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Thakur A, Subash S, Ahire D, Prasad B. Developmental Expression of Drug Transporters and Conjugating Enzymes Involved in Enterohepatic Recycling: Implication for Pediatric Drug Dosing. Clin Pharmacol Ther 2024; 116:1615-1626. [PMID: 39160670 PMCID: PMC11979781 DOI: 10.1002/cpt.3409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/17/2024] [Indexed: 08/21/2024]
Abstract
Around 50% of the drugs used in children have never been tested for safety and efficacy in this vulnerable population. Immature drug elimination pathways can lead to drug toxicity when pediatric doses are determined using empirical methods such as body-surface area or body-weight-normalized adult dosing. In the absence of clinical data, physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to predict drug pharmacokinetics in children. These models utilize developmental physiological data, including age-dependent differences in the abundance of drug-metabolizing enzymes and transporters (DMET), to mechanistically extrapolate adult pharmacokinetic data to children. The reported abundance data of hepatic DMET proteins in subcellular fractions isolated from frozen tissue are prone to high technical variability. Therefore, we carried out the proteomics-based quantification of hepatic drug transporters and conjugating enzymes in 50 pediatric and 8 adult human hepatocyte samples. Out of the 34 studied proteins, 28 showed a significant increase or decrease with age. While MRP6, OAT7, and SULT1E1 were highest in < 1-year-old samples, the abundance of P-gp and UGT1A4 was negligible in < 1-year-old samples and increased significantly after 1 year of age. Incorporation of the age-dependent abundance data in PBPK models can help improve pediatric dose prediction, leading to safer drug pharmacotherapy in children.
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Affiliation(s)
- Aarzoo Thakur
- College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, US
| | - Sandhya Subash
- College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, US
| | - Deepak Ahire
- College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, US
| | - Bhagwat Prasad
- College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, US
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2
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Marin JJG, Cives-Losada C, Macias RIR, Romero MR, Marijuan RP, Hortelano-Hernandez N, Delgado-Calvo K, Villar C, Gonzalez-Santiago JM, Monte MJ, Asensio M. Impact of liver diseases and pharmacological interactions on the transportome involved in hepatic drug disposition. Biochem Pharmacol 2024; 228:116166. [PMID: 38527556 DOI: 10.1016/j.bcp.2024.116166] [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: 01/18/2024] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rebeca P Marijuan
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | | | - Kevin Delgado-Calvo
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Villar
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Jesus M Gonzalez-Santiago
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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Becker PC, Güth-Steffens M, Lazarow K, Sonntag N, Braun D, Masfaka I, Renko K, Schomburg L, Köhrle J, von Kries JP, Schweizer U, Krause G, Protze J. Identification of Human TRIAC Transmembrane Transporters. Thyroid 2024; 34:920-930. [PMID: 38801167 DOI: 10.1089/thy.2023.0592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Background: 3,5,3'-Triiodothyroacetic acid (TRIAC) is a T3-receptor agonist pharmacologically used in patients to mitigate T3 resistance. It is additionally explored to treat some symptoms of patients with inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8, SLC16A2). MCT8 is expressed along the blood-brain barrier, on neurons, astrocytes, and oligodendrocytes. Hence, pathogenic variants in MCT8 limit the access of TH into and their functions within the brain. TRIAC was shown to enter the brain independently of MCT8 and to modulate expression of TH-dependent genes. The aim of the study was to identify transporters that facilitate TRIAC uptake into cells. Methods: We performed a whole-genome RNAi screen in HepG2 cells stably expressing a T3-receptor-dependent luciferase reporter gene. Validation of hits from the primary and confirmatory secondary screen involved a counter screen with siRNAs and compared the cellular response to TRIAC to the effect of T3, in order to exclude siRNAs targeting the gene expression machinery. MDCK1 cells were stably transfected with cDNA encoding C-terminally myc-tagged versions of the identified TRIAC-preferring transporters. Several individual clones were selected after immunocytochemical characterization for biochemical characterization of their 125I-TRIAC transport activities. Results: We identified SLC22A9 and SLC29A2 as transporters mediating cellular uptake of TRIAC. SLC22A9 encodes the organic anion transporter 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver, and other organs. Competition with the SLC22A9/OAT7 substrate estrone-3-sulfate reduced 125I-TRIAC uptake. SLC29A2 encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed, including pituitary and brain. Coincubation with the SLC29A2/ENT2 inhibitor nitrobenzyl-6-thioinosine reduced 125I-TRIAC uptake. Moreover, ABCD1, an ATP-dependent peroxisomal pump, was identified as a 125I-TRIAC exporter in transfected MDCK1 cells. Conclusions: Knowledge of TRIAC transporter expression patterns, also during brain development, may thus in the future help to interpret observations on TRIAC effects, as well as understand why TRIAC may not show a desirable effect on cells or organs not expressing appropriate transporters. The identification of ABCD1 highlights the sensitivity of our established screening assay, but it may not hold significant relevance for patients undergoing TRIAC treatment.
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Affiliation(s)
- Paul Carlos Becker
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Mandy Güth-Steffens
- Rheinische Friedrich-Wilhelms-Universität, Universitätsklinikum Bonn, Bonn, Germany
| | - Katina Lazarow
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Niklas Sonntag
- Rheinische Friedrich-Wilhelms-Universität, Universitätsklinikum Bonn, Bonn, Germany
| | - Doreen Braun
- Rheinische Friedrich-Wilhelms-Universität, Universitätsklinikum Bonn, Bonn, Germany
| | - Islam Masfaka
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Kostja Renko
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Charite Universitätsmedizin Berlin, Berlin, Germany
- German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Lutz Schomburg
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Charite Universitätsmedizin Berlin, Berlin, Germany
| | - Josef Köhrle
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Charite Universitätsmedizin Berlin, Berlin, Germany
| | | | - Ulrich Schweizer
- Rheinische Friedrich-Wilhelms-Universität, Universitätsklinikum Bonn, Bonn, Germany
| | - Gerd Krause
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Jonas Protze
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
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Yee SW, Ferrández-Peral L, Alentorn-Moron P, Fontsere C, Ceylan M, Koleske ML, Handin N, Artegoitia VM, Lara G, Chien HC, Zhou X, Dainat J, Zalevsky A, Sali A, Brand CM, Wolfreys FD, Yang J, Gestwicki JE, Capra JA, Artursson P, Newman JW, Marquès-Bonet T, Giacomini KM. Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates. Nat Commun 2024; 15:4380. [PMID: 38782905 PMCID: PMC11116522 DOI: 10.1038/s41467-024-48569-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.
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Affiliation(s)
- Sook Wah Yee
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Luis Ferrández-Peral
- Institute of Evolutionary Biology (UPF-CSIC), PRBB, Dr. Aiguader 88, 08003, Barcelona, Spain
| | - Pol Alentorn-Moron
- Institute of Evolutionary Biology (UPF-CSIC), PRBB, Dr. Aiguader 88, 08003, Barcelona, Spain
| | - Claudia Fontsere
- Institute of Evolutionary Biology (UPF-CSIC), PRBB, Dr. Aiguader 88, 08003, Barcelona, Spain
- Center for Evolutionary Hologenomics, The Globe Institute, University of Copenhagen, Øster Farimagsgade 5A, 1352, Copenhagen, Denmark
| | - Merve Ceylan
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Megan L Koleske
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Niklas Handin
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Virginia M Artegoitia
- United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, 95616, USA
| | - Giovanni Lara
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Huan-Chieh Chien
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Xujia Zhou
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Jacques Dainat
- Joint Research Unit for Infectious Diseases and Vectors Ecology Genetics Evolution and Control (MIVEGEC), University of Montpellier, French National Center for Scientific Research (CNRS 5290), French National Research Institute for Sustainable Development (IRD 224), 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France
| | - Arthur Zalevsky
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Andrej Sali
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, US
| | - Colin M Brand
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Finn D Wolfreys
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - Jia Yang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Jason E Gestwicki
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
- Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA
| | - John A Capra
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Per Artursson
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
- Science for Life Laboratories, Uppsala University, Uppsala, Sweden
| | - John W Newman
- United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, 95616, USA
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Tomàs Marquès-Bonet
- Institute of Evolutionary Biology (UPF-CSIC), PRBB, Dr. Aiguader 88, 08003, Barcelona, Spain
- Catalan Institution of Research and Advanced Studies (ICREA), Passeig de Lluís Companys, 23, 08010, Barcelona, Spain
- CNAG, Centro Nacional de Analisis Genomico, Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain
- Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, Edifici ICTA-ICP, c/ Columnes s/n, 08193, Cerdanyola del Vallès, Barcelona, Spain
| | - Kathleen M Giacomini
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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Wang H, Bin Wang, Pan MB, Jiang ST, Wang YC, Zhu Y, Zhang QC, Dong YF. Disorders in the gut and liver are involved in depression contagion between isosexual post-stroke depression mice and the healthy cohabitors. Behav Brain Res 2023; 439:114246. [PMID: 36481213 DOI: 10.1016/j.bbr.2022.114246] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Despite the accumulated evidence that pair housing could attenuate post-stroke depression (PSD), but less attention has been paid to the healthy cohabitors, and the underlying mechanisms remain unclear. This study aimed to determine whether there is depressive contagion between PSD mice and their healthy cohabitors. PSD was induced by middle cerebral artery occlusion (MCAO) plus restraint stress for four weeks. Three days after MCAO, the mice were restrained two hours per day and isosexually pair-housed for four weeks. The results showed that, compared with the partners pair housed with normal control mice (Ctrl group), the partners pair housed with PSD mice (CH group) displayed depressive-like behaviors, including decreased sucrose preference rate, significantly shorter duration in the center arena and reduced total distance in the open-field test, and extended immobile time in forced swimming test and tail-suspension test without sex differences. Regarding the change in the body weight, only the males showed a significant reduction on days 17 and 24 after treatment. Furthermore, the CH group showed significantly increased corticosterone and decreased oxytocin (OXT) levels in serum, while the mRNA levels of OXT, vasopressin and oxytocin receptor were remarkably upregulated in the hypothalamus of the CH group. However, there was no significant change in the vasopressin receptor V1a. Interestingly, compared with the Ctrl group, there was a significant decrease in butyrate in serum of the CH group. Consistently, they had mild liver dysfunction with increased alanine transaminase, extended hepatic sinus surrounded by enhanced SLC22A9, and significantly increased Iba1-positive macrophages. Moreover, the expression of tight junction protein (Occludin and ZO-1) obviously decreased in the colon with increasing Iba1-positive cells. These results suggest that isosexual pair-housing with PSD mice causes the healthy partners to develop depressive-like behaviors with disturbances in the gut and liver.
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Affiliation(s)
- Hui Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Bin Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Mei-Bo Pan
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Su-Ting Jiang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yi-Chen Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Zhu
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Qi-Chun Zhang
- Department of Clinical Pharmacy and Toxicity, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yin-Feng Dong
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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7
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Mundula T, Baldi S, Gerace E, Amedei A. Role of the Intestinal Microbiota in the Genesis of Major Depression and the Response to Antidepressant Drug Therapy: A Narrative Review. Biomedicines 2023; 11:550. [PMID: 36831086 PMCID: PMC9953611 DOI: 10.3390/biomedicines11020550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
A major depressive disorder is a serious mental illness characterized by a pervasive low mood that negatively concerns personal life, work life, or education, affecting millions of people worldwide. To date, due to the complexity of the disease, the most common and effective treatments consist of a multi-therapy approach, including psychological, social, and pharmacological support with antidepressant drugs. In general, antidepressants are effective in correcting chemical imbalances of neurotransmitters in the brain, but recent evidence has underlined the pivotal role of gut microbiota (GM) also in the regulation of their pharmacokinetics/pharmacodynamics, through indirect or direct mechanisms. The study of these complex interactions between GM and drugs is currently under the spotlight, and it has been recently named "pharmacomicrobiomics". Hence, the purpose of this review is to summarize the contribution of GM and its metabolites in depression, as well as their role in the metabolism and activity of antidepressant drugs, in order to pave the way for the personalized administration of antidepressant therapies.
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Affiliation(s)
- Tiziana Mundula
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elisabetta Gerace
- Department of Health Sciences, Clinical Pharmacology and Oncology Unit, University of Florence, 50139 Florence, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Interdisciplinary Internal Medicine Unit, Careggi University Hospital, 50134 Florence, Italy
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8
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Nies AT, Schaeffeler E, Schwab M. Hepatic solute carrier transporters and drug therapy: Regulation of expression and impact of genetic variation. Pharmacol Ther 2022; 238:108268. [DOI: 10.1016/j.pharmthera.2022.108268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/25/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
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9
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van Deuren T, Blaak EE, Canfora EE. Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use. Obes Rev 2022; 23:e13498. [PMID: 35856338 PMCID: PMC9541926 DOI: 10.1111/obr.13498] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/04/2022] [Accepted: 06/28/2022] [Indexed: 12/17/2022]
Abstract
Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid butyrate, a major end product of the bacterial fermentation of indigestible carbohydrates, is reputed to have anti-inflammatory properties and positive effects on body weight control and insulin sensitivity. However, whether butyrate has therapeutic potential for the treatment and prevention of obesity and obesity-related complications remains to be elucidated. Overall, animal studies strongly indicate that butyrate administered via various routes (e.g., orally) positively affects adipose tissue metabolism and functioning, energy and substrate metabolism, systemic and tissue-specific inflammation, and insulin sensitivity and body weight control. A limited number of human studies demonstrated interindividual differences in clinical effectiveness suggesting that outcomes may depend on the metabolic, microbial, and lifestyle-related characteristics of the target population. Hence, despite abundant evidence from animal data, support of human data is urgently required for the implementation of evidence-based oral and gut-derived butyrate interventions. To increase the efficacy of butyrate-focused interventions, future research should investigate which factors impact treatment outcomes including baseline gut microbial activity and functionality, thereby optimizing targeted-interventions and identifying individuals that merit most from such interventions.
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Affiliation(s)
- Thirza van Deuren
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Ellen E Blaak
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Emanuel E Canfora
- Department of Human Biology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
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10
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Ali Q, Ma S, La S, Guo Z, Liu B, Gao Z, Farooq U, Wang Z, Zhu X, Cui Y, Li D, Shi Y. Microbial short-chain fatty acids: a bridge between dietary fibers and poultry gut health. Anim Biosci 2022; 35:1461-1478. [PMID: 35507857 PMCID: PMC9449382 DOI: 10.5713/ab.21.0562] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/18/2022] [Indexed: 11/27/2022] Open
Abstract
The maintenance of poultry gut health is complex depending on the intricate balance among diet, the commensal microbiota, and the mucosa, including the gut epithelium and the superimposing mucus layer. Changes in microflora composition and abundance can confer beneficial or detrimental effects on fowl. Antibiotics have devastating impacts on altering the landscape of gut microbiota, which further leads to antibiotic resistance or spread the pathogenic populations. By eliciting the landscape of gut microbiota, strategies should be made to break down the regulatory signals of pathogenic bacteria. The optional strategy of conferring dietary fibers (DFs) can be used to counterbalance the gut microbiota. DFs are the non-starch carbohydrates indigestible by host endogenous enzymes but can be fermented by symbiotic microbiota to produce short-chain fatty acids (SCFAs). This is one of the primary modes through which the gut microbiota interacts and communicate with the host. The majority of SCFAs are produced in the large intestine (particularly in the caecum), where they are taken up by the enterocytes or transported through portal vein circulation into the bloodstream. Recent shreds of evidence have elucidated that SCFAs affect the gut and modulate the tissues and organs either by activating G-protein-coupled receptors or affecting epigenetic modifications in the genome through inducing histone acetylase activities and inhibiting histone deacetylases. Thus, in this way, SCFAs vastly influence poultry health by promoting energy regulation, mucosal integrity, immune homeostasis, and immune maturation. In this review article, we will focus on DFs, which directly interact with gut microbes and lead to the production of SCFAs. Further, we will discuss the current molecular mechanisms of how SCFAs are generated, transported, and modulated the pro-and anti-inflammatory immune responses against pathogens and host physiology and gut health.
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11
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Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates. Front Pharmacol 2022; 12:802539. [PMID: 35095509 PMCID: PMC8793843 DOI: 10.3389/fphar.2021.802539] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022] Open
Abstract
Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.
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Affiliation(s)
- Erkka Järvinen
- Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Feng Deng
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Wilma Kiander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Alli Sinokki
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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12
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Yee SW, Giacomini KM. Emerging Roles of the Human Solute Carrier 22 Family. Drug Metab Dispos 2021; 50:DMD-MR-2021-000702. [PMID: 34921098 PMCID: PMC9488978 DOI: 10.1124/dmd.121.000702] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/22/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022] Open
Abstract
The human Solute Carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi-membrane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs) and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmacologically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several including the renal transporters, OCT2, OAT1 and OAT3 are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters (SLC22A5 (OCTN2) and SLC22A12 (URAT1) lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response and various phenotypic traits. Three members in this family were deorphaned in very recently: SLC22A14, SLC22A15 and SLC22A24, and found to transport specific compounds such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid conjugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the substrates, expression patterns and transporter mechanisms of individual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described. Significance Statement In recent years, three members of the SLC22 family of transporters have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understanding of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides overview of SLC22 family members of their physiologic and pharmacologic roles, the impact of genetic variants in the SLC22 family on disease and drug response, and summary of recent studies deorphaning SLC22 family members.
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Affiliation(s)
- Sook Wah Yee
- Bioengineering and Therapeutic Sciences, Univerity of California, San Francisco, United States
| | - Kathleen M Giacomini
- Bioengineering and Therapeutic Sciences, Univerity of California, San Francisco, United States
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13
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Zhang M, Wang Y, Zhao X, Liu C, Wang B, Zhou J. Mechanistic basis and preliminary practice of butyric acid and butyrate sodium to mitigate gut inflammatory diseases: a comprehensive review. Nutr Res 2021; 95:1-18. [PMID: 34757305 DOI: 10.1016/j.nutres.2021.08.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/19/2021] [Accepted: 08/26/2021] [Indexed: 01/02/2023]
Abstract
A key event featured in the early stage of chronic gut inflammatory diseases is the disordered recruitment and excess accumulation of immune cells in the gut lamina propria. This process is followed by the over-secretion of pro-inflammatory factors and the prolonged overactive inflammatory responses. Growing evidence has suggested that gut inflammatory diseases may be mitigated by butyric acid (BA) or butyrate sodium (NaB). Laboratory studies show that BA and NaB can enhance gut innate immune function through G-protein-mediated signaling pathways while mitigating the overactive inflammatory responses by inhibiting histone deacetylase. The regulatory effects may occur in both epithelial enterocytes and the immune cells in the lamina propria. Prior to further clinical trials, comprehensive literature reviews and rigid examination concerning the underlying mechanism are necessary. To this end, we collected and reviewed 197 published reports regarding the mechanisms, bioactivities, and clinical effects of BA and NaB to modulate gut inflammatory diseases. Our review found insufficient evidence to guarantee the safety of clinical practice of BA and NaB, either by anal enema or oral administration of capsule or tablet. The safety of clinical use of BA and NaB should be further evaluated. Alternatively, dietary patterns rich in "fruits, vegetables and beans" may be an effective and safe approach to prevent gut inflammatory disease, which elevates gut microbiota-dependent production of BA. Our review provides a comprehensive reference to future clinical trials of BA and NaB to treat gut inflammatory diseases.
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Affiliation(s)
- Mingbao Zhang
- Department of Gastroenterology and Hepatology, Second Hospital of Shandong University, Shandong University, 250012 China
| | - Yanan Wang
- Department of Gastroenterology and Hepatology, Second Hospital of Shandong University, Shandong University, 250012 China
| | - Xianqi Zhao
- School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China
| | - Chang Liu
- School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China
| | - Baozhen Wang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China.
| | - Jun Zhou
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012 China.
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14
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Boocock J, Leask M, Okada Y, Matsuo H, Kawamura Y, Shi Y, Li C, Mount DB, Mandal AK, Wang W, Cadzow M, Gosling AL, Major TJ, Horsfield JA, Choi HK, Fadason T, O'Sullivan J, Stahl EA, Merriman TR. Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control. Hum Mol Genet 2021; 29:923-943. [PMID: 31985003 DOI: 10.1093/hmg/ddaa013] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/23/2019] [Accepted: 01/20/2020] [Indexed: 12/17/2022] Open
Abstract
High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control; however, there has been little progress in understanding the molecular basis of the associated loci. Here, we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify 10 new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new candidate loci. By cis- and trans-eQTL colocalization analysis, we identified 34 and 20 genes, respectively, where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Functional fine mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1 and HNF4G) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.
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Affiliation(s)
- James Boocock
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Megan Leask
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.,Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
| | | | - Hirotaka Matsuo
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yusuke Kawamura
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yongyong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiaric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Changgui Li
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - David B Mount
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA.,Renal Division, VA Boston Healthcare System, Harvard Medical School, Boston MA, USA
| | - Asim K Mandal
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA
| | - Weiqing Wang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, NY, USA
| | - Murray Cadzow
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Anna L Gosling
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Tanya J Major
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Julia A Horsfield
- Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand
| | - Hyon K Choi
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tayaza Fadason
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - Eli A Stahl
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, NY, USA
| | - Tony R Merriman
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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15
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Du K, Bereswill S, Heimesaat MM. A literature survey on antimicrobial and immune-modulatory effects of butyrate revealing non-antibiotic approaches to tackle bacterial infections. Eur J Microbiol Immunol (Bp) 2021; 11:1-9. [PMID: 33735105 PMCID: PMC8042652 DOI: 10.1556/1886.2021.00001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
The excessive prescription of antibiotics has led to an increasing number of antimicrobial resistances, posing a major public health concern. Therefore, the pharmacological research has shifted its focus to the identification of natural compounds that exhibit anti-pathogenic properties without triggering antibiotic resistance. Butyrate has received increasing attention as a promising candidate for the treatment of bacterial infections in the gastrointestinal tract, particularly when antibiotic treatment is contraindicated. This literature survey summarizes recently investigated antibacterial and immunemodulatory effects of butyrate. This survey revealed that butyrate exerts direct antimicrobial effects against distinct strains of Acinetobacter baumannii, Escherichia coli, Bacillus, and Staphylococcus species. In addition, in vitro and in vivo studies confirmed indirect antimicrobial effects of butyrate, which were exhibited via induction of host defensin production as well as by activation of innate and adaptive immune responses. Finally, the synergistic action of butyrate in combination with other antimicrobial compounds results in a striking clearance of bacterial pathogens. In conclusion, butyrate and its derivatives might be considered as promising antibacterial and immune-modulatory agents in order to tackle bacterial infections without antibiotics.
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Affiliation(s)
- Ke Du
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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16
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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17
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Rea K, Dinan TG, Cryan JF. Gut Microbiota: A Perspective for Psychiatrists. Neuropsychobiology 2020; 79:50-62. [PMID: 31726457 DOI: 10.1159/000504495] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/31/2019] [Indexed: 11/19/2022]
Abstract
There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.
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Affiliation(s)
- Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland, .,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland,
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18
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Nies AT, Weiss S, Schaeffeler E, Hannemann A, Völker U, Wallaschofski H, Schwab M. The Membrane Transporter OAT7 (SLC22A9) Is Not a Susceptibility Factor for Osteoporosis in Europeans. Front Endocrinol (Lausanne) 2020; 11:532. [PMID: 33013684 PMCID: PMC7461822 DOI: 10.3389/fendo.2020.00532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/30/2020] [Indexed: 01/14/2023] Open
Abstract
Bone production, maintenance, and modeling are a well-balanced process involving mineralization by osteoblasts and resorption by osteoclasts. Sex steroid hormones, including their conjugated forms, contribute majorly to maintaining this balance. Recently, variants in the SLC22A9 gene have been associated with osteoporosis in Korean females. We had recently shown that SLC22A9, encoding organic anion transporter 7 (OAT7), is an uptake transporter of estrone sulfate and identified several genetic variants in Europeans leading to functional consequences in vitro. We therefore hypothesized that SLC22A9 genetic variants may contribute to the pathophysiology of osteoporosis in Europeans. To test this hypothesis, we examined the associations of SLC22A9 variants with bone quality, fractures, and bone turnover markers. We genotyped SLC22A9 variants in 5,701 (2,930 female) subjects (age range, 20-93 years) extracted from the population-based Study of Health in Pomerania (SHIP and SHIP-TREND) covered by the Illumina Infinium HumanExome BeadChip version v1.0 (Exome Chip). Descriptive data (e.g., history of fractures), ultrasonography of the calcaneus, as well as serum concentrations of carboxy-terminal telopeptide of type I collagen, amino-terminal propeptide of type I procollagen, and vitamin D were determined. Comprehensive statistical analyses revealed no association between low-frequency and rare SLC22A9 variants and bone quality, fractures, and bone turnover markers. Our results indicate that single genetic SLC22A9 variants do not have a major impact on osteoporosis risk prediction in Europeans, yet findings need to be replicated in larger-scale studies.
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Affiliation(s)
- Anne T. Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald and University of Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Anke Hannemann
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald and University of Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Henri Wallaschofski
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
- Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
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19
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Engelhart DC, Granados JC, Shi D, Saier MH, Baker ME, Abagyan R, Nigam SK. Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs. Int J Mol Sci 2020; 21:E1791. [PMID: 32150922 PMCID: PMC7084758 DOI: 10.3390/ijms21051791] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 02/07/2023] Open
Abstract
The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.
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Affiliation(s)
- Darcy C. Engelhart
- Department of Biology, University of California San Diego, San Diego, CA 92093, USA;
| | - Jeffry C. Granados
- Department of Bioengineering, University of California San Diego, San Diego, CA 92093, USA;
| | - Da Shi
- School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA 92093, USA; (D.S.); (R.A.)
| | - Milton H. Saier
- Department of Molecular Biology, Division of Biological Sciences, University of California San Diego, San Diego, CA 92093, USA;
| | - Michael E. Baker
- Department of Medicine, University of California San Diego, San Diego, CA 92093, USA;
| | - Ruben Abagyan
- School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA 92093, USA; (D.S.); (R.A.)
| | - Sanjay K. Nigam
- Department of Medicine, University of California San Diego, San Diego, CA 92093, USA;
- Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA
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20
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Li TT, An JX, Xu JY, Tuo BG. Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver. World J Clin Cases 2019; 7:3915-3933. [PMID: 31832394 PMCID: PMC6906560 DOI: 10.12998/wjcc.v7.i23.3915] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 02/05/2023] Open
Abstract
Organic anion transporters (OATs) and organic anion transporter polypeptides (OATPs) are classified within two SLC superfamilies, namely, the SLC22A superfamily and the SLCO superfamily (formerly the SLC21A family), respectively. They are expressed in many tissues, such as the liver and kidney, and mediate the absorption and excretion of many endogenous and exogenous substances, including various drugs. Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm. OATs and OATPs are abundantly expressed in the liver, where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs. However, differences in the locations of glycosylation sites, phosphorylation sites, and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver, which ultimately results in their different roles in the liver. To date, few articles have addressed these aspects of OAT and OATP structures, and we study further the similarities and differences in their structures, tissue distribution, substrates, and roles in liver diseases.
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Affiliation(s)
- Ting-Ting Li
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jia-Xing An
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Bi-Guang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
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Pan G. Roles of Hepatic Drug Transporters in Drug Disposition and Liver Toxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1141:293-340. [PMID: 31571168 DOI: 10.1007/978-981-13-7647-4_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatic drug transporters are mainly distributed in parenchymal liver cells (hepatocytes), contributing to drug's liver disposition and elimination. According to their functions, hepatic transporters can be roughly divided into influx and efflux transporters, translocating specific molecules from blood into hepatic cytosol and mediating the excretion of drugs and metabolites from hepatic cytosol to blood or bile, respectively. The function of hepatic transport systems can be affected by interspecies differences and inter-individual variability (polymorphism). In addition, some drugs and disease can redistribute transporters from the cell surface to the intracellular compartments, leading to the changes in the expression and function of transporters. Hepatic drug transporters have been associated with the hepatic toxicity of drugs. Gene polymorphism of transporters and altered transporter expressions and functions due to diseases are found to be susceptible factors for drug-induced liver injury (DILI). In this chapter, the localization of hepatic drug transporters, their regulatory factors, physiological roles, and their roles in drug's liver disposition and DILI are reviewed.
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Affiliation(s)
- Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, Shanghai, China.
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22
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Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99:1877-2013. [PMID: 31460832 DOI: 10.1152/physrev.00018.2018] [Citation(s) in RCA: 2692] [Impact Index Per Article: 448.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
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Affiliation(s)
- John F. Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kenneth J. O'Riordan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitlin S. M. Cowan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kiran V. Sandhu
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Thomaz F. S. Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcus Boehme
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Martin G. Codagnone
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Sofia Cussotto
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Christine Fulling
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Anna V. Golubeva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Katherine E. Guzzetta
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Minal Jaggar
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitriona M. Long-Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joshua M. Lyte
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Jason A. Martin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Alicia Molinero-Perez
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emanuela Morelli
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Enrique Morillas
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Rory O'Connor
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joana S. Cruz-Pereira
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Veronica L. Peterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Nathaniel L. Ritz
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Eoin Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Simon Spichak
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emily M. Teichman
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcel van de Wouw
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Ana Paula Ventura-Silva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Shauna E. Wallace-Fitzsimons
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Niall Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
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23
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Abstract
Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.
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24
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Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population. J Hum Genet 2019; 64:473-480. [PMID: 30824882 DOI: 10.1038/s10038-019-0586-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/24/2019] [Accepted: 02/12/2019] [Indexed: 12/14/2022]
Abstract
Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10-7). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10-8) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.
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25
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Wagner JB, Abdel-Rahman S, Gaedigk R, Gaedigk A, Raghuveer G, Staggs VS, Kauffman R, Van Haandel L, Leeder JS. Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia. Clin Pharmacol Ther 2019; 105:1501-1512. [PMID: 30549267 DOI: 10.1002/cpt.1330] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 11/20/2018] [Indexed: 11/07/2022]
Abstract
This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.
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Affiliation(s)
- Jonathan B Wagner
- Ward Family Heart Center, Children's Mercy, Kansas City, Missouri, USA
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Susan Abdel-Rahman
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Roger Gaedigk
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Andrea Gaedigk
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Geetha Raghuveer
- Ward Family Heart Center, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Vincent S Staggs
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
- Health Services & Outcomes Research, Children's Mercy, Kansas City, Missouri, USA
| | - Ralph Kauffman
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Leon Van Haandel
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - J Steven Leeder
- Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
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Vildhede A, Kimoto E, Rodrigues AD, Varma MVS. Quantification of Hepatic Organic Anion Transport Proteins OAT2 and OAT7 in Human Liver Tissue and Primary Hepatocytes. Mol Pharm 2018; 15:3227-3235. [PMID: 29906129 DOI: 10.1021/acs.molpharmaceut.8b00320] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Organic anion transporter (OAT) 2 and OAT7 were recently shown to be involved in the hepatic uptake of drugs; however, there is limited understanding of the population variability in the expression of these transporters in liver. There is also a need to derive relative expression-based scaling factors (REFs) that can be used to bridge in vitro functional data to the in vivo drug disposition. To this end, we quantified OAT2 and OAT7 surrogate peptide abundance in a large number of human liver tissue samples ( n = 52), as well as several single-donor cryopreserved human hepatocyte lots ( n = 30) by a novel, validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The average surrogate peptide expression of OAT2 and OAT7 in the liver samples was 1.52 ± 0.57 and 4.63 ± 1.58 fmol/μg membrane protein, respectively. While we noted statistically significant differences ( p < 0.05) in hepatocyte and liver tissue abundances for both OAT2 and OAT7, the differences were relatively small (1.8- and 1.5-fold difference in median values, respectively). Large interindividual variability was noted in the hepatic expression of OAT2 (16-fold in liver tissue and 23-fold in hepatocytes). OAT7, on the other hand, showed less interindividual variability (4-fold) in the livers, but high variability for the hepatocyte lots (27-fold). A significant positive correlation in OAT2 and OAT7 expression was observed, but expression levels were neither associated with age nor sex. In conclusion, our data suggest marked interindividual variability in the hepatic expression of OAT2/7, which may contribute to the pharmacokinetic variability of their substrates. Because both transporters were less abundant in hepatocytes than livers, a REF-based approach is recommended when scaling in vitro hepatocyte transport data to predict hepatic drug clearance and liver exposure of OAT2/7 substrates.
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Affiliation(s)
- Anna Vildhede
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design , Pfizer Worldwide R&D , Groton , Connecticut 06340 , United States
| | - Emi Kimoto
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design , Pfizer Worldwide R&D , Groton , Connecticut 06340 , United States
| | - A David Rodrigues
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design , Pfizer Worldwide R&D , Groton , Connecticut 06340 , United States
| | - Manthena V S Varma
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design , Pfizer Worldwide R&D , Groton , Connecticut 06340 , United States
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27
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Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition. J Pers Med 2018; 8:jpm8020014. [PMID: 29659532 PMCID: PMC6023491 DOI: 10.3390/jpm8020014] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.
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28
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Mathialagan S, Costales C, Tylaska L, Kimoto E, Vildhede A, Johnson J, Johnson N, Sarashina T, Hashizume K, Isringhausen CD, Vermeer LMM, Wolff AR, Rodrigues AD. In vitro studies with two human organic anion transporters: OAT2 and OAT7. Xenobiotica 2017; 48:1037-1049. [DOI: 10.1080/00498254.2017.1384595] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Sumathy Mathialagan
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Chester Costales
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Laurie Tylaska
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Emi Kimoto
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Anna Vildhede
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Jillian Johnson
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | - Nathaniel Johnson
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
| | | | | | | | | | | | - A. David Rodrigues
- Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc, Groton, CT, USA,
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29
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Patel M, Taskar KS, Zamek-Gliszczynski MJ. Importance of Hepatic Transporters in Clinical Disposition of Drugs and Their Metabolites. J Clin Pharmacol 2017; 56 Suppl 7:S23-39. [PMID: 27385177 DOI: 10.1002/jcph.671] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/16/2015] [Indexed: 01/04/2023]
Abstract
This review provides a practical clinical perspective on the relevance of hepatic transporters in pharmacokinetics and drug-drug interactions (DDIs). Special emphasis is placed on transporters with clear relevance to clinical DDIs, efficacy, and safety. Basolateral OATP1B1 and 1B3 emerged as important hepatic drug uptake pathways, sites for systemic DDIs, and sources of pharmacogenetic variability. As the first step in hepatic drug removal from the circulation, OATPs are an important determinant of systemic pharmacokinetics, specifically influencing systemic absorption, clearance, and hepatic distribution for subsequent metabolism and/or excretion. Biliary excretion of parent drugs is a less prevalent clearance pathway than metabolism or urinary excretion, but BCRP and MRP2 are critically important to biliary/fecal elimination of drug metabolites. Inhibition of biliary excretion is typically not apparent at the level of systemic pharmacokinetics but can markedly increase liver exposure. Basolateral efflux transporters MRP3 and MRP4 mediate excretion of parent drugs and, more commonly, polar metabolites from hepatocytes into blood. Basolateral excretion is an area in need of further clinical investigation, which will necessitate studies more complex than just systemic pharmacokinetics. Clinical relevance of hepatic uptake is relatively well appreciated, and clinical consequences of hepatic excretion (biliary and basolateral) modulation remain an active research area.
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Affiliation(s)
- Mitesh Patel
- Mechanistic Safety and Disposition, GlaxoSmithKline, King of Prussia, PA, USA
| | - Kunal S Taskar
- Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, Hertfordshire, UK
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Zhou F, Zhu L, Wang K, Murray M. Recent advance in the pharmacogenomics of human Solute Carrier Transporters (SLCs) in drug disposition. Adv Drug Deliv Rev 2017; 116:21-36. [PMID: 27320645 DOI: 10.1016/j.addr.2016.06.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/01/2016] [Accepted: 06/08/2016] [Indexed: 12/11/2022]
Abstract
Drug pharmacokinetics is influenced by the function of metabolising enzymes and influx/efflux transporters. Genetic variability of these genes is known to impact on clinical therapies. Solute Carrier Transporters (SLCs) are the primary influx transporters responsible for the cellular uptake of drug molecules, which consequently, impact on drug efficacy and toxicity. The Organic Anion Transporting Polypeptides (OATPs), Organic Anion Transporters (OATs) and Organic Cation Transporters (OCTs/OCTNs) are the most important SLCs involved in drug disposition. The information regarding the influence of SLC polymorphisms on drug pharmacokinetics is limited and remains a hot topic of pharmaceutical research. This review summarises the recent advance in the pharmacogenomics of SLCs with an emphasis on human OATPs, OATs and OCTs/OCTNs. Our current appreciation of the degree of variability in these transporters may contribute to better understanding the inter-patient variation of therapies and thus, guide the optimisation of clinical treatments.
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Thakkar N, Slizgi JR, Brouwer KLR. Effect of Liver Disease on Hepatic Transporter Expression and Function. J Pharm Sci 2017; 106:2282-2294. [PMID: 28465155 DOI: 10.1016/j.xphs.2017.04.053] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/20/2017] [Accepted: 04/21/2017] [Indexed: 12/27/2022]
Abstract
Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.
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Affiliation(s)
- Nilay Thakkar
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Jason R Slizgi
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
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Shen H, Lai Y, Rodrigues AD. Organic Anion Transporter 2: An Enigmatic Human Solute Carrier. Drug Metab Dispos 2017; 45:228-236. [PMID: 27872146 DOI: 10.1124/dmd.116.072264] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 11/17/2016] [Indexed: 12/28/2022] Open
Abstract
As a member of the solute carrier 22A (SLC22A) family, organic anion transporter 2 (OAT2; SLC22A7) is emerging as an important drug transporter because of its expression in both the liver and kidney, two major eliminating organs, and its ability to transport not only a wide variety of xenobiotics but also numerous physiologically important endogenous compounds, like creatinine and cGMP. However, OAT2 has received relatively little attention compared with other OATs and solute carriers (SLCs), like organic cation transporters, sodium-dependent taurocholate cotransporting polypeptide, multidrug and toxin extrusion proteins, and organic anion-transporting polypeptides. Overall, the literature describing OAT2 is rapidly evolving, with numerous publications contradicting each other regarding the transport mechanism, tissue distribution, and transport of creatinine and cGMP, two important endogenous OAT2 substrates. Despite its status as a liver and kidney SLC, tools for assessing its activity and inhibition are lacking, and its role in drug disposition and elimination remains to be defined. The current review focuses on the available and emerging literature describing OAT2. We envision that OAT2 will gain more prominence as its expression, substrate, and inhibitor profile is investigated further and compared with other SLCs.
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Affiliation(s)
- Hong Shen
- Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (H.S., Y.L.), and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer World Wide Research and Development, Groton, Connecticut (A.D.R.)
| | - Yurong Lai
- Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (H.S., Y.L.), and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer World Wide Research and Development, Groton, Connecticut (A.D.R.)
| | - A David Rodrigues
- Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (H.S., Y.L.), and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer World Wide Research and Development, Groton, Connecticut (A.D.R.)
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Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells. Pharmaceutics 2016; 9:pharmaceutics9010003. [PMID: 28036031 PMCID: PMC5374369 DOI: 10.3390/pharmaceutics9010003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/17/2016] [Accepted: 12/22/2016] [Indexed: 12/31/2022] Open
Abstract
Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP) activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP), organic anion-transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1), and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP). Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2), OCT1 and bile salt export pump) or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3) in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR)- and nuclear factor erythroid 2-related factor 2 (Nrf2)-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation.
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Sharma M, Shukla G. Metabiotics: One Step ahead of Probiotics; an Insight into Mechanisms Involved in Anticancerous Effect in Colorectal Cancer. Front Microbiol 2016; 7:1940. [PMID: 27994577 PMCID: PMC5133260 DOI: 10.3389/fmicb.2016.01940] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 11/18/2016] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is closely associated with environment, diet and lifestyle. Normally it is treated with surgery, radiotherapy or chemotherapy but increasing systemic toxicity, resistance and recurrence is prompting scientists to devise new potent and safer alternate prophylactic or therapeutic strategies. Among these, probiotics, prebiotics, synbiotics, and metabiotics are being considered as the promising candidates. Metabiotics or probiotic derived factors can optimize various physiological functions of the host and offer an additional advantage to be utilized even in immunosuppressed individuals. Interestingly, anti colon cancer potential of probiotic strains has been attributable to metabiotics that have epigenetic, antimutagenic, immunomodulatory, apoptotic, and antimetastatic effects. Thus, it's time to move one step further to utilize metabiotics more smartly by avoiding the risks associated with probiotics even in certain normal/or immuno compromised host. Here, an attempt is made to provide insight into the adverse effects associated with probiotics and beneficial aspects of metabiotics with main emphasis on the modulatory mechanisms involved in colon cancer.
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Affiliation(s)
- Mridul Sharma
- Department of Microbiology, Panjab University Chandigarh, India
| | - Geeta Shukla
- Department of Microbiology, Panjab University Chandigarh, India
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Genotyping of coding single nucleotide variants of the hOAT2[SLC22A7] gene in Japanese patients with non-viral liver tumor. GENE REPORTS 2016. [DOI: 10.1016/j.genrep.2016.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
Cells need to strictly control their internal milieu, a function which is performed by the plasma membrane. Selective passage of molecules across the plasma membrane is controlled by transport proteins. As the liver is the central organ for drug metabolism, hepatocytes are equipped with numerous drug transporters expressed at the plasma membrane. Drug disposition includes absorption, distribution, metabolism, and elimination of a drug and hence multiple passages of drugs and their metabolites across membranes. Consequently, understanding the exact mechanisms of drug transporters is essential both in drug development and in drug therapy. While many drug transporters are expressed in hepatocytes, and some of them are well characterized, several transporters have only recently been identified as new drug transporters. Novel powerful tools to deorphanize (drug) transporters are being applied and show promising results. Although a large set of tools are available for studying transport in vitro and in isolated cells, tools for studying transport in living organisms, including humans, are evolving now and rely predominantly on imaging techniques, e.g. positron emission tomography. Imaging is an area which, certainly in the near future, will provide important insights into "transporters at work" in vivo.
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Affiliation(s)
- Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland
| | - Bruno Hagenbuch
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, 66160, USA
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Stilling RM, van de Wouw M, Clarke G, Stanton C, Dinan TG, Cryan JF. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int 2016; 99:110-132. [DOI: 10.1016/j.neuint.2016.06.011] [Citation(s) in RCA: 587] [Impact Index Per Article: 65.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/30/2016] [Accepted: 06/21/2016] [Indexed: 02/07/2023]
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Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 2016; 6:363-373. [PMID: 27709005 PMCID: PMC5045553 DOI: 10.1016/j.apsb.2016.07.013] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 06/30/2016] [Accepted: 07/07/2016] [Indexed: 12/12/2022] Open
Abstract
The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug-drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.
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Key Words
- ABC, ATP-binding cassette
- ATP, adenosine triphosphate
- AUC, area under the plasma concentration curve
- BBB, blood–brain barrier
- CHO, Chinese hamster ovary
- CL, plasma clearance
- CLR, renal clearance
- Cmax, maximum plasma concentration
- DDIs, drug–drug interactions
- Drug–drug interactions
- FDA, U.S. Food and Drug Administration
- GSH, glutathione
- HEK, human embryonic kidney
- IC50, half maximal inhibitory concentration
- ITC, International Transporter Consortium
- Ki, inhibitory constant
- MATE, multidrug and toxin extrusion protein
- MPP+, 1-methyl-4-phenylpyridimium
- MRP, multidrug resistance-associated protein
- MSD, membrane-spanning domain
- MW, molecular weight
- NBD, nucleotide-binding domain
- NME, new molecular entity
- NSAID, non-steroidal anti-inflammatory drugs
- Nephrotoxicity
- OA, organic anion
- OAT or Oat, organic anion transporters
- OATP or Oatp, organic anion-transporting peptide
- OC, organic cation
- OCT or Oct, organic cation transporter
- OCTN, Organic zwitterions/cation transporters
- Organic anions
- Organic cations
- P-gp, P-glycoprotein
- PAH, p-aminohippurate
- Renal drug transporters
- SLC, solute carrier
- SNP, single-nucleotide polymorphism
- TEA, tetraethylammonium
- TMD, transmembrane domain
- URAT, urate transporter
- fe, fraction of the absorbed dose excreted unchanged in urine
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Ktsoyan ZA, Mkrtchyan MS, Zakharyan MK, Mnatsakanyan AA, Arakelova KA, Gevorgyan ZU, Sedrakyan AM, Hovhannisyan AI, Arakelyan AA, Aminov RI. Systemic Concentrations of Short Chain Fatty Acids Are Elevated in Salmonellosis and Exacerbation of Familial Mediterranean Fever. Front Microbiol 2016; 7:776. [PMID: 27252692 PMCID: PMC4877380 DOI: 10.3389/fmicb.2016.00776] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Gut microbiota-produced short chain fatty acids (SCFAs) play an important role in the normal human metabolism and physiology. Although the gradients of SCFAs from the large intestine, where they are largely produced, to the peripheral blood as well as the main routes of SCFA metabolism by different organs are known well for the healthy state, there is a paucity of information regarding how these are affected in disease. In particular, how the inflammation caused by infection or autoinflammatory disease affect the concentration of SCFAs in the peripheral venous blood. In this work, we revealed that diseases caused either by infectious agents (two Salmonella enterica serovars, S. Enteritidis, and S. Typhimurium) or by the exacerbation of an autoinflammatory disease, familial Mediterranean fever (FMF), both result in a significantly elevated systemic concentration of SCFAs. In the case of salmonellosis the concentration of SCFAs in peripheral blood was significantly and consistently higher, from 5- to 20-fold, compared to control. In the case of FMF, however, a significant increase of SCFAs in the peripheral venous blood was detected only in the acute phase of the disease, with a lesser impact in remission. It seems counterintuitive that the dysbiotic conditions, with a reduced number of gut microorganisms, produce such an effect. This phenomenon, however, must be appraised within the context of how the inflammatory diseases affect the normal physiology. We discuss a number of factors that may contribute to the “leak” and persistence of gut-produced SCFAs into the systemic circulation in infectious and autoinflammatory diseases.
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Affiliation(s)
- Zhanna A Ktsoyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Mkhitar S Mkrtchyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Magdalina K Zakharyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Armine A Mnatsakanyan
- Clinical Hospital of Infectious Diseases Nork, Ministry of Health of Republic of Armenia Yerevan, Armenia
| | - Karine A Arakelova
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Zaruhi U Gevorgyan
- Clinical Hospital of Infectious Diseases Nork, Ministry of Health of Republic of Armenia Yerevan, Armenia
| | - Anahit M Sedrakyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Alvard I Hovhannisyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Arsen A Arakelyan
- Institute of Molecular Biology of National Academy of Sciences of Republic of Armenia Yerevan, Armenia
| | - Rustam I Aminov
- School of Medicine and Dentistry, University of Aberdeen Aberdeen, UK
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Richards L, Li M, van Esch B, Garssen J, Folkerts G. The effects of short-chain fatty acids on the cardiovascular system. PHARMANUTRITION 2016. [DOI: 10.1016/j.phanu.2016.02.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Estudante M, Soveral G, Morais JG, Benet LZ. Insights into solute carriers: physiological functions and implications in disease and pharmacokinetics. MEDCHEMCOMM 2016. [DOI: 10.1039/c6md00188b] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SLCs transport many endogenous and exogenous compounds including drugs; SLCs dysfunction has implications in pharmacokinetics, drug toxicity or lack of efficacy.
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Affiliation(s)
- Margarida Estudante
- Department of Pharmacological Sciences
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
- Research Institute for Medicines (iMed.ULisboa)
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa)
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
| | - José G. Morais
- Department of Pharmacological Sciences
- Faculty of Pharmacy
- Universidade de Lisboa
- Portugal
- Research Institute for Medicines (iMed.ULisboa)
| | - Leslie Z. Benet
- Department of Bioengineering and Therapeutic Sciences
- University of California
- San Francisco
- USA
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42
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Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors. THE PHARMACOGENOMICS JOURNAL 2015; 16:341-51. [PMID: 26239079 DOI: 10.1038/tpj.2015.55] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 05/26/2015] [Accepted: 06/23/2015] [Indexed: 02/07/2023]
Abstract
Human organic anion transporter 7 (OAT7, SLC22A9) is a hepatic transport protein poorly characterized so far. We therefore sought to identify novel OAT7 substrates and factors contributing to variable hepatic OAT7 expression. Using OAT7-expressing cells, pravastatin was identified as a substrate. Hepatic SLC22A9/OAT7 mRNA and protein expression varied 28-fold and 15-fold, respectively, in 126 Caucasian liver samples. Twenty-four variants in SLC22A9 were genotyped, including three rare missense variants (rs377211288, rs61742518, rs146027075), which occurred only heterozygously. No variant significantly affected hepatic SLC22A9/OAT7 expression. The three missense variants, however, showed functional consequences when expressed in vitro. Hepatic nuclear factor 4-alpha (HNF4α) emerged as a major transcriptional regulator of SLC22A9 by a series of in silico and in vitro analyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4α, may contribute to pravastatin drug disposition and might affect response.The Pharmacogenomics Journal advance online publication, 4 August 2015; doi:10.1038/tpj.2015.55.
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Ahn SK, Suh CK, Cha SH. Polymorphisms of SLC22A9 (hOAT7) in Korean Females with Osteoporosis. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2015; 19:319-25. [PMID: 26170735 PMCID: PMC4499643 DOI: 10.4196/kjpp.2015.19.4.319] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 03/05/2015] [Accepted: 03/05/2015] [Indexed: 11/15/2022]
Abstract
Among solute carrier proteins, the organic anion transporters (OATs) play an important role for the elimination or reabsorption of endogenous and exogenous negatively charged anionic compounds. Among OATs, SLC22A9 (hOAT7) transports estrone sulfate with high affinity. The net decrease of estrogen, especially in post-menopausal women induces rapid bone loss. The present study was performed to search the SNP within exon regions of SLC22A9 in Korean females with osteoporosis. Fifty healthy controls and 50 osteoporosis patients were screened for the genetic polymorphism in the coding region of SLC22A9 using GC-clamped PCR and denaturing gradient gel electrophoresis (DGGE). Six SNPs were found on the SLC22A9 gene from Korean women with/without osteoporosis. The SNPs were located as follows: two SNPs in the osteoporosis group (A645G and T1277C), three SNPs in the control group (G1449T, C1467T and C1487T) and one SNP in both the osteoporosis and control groups (G767A). The G767A, T1277C and C1487T SNPs result in an amino acid substitution, from synonymous vs nonsynonymous substitution arginine to glutamine (R256Q), phenylalanine to serine (F426S) and proline to leucine (P496L), respectively. The Km values and Vmax of the wild type, R256Q, P496L and F426S were 8.84, 8.87, 9.83 and 12.74 µM, and 1.97, 1.96, 2.06 and 1.55 pmol/oocyte/h, respectively. The present study demonstrates that the SLC22A9 variant F426S is causing inter-individual variation that is leading to the differences in transport of the steroid sulfate conjugate (estrone sulfate) and, therefore this could be used as a marker for certain disease including osteoporosis.
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Affiliation(s)
- Seong Kyu Ahn
- Department of Tropical Medicine and Parasitology, College of Medicine, Inha University, Incheon 400-712, Korea
| | - Chang Kook Suh
- Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon 400-712, Korea
| | - Seok Ho Cha
- Department of Tropical Medicine and Parasitology, College of Medicine, Inha University, Incheon 400-712, Korea
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Nigam SK, Bush KT, Martovetsky G, Ahn SY, Liu HC, Richard E, Bhatnagar V, Wu W. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev 2015; 95:83-123. [PMID: 25540139 PMCID: PMC4281586 DOI: 10.1152/physrev.00025.2013] [Citation(s) in RCA: 349] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling.
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Affiliation(s)
- Sanjay K Nigam
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Kevin T Bush
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Gleb Martovetsky
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Sun-Young Ahn
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Henry C Liu
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Erin Richard
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Vibha Bhatnagar
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
| | - Wei Wu
- Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, Bioengineering, and Family and Preventative Medicine, University of California, San Diego, La Jolla, California
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Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid. Invest Radiol 2014; 49:78-86. [DOI: 10.1097/rli.0b013e3182a70043] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Pelis RM, Wright SH. SLC22, SLC44, and SLC47 transporters--organic anion and cation transporters: molecular and cellular properties. CURRENT TOPICS IN MEMBRANES 2014; 73:233-61. [PMID: 24745985 DOI: 10.1016/b978-0-12-800223-0.00006-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Transporters within the SLC22, SLC44, and SLC47 families of solute carriers mediate transport of a structurally diverse array of organic electrolytes, that is, molecules that are generally charged (cationic, anionic, or zwitterionic) at physiological pH. Transporters in the SLC22 family--all of which are members of the major facilitator superfamily (MFS) of transporters--represent a mechanistically diverse set of processes, including the organic anion transporters (OATs and URAT1) that physiologically operate as organic anion (OA) exchangers, the organic cation transporters (OCTs) that operate as electrogenic uniporters of organic cations (OCs), and the so-called "novel" organic cation transporters (OCTNs) that support Na-cotransport of selected zwitterions. Whereas the OCTNs display a high degree of substrate selectivity, the physiological hallmark of the OATs and OCTs is their multiselectivity--consistent with a principal role in renal and hepatic clearance of a wide array of both endogenous and xenobiotic compounds. SLC47 consists of members of the multidrug and toxin extruder (MATE) family, which are carriers that are obligatory exchangers and that physiologically support electroneutral H⁺ exchange. The MATEs also display a characteristic multiselectivity and are frequently paired with OCTs to mediate transepithelial OC secretion, with the OCTs typically supporting basolateral OC entry and the MATEs supporting apical OC efflux. The SLC44 family contains the choline transporter-like (CTL) transporters. Largely restricted to choline and a limited set of structural congeners, the CTLs appear to support the Na-independent, electrogenic uniport of choline, thereby providing choline for membrane biogenesis. The solution of X-ray crystal structures of representative prokaryotic MFS and MATE transporters has led to the development of homology models of mammalian OAT, OCT, and MATE transporters that, in turn, have supplemented studies of the molecular basis of the complex interactions of ligands with these multiselective proteins.
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Affiliation(s)
- Ryan M Pelis
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Stephen H Wright
- Department of Physiology, University of Arizona, Tucson, Arizona, USA.
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Volk C. OCTs, OATs, and OCTNs: structure and function of the polyspecific organic ion transporters of the SLC22 family. ACTA ACUST UNITED AC 2013. [DOI: 10.1002/wmts.100] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Christopher Volk
- Department of Natural Sciences; Bonn-Rhein-Sieg University of Applied Sciences; Rheinbach Germany
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Abstract
Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (∼1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.
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Affiliation(s)
- James L Boyer
- Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
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Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013; 34:413-35. [PMID: 23506881 DOI: 10.1016/j.mam.2012.10.010] [Citation(s) in RCA: 296] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 08/18/2012] [Indexed: 12/14/2022]
Abstract
The SLC22 family contains 13 functionally characterized human plasma membrane proteins each with 12 predicted α-helical transmembrane domains. The family comprises organic cation transporters (OCTs), organic zwitterion/cation transporters (OCTNs), and organic anion transporters (OATs). The transporters operate as (1) uniporters which mediate facilitated diffusion (OCTs, OCTNs), (2) anion exchangers (OATs), and (3) Na(+)/zwitterion cotransporters (OCTNs). They participate in small intestinal absorption and hepatic and renal excretion of drugs, xenobiotics and endogenous compounds and perform homeostatic functions in brain and heart. Important endogeneous substrates include monoamine neurotransmitters, l-carnitine, α-ketoglutarate, cAMP, cGMP, prostaglandins, and urate. It has been shown that mutations of the SLC22 genes encoding these transporters cause specific diseases like primary systemic carnitine deficiency and idiopathic renal hypouricemia and are correlated with diseases such as Crohn's disease and gout. Drug-drug interactions at individual transporters may change pharmacokinetics and toxicities of drugs.
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Affiliation(s)
- Hermann Koepsell
- University of Würzburg, Institute of Anatomy and Cell Biology, Koellikerstr. 6, 97070 Würzburg, Germany.
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Nakamura T, Nishi R, Tanaka T, Takagi K, Sakai K, Takai M, Morishima S, Yamauchi T, Ueda T. Variation of urate transport in the nephrons in subtypes of hyperuricemia. NEPHRON EXTRA 2013; 3:73-85. [PMID: 24052801 PMCID: PMC3776396 DOI: 10.1159/000354029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. METHODS Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. RESULTS The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R2) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R2 in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R2 were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R2 and Uua (r = -0.393, p < 0.0001). CONCLUSION IN THE UE, HYPERURICEMIA IS INDUCED MAINLY BY URATE UNDEREXCRETION, WHICH RESULTS FROM THE COMBINATION OF TWO MAIN CAUSES IN URATE TRANSPORTERS OF THE NEPHRON: significantly lower TSR and significantly higher R2. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia.
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Affiliation(s)
- Toru Nakamura
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
- Hayashi General Hospital, Echizen, Japan
| | - Rie Nishi
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
| | - Tuneo Tanaka
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
| | - Kazutaka Takagi
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
| | | | - Mihoko Takai
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
- Hayashi General Hospital, Echizen, Japan
| | | | - Takahiro Yamauchi
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
| | - Takanori Ueda
- First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Matsuoka, Japan
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