata K. Selenoneine, a novel selenium-containing compound, mediates detoxification mechanisms against methylmercury accumulation and toxicity in zebrafish embryo. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2013; 15:559-70. [PMID: 23709046 PMCID: PMC3742965 DOI: 10.1007/s10126-013-9508-1] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Accepted: 03/19/2013] [Indexed: 05/15/2023]
Abstract
The selenium (Se)-containing antioxidant selenoneine (2-selenyl-N α,N α,N α-trimethyl-L-histidine) has recently been discovered to be the predominant form of organic Se in tuna blood. Although dietary intake of fish Se has been suggested to reduce methylmercury (MeHg) toxicity, the molecular mechanism of MeHg detoxification by Se has not yet been determined. Here, we report evidence that selenoneine accelerates the excretion and demethylation of MeHg, mediated by a selenoneine-specific transporter, organic cations/carnitine transporter-1 (OCTN1). Selenoneine was incorporated into human embryonic kidney HEK293 cells transiently overexpressing OCTN1 and zebrafish blood cells by OCTN1. The K m for selenoneine uptake was 13.0 μM in OCTN1-overexpressing HEK293 cells and 9.5 μM in zebrafish blood cells, indicating high affinity of OCTN1 for selenoneine in human and zebrafish cells. When such OCTN1-expressing cells and embryos were exposed to MeHg-cysteine (MeHgCys), MeHg accumulation was decreased and the excretion and demethylation of MeHg were enhanced by selenoneine. In addition, exosomal secretion vesicles were detected in the culture water of embryos that had been microinjected with MeHgCys, suggesting that these may be responsible for MeHg excretion and demethylation. In contrast, OCTN1-deficient embryos accumulated MeHg, and MeHg excretion and demethylation were decreased. Furthermore, Hg accumulation was decreased in OCTN1-overexpressing HEK293 cells, but not in mock vector-transfected cells, indicating that selenoneine and OCTN1 can regulate MeHg detoxification in human cells. Thus, the selenoneine-mediated OCTN1 system regulates secretory lysosomal vesicle formation and MeHg demethylation.
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Affiliation(s)
- Michiaki Yamashita
- National Research Institute of Fisheries Science, 2-12-4 Fukuura, Yokohama, Kanagawa, 236-8648, Japan.
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46
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Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation. Int J Pharm 2013; 452:36-41. [DOI: 10.1016/j.ijpharm.2013.04.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 03/13/2013] [Accepted: 04/08/2013] [Indexed: 11/18/2022]
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47
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Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, Bode JG, Bolleyn J, Borner C, Böttger J, Braeuning A, Budinsky RA, Burkhardt B, Cameron NR, Camussi G, Cho CS, Choi YJ, Craig Rowlands J, Dahmen U, Damm G, Dirsch O, Donato MT, Dong J, Dooley S, Drasdo D, Eakins R, Ferreira KS, Fonsato V, Fraczek J, Gebhardt R, Gibson A, Glanemann M, Goldring CEP, Gómez-Lechón MJ, Groothuis GMM, Gustavsson L, Guyot C, Hallifax D, Hammad S, Hayward A, Häussinger D, Hellerbrand C, Hewitt P, Hoehme S, Holzhütter HG, Houston JB, Hrach J, Ito K, Jaeschke H, Keitel V, Kelm JM, Kevin Park B, Kordes C, Kullak-Ublick GA, LeCluyse EL, Lu P, Luebke-Wheeler J, Lutz A, Maltman DJ, Matz-Soja M, McMullen P, Merfort I, Messner S, Meyer C, Mwinyi J, Naisbitt DJ, Nussler AK, Olinga P, Pampaloni F, Pi J, Pluta L, Przyborski SA, Ramachandran A, Rogiers V, Rowe C, Schelcher C, Schmich K, Schwarz M, Singh B, Stelzer EHK, Stieger B, Stöber R, Sugiyama Y, Tetta C, Thasler WE, Vanhaecke T, Vinken M, Weiss TS, Widera A, Woods CG, Xu JJ, Yarborough KM, Hengstler JG. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 2013; 87:1315-530. [PMID: 23974980 PMCID: PMC3753504 DOI: 10.1007/s00204-013-1078-5] [Citation(s) in RCA: 1074] [Impact Index Per Article: 89.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 05/06/2013] [Indexed: 12/15/2022]
Abstract
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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Affiliation(s)
- Patricio Godoy
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | | | - Ute Albrecht
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Melvin E. Andersen
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Nariman Ansari
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Sudin Bhattacharya
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Johannes Georg Bode
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Jennifer Bolleyn
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
| | - Jan Böttger
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Albert Braeuning
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany
| | - Robert A. Budinsky
- Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI USA
| | - Britta Burkhardt
- BG Trauma Center, Siegfried Weller Institut, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Neil R. Cameron
- Department of Chemistry, Durham University, Durham, DH1 3LE UK
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Turin, Italy
| | - Chong-Su Cho
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - Yun-Jaie Choi
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - J. Craig Rowlands
- Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI USA
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General Visceral, and Vascular Surgery, Friedrich-Schiller-University Jena, 07745 Jena, Germany
| | - Georg Damm
- Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Olaf Dirsch
- Institute of Pathology, Friedrich-Schiller-University Jena, 07745 Jena, Germany
| | - María Teresa Donato
- Unidad de Hepatología Experimental, IIS Hospital La Fe Avda Campanar 21, 46009 Valencia, Spain
- CIBERehd, Fondo de Investigaciones Sanitarias, Barcelona, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Jian Dong
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Steven Dooley
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Dirk Drasdo
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, 04107 Leipzig, Germany
- INRIA (French National Institute for Research in Computer Science and Control), Domaine de Voluceau-Rocquencourt, B.P. 105, 78153 Le Chesnay Cedex, France
- UPMC University of Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu, 75252 Paris cedex 05, France
| | - Rowena Eakins
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Karine Sá Ferreira
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
- GRK 1104 From Cells to Organs, Molecular Mechanisms of Organogenesis, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Valentina Fonsato
- Department of Medical Sciences, University of Torino, 10126 Turin, Italy
| | - Joanna Fraczek
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Andrew Gibson
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Matthias Glanemann
- Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Chris E. P. Goldring
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - María José Gómez-Lechón
- Unidad de Hepatología Experimental, IIS Hospital La Fe Avda Campanar 21, 46009 Valencia, Spain
- CIBERehd, Fondo de Investigaciones Sanitarias, Barcelona, Spain
| | - Geny M. M. Groothuis
- Department of Pharmacy, Pharmacokinetics Toxicology and Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Lena Gustavsson
- Department of Laboratory Medicine (Malmö), Center for Molecular Pathology, Lund University, Jan Waldenströms gata 59, 205 02 Malmö, Sweden
| | - Christelle Guyot
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - David Hallifax
- Centre for Applied Pharmacokinetic Research (CAPKR), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT UK
| | - Seddik Hammad
- Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Adam Hayward
- Biological and Biomedical Sciences, Durham University, Durham, DH13LE UK
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Claus Hellerbrand
- Department of Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany
| | | | - Stefan Hoehme
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, 04107 Leipzig, Germany
| | - Hermann-Georg Holzhütter
- Institut für Biochemie Abteilung Mathematische Systembiochemie, Universitätsmedizin Berlin (Charité), Charitéplatz 1, 10117 Berlin, Germany
| | - J. Brian Houston
- Centre for Applied Pharmacokinetic Research (CAPKR), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT UK
| | | | - Kiyomi Ito
- Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585 Japan
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | | | - B. Kevin Park
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Claus Kordes
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Edward L. LeCluyse
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Peng Lu
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | | | - Anna Lutz
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | - Daniel J. Maltman
- Reinnervate Limited, NETPark Incubator, Thomas Wright Way, Sedgefield, TS21 3FD UK
| | - Madlen Matz-Soja
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Patrick McMullen
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | | | - Christoph Meyer
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jessica Mwinyi
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Dean J. Naisbitt
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Andreas K. Nussler
- BG Trauma Center, Siegfried Weller Institut, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Francesco Pampaloni
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Jingbo Pi
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Linda Pluta
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | - Stefan A. Przyborski
- Reinnervate Limited, NETPark Incubator, Thomas Wright Way, Sedgefield, TS21 3FD UK
- Biological and Biomedical Sciences, Durham University, Durham, DH13LE UK
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Vera Rogiers
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Cliff Rowe
- Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Celine Schelcher
- Department of Surgery, Liver Regeneration, Core Facility, Human in Vitro Models of the Liver, Ludwig Maximilians University of Munich, Munich, Germany
| | - Kathrin Schmich
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
| | - Michael Schwarz
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany
| | - Bijay Singh
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
| | - Ernst H. K. Stelzer
- Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
| | - Regina Stöber
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | - Yuichi Sugiyama
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama Biopharmaceutical R&D Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Ciro Tetta
- Fresenius Medical Care, Bad Homburg, Germany
| | - Wolfgang E. Thasler
- Department of Surgery, Ludwig-Maximilians-University of Munich Hospital Grosshadern, Munich, Germany
| | - Tamara Vanhaecke
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Mathieu Vinken
- Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Thomas S. Weiss
- Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany
| | - Agata Widera
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
| | - Courtney G. Woods
- The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
| | | | | | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
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48
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Dynamic Contrast-Enhanced MRI of the Liver in Mrp2-Deficient Rats Using the Hepatobiliary Contrast Agent Gd-EOB-DTPA. Invest Radiol 2013; 48:548-53. [DOI: 10.1097/rli.0b013e3182856a06] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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49
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Yoshikado T, Takada T, Yamamoto H, Tan JK, Ito K, Santa T, Suzuki H. Ticlopidine, a cholestatic liver injury-inducible drug, causes dysfunction of bile formation via diminished biliary secretion of phospholipids: involvement of biliary-excreted glutathione-conjugated ticlopidine metabolites. Mol Pharmacol 2013; 83:552-62. [PMID: 23220748 DOI: 10.1124/mol.112.081752] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025] Open
Abstract
The antiplatelet drug, ticlopidine (TIC), reportedly causes cholestatic liver injuries. The present study analyzed the effect of TIC on bile formation, revealing that the biliary secretion of phospholipids was significantly decreased in TIC-administered Sprague Dawley (SD) rats. However, the effect of TIC on biliary phospholipids was not observed in SD rats pretreated with diethylaminoethyl diphenylpropylacetate that inhibits cytochrome P450s (P450), or in Eisai hyperbilirubinemic rats (EHBR) lacking functional multidrug resistance-associated protein 2 (MRP2/ABCC2). These results suggest that glutathione-conjugated TIC metabolites (TIC-SGs), which were formed in the liver after P450s-mediated metabolism and were excreted extensively into bile by MRP2, mediated the observed alterations of the bile composition. Administration of TIC caused significant liver injuries in SD rats, with decreased biliary phospholipids, but not in EHBR, consistent with the in vitro observation that phospholipid-bile acid-mixed micelles moderated the cytotoxic effects of bile acids. Further analyses revealed that TIC-SGs did not directly inhibit multidrug resistance 3 P-glycoprotein (MDR3/ABCB4)-mediated phosphatidylcholine efflux in vitro. Because the diminished biliary secretion of phospholipids with TIC administration was restored by taurocholate infusion in SD rats, the decreased biliary concentration of bile acids, due to the stimulation of bile acid-independent bile flow driven by TIC-SGs, might have indirectly attenuated phospholipid secretion. In conclusion, extensive biliary excretion of TIC-SGs decreased the biliary secretion of phospholipids, which might have increased the risk of TIC-induced cholestatic liver injury.
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Affiliation(s)
- Takashi Yoshikado
- Department of Pharmacy, the University of Tokyo Hospital, Laboratory of Biomedical and Pharmaceutical Analysis, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan
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50
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Pramanik D, Campbell NR, Das S, Gupta S, Chenna V, Bisht S, Sysa-Shah P, Bedja D, Karikari C, Steenbergen C, Gabrielson KL, Maitra A, Maitra A. A composite polymer nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated cardiomyopathy. Oncotarget 2013; 3:640-50. [PMID: 22791660 PMCID: PMC3442295 DOI: 10.18632/oncotarget.543] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.
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Affiliation(s)
- Dipankar Pramanik
- The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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