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1
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Zu Y, Gao Q, He Y, Deng Q, Li G, Li X, Shang T, Cheng X, Zhu C, Wang J, Liu D, Zhang C. MiR-128-3p mediates MRP2 internalization in estrogen-induced cholestasis through targeting PDZK1. ACTA MATERIA MEDICA 2025; 4. [DOI: 10.15212/amm-2024-0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Estrogens have been reported to cause dysfunction in biliary transport systems, thereby inducing cholestasis. Multidrug resistance-associated protein 2 (MRP2) is a transporter responsible for independent bile flow. Emerging evidence indicates that PDZ domain containing 1 (PDZK1) regulates localization of MRP2; however, PDZK1’s role and regulatory machinery in MRP2-mediated estrogen-induced cholestasis (EIC) remain unclear. Herein, in a mouse model of EIC, we observed downregulated PDZK1 expression in the liver and enhanced intracellular domain MRP2 internalization. Notably, expression of miR-128-3p, a potential biomarker of estrogen-related cholestasis discovered by our group, was significantly elevated. We demonstrated that miR-128-3p targeted the 3’-untranslated region of PDZK1 in EIC and consequently promoted MRP2 internalization. Accordingly, miR-128-3p suppression upregulated PDZK1, thereby suppressing MRP2 internalization and significantly attenuating cholestatic liver disease. Furthermore, we observed MRP2 internalization and PDZK1 downregulation, as well as excessive miR-128-3p, in clinical samples from patients with cholestatic liver injury. Overall, our findings illustrate that miR-128-3p inhibits PDZK1 expression, thereby inhibiting the membrane localization of MRP2 in EIC. Enhancing or restoring PDZK1 expression might therefore have therapeutic potential for cholestatic liver injury.
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2
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Wilkins H, Knerler SA, Warshanna A, Colón Ortiz R, Haas K, Orsburn BC, Williams DW. All Blood Brain Barrier Cell Types Demonstrate Capability to Influence Differential Tenofovir and Emtricitabine Metabolism and Transport in the Brain. ACS Pharmacol Transl Sci 2024; 7:3626-3640. [PMID: 39539261 PMCID: PMC11555524 DOI: 10.1021/acsptsci.4c00510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024]
Abstract
The blood brain barrier (BBB) represents a significant obstacle in brain drug penetration that challenges efforts in the treatment of neurological disorders. Therapeutically targeting the brain requires interactions with each BBB cell type, including endothelial cells, pericytes, and astrocytes. Yet, the relative contribution of these BBB cell types to the mechanisms that facilitate brain drug disposition is not well characterized. Here, we use first-line antiretroviral therapies, tenofovir (TFV) and emtricitabine (FTC), as models to investigate the mechanisms of drug transport and metabolism at the BBB that may influence access of the drug to the brain. We evaluated regional and cell-type-specific drug metabolism and transport mechanisms using rhesus macaques and in vitro treatment of primary human cells. We report heterogeneous distribution of TFV, FTC, and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug-metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rival hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition. Further, our work highlights pharmacologically active pathways at the BBB that may regulate brain drug disposition and impact therapeutic efforts to alleviate neurologic disease.
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Affiliation(s)
- Hannah
N. Wilkins
- Department
of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Stephen A. Knerler
- Department
of Pharmacology and Chemical Biology, Emory
University School of Medicine, Atlanta, Georgia 30322, United States
| | - Ahmed Warshanna
- Department
of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Rodnie Colón Ortiz
- Department
of Neuroscience, Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205, United States
| | - Kate Haas
- Department
of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Benjamin C. Orsburn
- Department
of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Dionna W. Williams
- Department
of Pharmacology and Chemical Biology, Emory
University School of Medicine, Atlanta, Georgia 30322, United States
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3
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Wilkins HN, Knerler SA, Warshanna A, Ortiz RC, Haas K, Orsburn BC, Williams DW. Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.01.606165. [PMID: 39149336 PMCID: PMC11326144 DOI: 10.1101/2024.08.01.606165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Therapeutically targeting the brain requires interactions with endothelial cells, pericytes, and astrocytes at the blood brain barrier (BBB). We evaluated regional and cell-type specific drug metabolism and transport mechanisms using rhesus macaques and in vitro treatment of primary human cells. Here, we report heterogenous distribution of representative drugs, tenofovir (TFV), emtricitabine (FTC), and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rivaled hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity, rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition.
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Affiliation(s)
- Hannah N. Wilkins
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stephen A. Knerler
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ahmed Warshanna
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Rodnie Colón Ortiz
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kate Haas
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Benjamin C. Orsburn
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dionna W. Williams
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
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4
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Miners JO, Polasek TM, Hulin JA, Rowland A, Meech R. Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance. Pharmacol Ther 2023:108459. [PMID: 37263383 DOI: 10.1016/j.pharmthera.2023.108459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/03/2023]
Abstract
Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be research priority.
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Affiliation(s)
- John O Miners
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Thomas M Polasek
- Certara, Princeton, NJ, USA; Centre for Medicines Use and Safety, Monash University, Melbourne, Australia
| | - Julie-Ann Hulin
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Andrew Rowland
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Robyn Meech
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
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5
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Vansell NR. Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats. Drug Metab Dispos 2022; 50:508-517. [PMID: 35046065 DOI: 10.1124/dmd.121.000498] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 12/23/2021] [Indexed: 02/13/2025] Open
Abstract
Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and, in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of thyroxine (T4) glucuronidation by UDP-glycosyltransferase (UGT) enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in thyroid-stimulating hormone. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (e.g., organic anion transporter polypeptides) and efflux (e.g., multidrug resistance proteins) transporters, data exist that support transporters as additional target sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (triiodothyronine more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals have contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also require further study. SIGNIFICANCE STATEMENT: Key advances in understanding the target sites for altered disposition of thyroid hormones have occurred in the last 2 decades to better inform potential sites of action of inducing chemicals. Ultimately, the knowledge of inducible thyroid hormone transport into and out of liver, beyond induction of glucuronidation, should be considered and applied to screening and risk assessment paradigms when assessing an inducer's potential to alter thyroid homeostasis in nonclinical species and humans.
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6
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Katekar R, Singh P, Garg R, Verma S, Gayen JR. Emerging nanotechnology based combination therapies of taxanes for multiple drug-resistant cancers. Pharm Dev Technol 2021; 27:95-107. [PMID: 34806547 DOI: 10.1080/10837450.2021.2009861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
'One drug- one target' to 'multiple drug- multiple targets' paradigm shifted to produce combination therapies, have found great outcomes to overcome multiple drug resistance (MDR). MDR is a significant barrier to the delivery of taxane-based anticancer medicines such as docetaxel, paclitaxel, and cabazitaxel. Due to MDR induced by drug efflux transporters, clinical application of these medications is impeded. To date, nanoformulations such as liposomes, micelles, polymeric nanoparticles, and gold nanoparticles have been investigated to deliver taxanes alone and in combination to reverse drug resistance. Despite the fact that various groups have already looked into taxane nano formulations in the literature, there isn't much in the way of polypharmacology and advanced nanoformulations with a focus on MDR. In this overview, we briefly covered the insights regarding MDR, difficulties related to current pharmaceutical products of taxanes, combination therapies of taxanes to combat MDR, all of which can be used to delve into cancer treatment.
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Affiliation(s)
- Roshan Katekar
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.,Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
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7
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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: 47] [Impact Index Per Article: 9.4] [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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8
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Deferm N, De Vocht T, Qi B, Van Brantegem P, Gijbels E, Vinken M, de Witte P, Bouillon T, Annaert P. Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 2019; 49:520-548. [PMID: 31589080 DOI: 10.1080/10408444.2019.1635081] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.
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Affiliation(s)
- Neel Deferm
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Tom De Vocht
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Bing Qi
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Van Brantegem
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Eva Gijbels
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter de Witte
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Thomas Bouillon
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Annaert
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
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9
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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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10
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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11
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Briz O, Perez-Silva L, Al-Abdulla R, Abete L, Reviejo M, Romero MR, Marin JJG. What "The Cancer Genome Atlas" database tells us about the role of ATP-binding cassette (ABC) proteins in chemoresistance to anticancer drugs. Expert Opin Drug Metab Toxicol 2019; 15:577-593. [PMID: 31185182 DOI: 10.1080/17425255.2019.1631285] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Chemotherapy remains the only option for advanced cancer patients when other alternatives are not feasible. Nevertheless, the success rate of this type of therapy is often low due to intrinsic or acquired mechanisms of chemoresistance. Among them, drug extrusion from cancer cells through ATP-binding cassette (ABC) proteins plays an important role. ABC pumps are primary active transporters involved in the barrier and secretory functions of many healthy cells. Areas covered: In this review, we have used The Cancer Genome Atlas (TCGA) database to explore the relationship between the expression of the major ABC proteins involved in cancer chemoresistance in the most common types of cancer, and the drugs used in the treatment of these tumors that are substrates of these pumps. Expert opinion: From unicellular organisms to humans, several ABC proteins play a major role in detoxification processes. Cancer cells exploit this ability to protect themselves from cytostatic drugs. Among the ABC pumps, MDR1, MRPs and BCRP are able to export many antitumor drugs and are expressed in several types of cancer, and further up-regulated during treatment. This event results in the enhanced ability of tumor cells to reduce intracellular drug concentrations and hence the pharmacological effect of chemotherapy.
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Affiliation(s)
- Oscar Briz
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain.,b Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd) , Carlos III National Institute of Health , Madrid , Spain
| | - Laura Perez-Silva
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain
| | - Ruba Al-Abdulla
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain
| | - Lorena Abete
- c Department of Physiology and Pharmacology "V. Erspamer" , Sapienza University of Rome , Rome , Italy
| | - Maria Reviejo
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain
| | - Marta R Romero
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain.,b Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd) , Carlos III National Institute of Health , Madrid , Spain
| | - Jose J G Marin
- a Experimental Hepatology and Drug Targeting (HEVEFARM) , University of Salamanca, IBSAL , Salamanca , Spain.,b Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd) , Carlos III National Institute of Health , Madrid , Spain
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12
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Koehn LM, Dziegielewska KM, Møllgård K, Saudrais E, Strazielle N, Ghersi-Egea JF, Saunders NR, Habgood MD. Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide. Sci Rep 2019; 9:5998. [PMID: 30979952 PMCID: PMC6461637 DOI: 10.1038/s41598-019-42402-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/28/2019] [Indexed: 02/07/2023] Open
Abstract
Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.
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Affiliation(s)
- Liam M Koehn
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Katarzyna M Dziegielewska
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Kjeld Møllgård
- Institute of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Elodie Saudrais
- IBIP facility and Fluid team, Lyon Neuroscience Research center, NSERM U1028 CNRS UMR5292, Université de Lyon-1, Lyon, France
| | - Nathalie Strazielle
- IBIP facility and Fluid team, Lyon Neuroscience Research center, NSERM U1028 CNRS UMR5292, Université de Lyon-1, Lyon, France.,Brain-I, Lyon, France
| | - Jean-Francois Ghersi-Egea
- IBIP facility and Fluid team, Lyon Neuroscience Research center, NSERM U1028 CNRS UMR5292, Université de Lyon-1, Lyon, France
| | - Norman R Saunders
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia.
| | - Mark D Habgood
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia
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13
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New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018; 2018:2313675. [PMID: 30148122 PMCID: PMC6083523 DOI: 10.1155/2018/2313675] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
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14
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The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis. Int J Mol Sci 2018; 19:ijms19041260. [PMID: 29690611 PMCID: PMC5979375 DOI: 10.3390/ijms19041260] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/13/2018] [Accepted: 04/19/2018] [Indexed: 02/06/2023] Open
Abstract
The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis.
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15
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Yang G, Ge S, Singh R, Basu S, Shatzer K, Zen M, Liu J, Tu Y, Zhang C, Wei J, Shi J, Zhu L, Liu Z, Wang Y, Gao S, Hu M. Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metab Rev 2017; 49:105-138. [PMID: 28266877 DOI: 10.1080/03602532.2017.1293682] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
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Affiliation(s)
- Guangyi Yang
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.,b Hubei Provincial Technology and Research Center for Comprehensive Development of Medicinal Herbs, Hubei University of Medicine , Shiyan , Hubei , China
| | - Shufan Ge
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Rashim Singh
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Sumit Basu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Katherine Shatzer
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Ming Zen
- d Department of Thoracic and Cardiomacrovascular Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jiong Liu
- e Department of Digestive Diseases Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Yifan Tu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA
| | - Chenning Zhang
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jinbao Wei
- a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China
| | - Jian Shi
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Lijun Zhu
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Zhongqiu Liu
- f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China
| | - Yuan Wang
- g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
| | - Song Gao
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.,g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
| | - Ming Hu
- c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.,g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China
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16
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Kotsampasakou E, Escher SE, Ecker GF. Linking organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3) interaction profiles to hepatotoxicity - The hyperbilirubinemia use case. Eur J Pharm Sci 2017; 100:9-16. [PMID: 28063966 DOI: 10.1016/j.ejps.2017.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/26/2016] [Accepted: 01/02/2017] [Indexed: 02/07/2023]
Abstract
Hyperbilirubinemia is a pathological condition of excessive accumulation of conjugated or unconjugated bilirubin in blood. It has been associated with neurotoxicity and non-neural organ dysfunctions, while it can also be a warning of liver side effects. Hyperbilirubinemia can either be a result of overproduction of bilirubin due to hemolysis or dyserythropoiesis, or the outcome of impaired bilirubin elimination due to liver transporter malfunction or inhibition. There are several reports in literature that inhibition of organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) might lead to hyperbilirubinemia. In this study we created a set of classification models for hyperbilirubinemia, which, besides physicochemical descriptors, also include the output of classification models of human OATP1B1 and 1B3 inhibition. Models were based on either human data derived from public toxicity reports or animal data extracted from the eTOX database VITIC. The generated models showed satisfactory accuracy (68%) and area under the curve (AUC) for human data and 71% accuracy and 70% AUC for animal data. However, our results did not indicate strong association between OATP inhibition and hyperbilirubinemia, neither for humans nor for animals.
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Affiliation(s)
- Eleni Kotsampasakou
- University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria
| | - Sylvia E Escher
- Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Strasse 1, 30625 Hannover, Germany
| | - Gerhard F Ecker
- University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
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17
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Zheng L, Zhu L, Zhao M, Shi J, Li Y, Yu J, Jiang H, Wu J, Tong Y, Liu Y, Hu M, Lu L, Liu Z. In Vivo Exposure of Kaempferol Is Driven by Phase II Metabolic Enzymes and Efflux Transporters. AAPS JOURNAL 2016; 18:1289-1299. [PMID: 27393480 DOI: 10.1208/s12248-016-9951-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 06/16/2016] [Indexed: 12/28/2022]
Abstract
Kaempferol is a well-known flavonoid; however, it lacks extensive pharmacokinetic studies. Phase II metabolic enzymes and efflux transporters play an important role in the disposition of flavonoids. This study aimed to investigate the mechanism by which phase II metabolic enzymes and efflux transporters determine the in vivo exposure of kaempferol. Pharmacokinetic analysis in Sprague-Dawley rats revealed that kaempferol was mostly biotransformed to conjugates, namely, kaempferol-3-glucuronide (K-3-G), kaempferol-7-glucuronide (K-7-G), and kaempferol-7-sulfate, in plasma. K-3-G represented the major metabolite. Compared with that in wild-type mice, pharmacokinetics in knockout FVB mice demonstrated that the absence of multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) significantly increased the area under the curve (AUC) of the conjugates. The lack of MRP1 resulted in a much lower AUC of the conjugates. Intestinal perfusion in rats revealed that the glucuronide conjugates were mainly excreted in the small intestine, but 7-sulfate was mainly excreted in the colon. In Caco-2 monolayers, K-7-G efflux toward the apical (AP) side was significantly higher than K-3-G efflux. In contrast, K-3-G efflux toward the basolateral (BL) side was significantly higher than K-7-G efflux. The BL-to-AP efflux was significantly reduced in the presence of the MRP2 inhibitor LTC4. The AP-to-BL efflux was significantly decreased in the presence of the BL-side MRPs inhibitor MK571. The BCRP inhibitor Ko143 decreased the glucuronide conjugate efflux. Therefore, kaempferol is mainly exposed as K-3-G in vivo, which is driven by phase II metabolic enzymes and efflux transporters (i.e., BCRP and MRPs).
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Affiliation(s)
- Liang Zheng
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Lijun Zhu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Min Zhao
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Jian Shi
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Yuhuan Li
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Jia Yu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Huangyu Jiang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Jinjun Wu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Yunli Tong
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Yuting Liu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China
| | - Ming Hu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China.,Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA
| | - Linlin Lu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China.
| | - Zhongqiu Liu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China. .,International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, People's Republic of China.
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18
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Fu ZD, Selwyn FP, Cui JY, Klaassen CD. RNA Sequencing Quantification of Xenobiotic-Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice. Drug Metab Dispos 2016; 44:842-56. [PMID: 27048750 PMCID: PMC4885488 DOI: 10.1124/dmd.115.068270] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 04/04/2016] [Indexed: 12/31/2022] Open
Abstract
Previous reports on tissue distribution of xenobiotic-processing genes (XPGs) have limitations, because many non-cytochrome P450 phase I enzymes have not been investigated, and one cannot compare the real mRNA abundance of multiple XPGs using conventional quantification methods. Therefore, this study aimed to quantify and compare the mRNA abundance of all major XPGs in the liver and intestine using RNA sequencing. The mRNA profiles of 304 XPGs, including phase I, phase II enzymes, phase II cosubstrate synthetic enzymes, xenobiotic transporters, as well as xenobiotic-related transcription factors, were systematically examined in the liver and various sections of the intestine in adult male C57BL/6J mice. By two-way hierarchical clustering, over 80% of the XPGs had tissue-divergent expression, which partitioned into liver-predominant, small intestine-predominant, and large intestine-predominant patterns. Among the genes, 54% were expressed highest in the liver, 21% in the duodenum, 4% in the jejunum, 6% in the ileum, and 15% in the large intestine. The highest-expressed XPG in the liver was Mgst1; in the duodenum, Cyp3a11; in the jejunum and ileum, Ces2e; and in the large intestine, Cyp2c55. Interestingly, XPGs in the same family usually exhibited highly different tissue distribution patterns, and many XPGs were almost exclusively expressed in one tissue and minimally expressed in others. In conclusion, the present study is among the first and the most comprehensive investigations of the real mRNA abundance and tissue-divergent expression of all major XPGs in mouse liver and intestine, which aids in understanding the tissue-specific biotransformation and toxicity of drugs and other xenobiotics.
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Affiliation(s)
- Zidong Donna Fu
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Felcy Pavithra Selwyn
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Curtis D Klaassen
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
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19
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Yeh DYW, Yang YC, Wang JJ. Hepatic Warm Ischemia-Reperfusion-Induced Increase in Pulmonary Capillary Filtration Is Ameliorated by Administration of a Multidrug Resistance-Associated Protein 1 Inhibitor and Leukotriene D4 Antagonist (MK-571) Through Reducing Neutrophil Infiltration and Pulmonary Inflammation and Oxidative Stress in Rats. Transplant Proc 2016; 47:1087-91. [PMID: 26036526 DOI: 10.1016/j.transproceed.2014.10.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 10/28/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND Hepatopulmonary syndrome (HPS) is the major complication subsequent to liver ischemia and reperfusion (I/R) injury after resection or transplantation of liver. Hallmarks of HPS include increases in pulmonary leukotrienes and neutrophil recruitment and infiltrating across capillaries. We aimed to investigate the protective efficacy of MK-571, a multidrug resistance-associated protein 1 inhibitor and leukotriene D4 agonist, against hepatic I/R injury-associated change in capillary filtration. METHODS Eighteen Sprague-Dawley male rats were evenly divided into a sham-operated group, a hepatic I/R group, and an MK-571-treated I/R group. MK-571 was administered intraperitoneally 15 min before hepatic ischemia and every 12 hours during reperfusion. Ischemia was conducted by occluding the hepatic artery and portal vein for 30 min, followed by removing the clamps and closing the incision. Forty-eight hours after hepatic ischemia, we assessed the pulmonary capillary filtration coefficient (Kfc) through the use of in vitro-isolated, perfused rat lung preparation. We also measured the lung wet-to-dry weight ratio (W/D) and protein concentration in broncho-alveolar lavage fluid (PCBAL). Lung inflammation and oxidative stress were evaluated by use of tissue tumor necrosis factor (TNF)-α and malondialdehyde levels and lavage differential macrophage and neutrophil cell count. RESULTS Hepatic I/R injury markedly increased Kfc, W/D, PCBAL, tissue TNF-α level, and differential neutrophil cell count (P < .05). MK-571 treatment reduced neutrophil infiltration and lung inflammation and improved pulmonary capillary filtration, collectively suggesting lung protection. CONCLUSIONS Treatment with MK-571 before and during hepatic ischemia and reperfusion protects lung against pulmonary capillary barrier function impairment through decreasing pulmonary lung inflammation and lavage neutrophils.
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Affiliation(s)
- D Y-W Yeh
- Division of Chest Medicine, Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Y-C Yang
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - J-J Wang
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
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20
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Mellor CL, Steinmetz FP, Cronin MTD. The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways. Crit Rev Toxicol 2015; 46:138-52. [PMID: 26451809 DOI: 10.3109/10408444.2015.1089471] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The development of adverse outcome pathways (AOPs) is becoming a key component of twenty-first century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organized toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands, there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This article reviews and summarizes the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.
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Affiliation(s)
- Claire L Mellor
- a School of Pharmacy and Biomolecular Sciences , Liverpool John Moores University , Liverpool , England
| | - Fabian P Steinmetz
- a School of Pharmacy and Biomolecular Sciences , Liverpool John Moores University , Liverpool , England
| | - Mark T D Cronin
- a School of Pharmacy and Biomolecular Sciences , Liverpool John Moores University , Liverpool , England
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21
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Slachtova L, Seda O, Behunova J, Mistrik M, Martasek P. Genetic and biochemical study of dual hereditary jaundice: Dubin-Johnson and Gilbert's syndromes. Haplotyping and founder effect of deletion in ABCC2. Eur J Hum Genet 2015; 24:704-9. [PMID: 26350512 DOI: 10.1038/ejhg.2015.181] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 07/09/2015] [Accepted: 07/21/2015] [Indexed: 12/11/2022] Open
Abstract
Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013_1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families.
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Affiliation(s)
- Lenka Slachtova
- Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
| | - Ondrej Seda
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
| | - Jana Behunova
- Department of Pediatrics, P. J. Safarik University, Kosice, Vienna, Slovakia.,Institute of Medical Genetics, University of Vienna, Vienna, Austria
| | - Martin Mistrik
- Department of Medical Genetics, Alpha Medical, Spisska Nova Ves, Slovakia
| | - Pavel Martasek
- Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
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22
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van der Schoor LWE, Verkade HJ, Kuipers F, Jonker JW. New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition. Expert Opin Drug Metab Toxicol 2014; 11:273-93. [PMID: 25380746 DOI: 10.1517/17425255.2015.981152] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION For the elimination of environmental chemicals and metabolic waste products, the body is equipped with a range of broad specificity transporters that are present in excretory organs as well as in several epithelial blood-tissue barriers. AREAS COVERED ABCC2 and ABCC3 (also known as MRP2 and MRP3) mediate the transport of various conjugated organic anions, including many drugs, toxicants and endogenous compounds. This review focuses on the physiology of these transporters, their roles in drug disposition and how they affect drug sensitivity and toxicity. It also examines how ABCC2 and ABCC3 are coordinately regulated at the transcriptional level by members of the nuclear receptor (NR) family of ligand-modulated transcription factors and how this can be therapeutically exploited. EXPERT OPINION Mutations in both ABCC2 and ABCC3 have been associated with changes in drug disposition, sensitivity and toxicity. A defect in ABCC2 is associated with Dubin-Johnson syndrome, a recessively inherited disorder characterized by conjugated hyperbilirubinemia. Pharmacological manipulation of the activity of these transporters can potentially improve the pharmacokinetics and thus therapeutic activity of substrate drugs but also affect the physiological function of these transporters and consequently ameliorate associated disease states.
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Affiliation(s)
- Lori W E van der Schoor
- University of Groningen, University Medical Center Groningen, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics , Hanzeplein 1, 9713 GZ Groningen , The Netherlands
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23
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Chang E, Park EY, Woo YM, Kang DH, Hwang YH, Ahn C, Park JH. Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney. Am J Physiol Renal Physiol 2014; 308:F1004-11. [PMID: 25143454 DOI: 10.1152/ajprenal.00159.2014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 08/19/2014] [Indexed: 11/22/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance-associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD.
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Affiliation(s)
- EunSun Chang
- Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea
| | - Eun Young Park
- Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea
| | - Yu mi Woo
- Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea
| | - Duk-Hee Kang
- Department of Nephrology in Ewha Woman's University, Seoul, Republic of Korea
| | - Young-Hwan Hwang
- Department of Internal Medicine, Eulji General Hospital, Seoul, Republic of Korea; and
| | - Curie Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Hoon Park
- Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea;
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24
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Cai JS, Chen JH. The mechanism of enterohepatic circulation in the formation of gallstone disease. J Membr Biol 2014; 247:1067-82. [PMID: 25107305 PMCID: PMC4207937 DOI: 10.1007/s00232-014-9715-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 07/25/2014] [Indexed: 12/25/2022]
Abstract
Bile acids entering into enterohepatic circulating are primary acids synthesized from cholesterol in hepatocyte. They are secreted actively across canalicular membrane and carried in bile to gallbladder, where they are concentrated during digestion. About 95 % BAs are actively taken up from the lumen of terminal ileum efficiently, leaving only approximately 5 % (or approximately 0.5 g/d) in colon, and a fraction of bile acids are passively reabsorbed after a series of modifications in the human large intestine including deconjugation and oxidation of hydroxy groups. Bile salts hydrolysis and hydroxy group dehydrogenation reactions are performed by a broad spectrum of intestinal anaerobic bacteria. Next, hepatocyte reabsorbs bile acids from sinusoidal blood, which are carried to liver through portal vein via a series of transporters. Bile acids (BAs) transporters are critical for maintenance of the enterohepatic BAs circulation, where BAs exert their multiple physiological functions including stimulation of bile flow, intestinal absorption of lipophilic nutrients, solubilization, and excretion of cholesterol. Tight regulation of BA transporters via nuclear receptors (NRs) is necessary to maintain proper BA homeostasis. In conclusion, disturbances of enterohepatic circulation may account for pathogenesis of gallstones diseases, including BAs transporters and their regulatory NRs and the metabolism of intestinal bacterias, etc.
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Affiliation(s)
- Jian-Shan Cai
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road, Shanghai, 200040, People's Republic of China,
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25
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Vasheka IP, Vesel'skyĭ SP, Horenko ZA, Hrinchenko OA, Karbovs'ka LS, Makarchuk MI. The influence of amylin on the bile acid spectrum in rats. ACTA ACUST UNITED AC 2014. [DOI: 10.15407/fz60.03.046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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26
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Klein DM, Wright SH, Cherrington NJ. Xenobiotic transporter expression along the male genital tract. Reprod Toxicol 2014; 47:1-8. [PMID: 24814985 DOI: 10.1016/j.reprotox.2014.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 04/11/2014] [Accepted: 04/29/2014] [Indexed: 12/18/2022]
Abstract
The male genital tract plays an important role in protecting sperm by forming a distinct compartment separate from the body which limits exposure to potentially toxic substrates. Transporters along this tract can influence the distribution of xenobiotics into the male genital tract through efflux back into the blood or facilitating the accumulation of toxicants. The aim of this study was to quantitatively determine the constitutive mRNA expression of 30 xenobiotic transporters in caput and cauda regions of the epididymis, vas deferens, prostate, and seminal vesicles from adult Sprague-Dawley rats. The epididymis was found to express at least moderate levels of 18 transporters, vas deferens 15, seminal vesicles 23, and prostate 18. Constitutive expression of these xenobiotic transporters in the male genital tract may provide insight into the xenobiotics that can potentially be transported into these tissues and may provide the molecular mechanism for site specific toxicity of select agents.
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Affiliation(s)
- David M Klein
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721, United States
| | - Stephen H Wright
- University of Arizona, Department of Physiology, Tucson, AZ 85721, United States
| | - Nathan J Cherrington
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721, United States.
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27
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Yang H, Wang H. Signaling control of the constitutive androstane receptor (CAR). Protein Cell 2014; 5:113-23. [PMID: 24474196 PMCID: PMC3956974 DOI: 10.1007/s13238-013-0013-0] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 12/07/2013] [Indexed: 01/30/2023] Open
Abstract
The constitutive androstane receptor (CAR, NR1I3) plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent (indirect) mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mechanisms yet to be fully understood. Accumulating evidence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be functionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our understanding of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.
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Affiliation(s)
- Hui Yang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD, 21201, USA
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Evaluation of Antioxidant, Immunomodulatory Activities, and Safety of Ethanol Extract and Fractions of Gongronema latifolium Fruit. INTERNATIONAL SCHOLARLY RESEARCH NOTICES 2014; 2014:695272. [PMID: 27433504 PMCID: PMC4897319 DOI: 10.1155/2014/695272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 07/29/2014] [Accepted: 08/13/2014] [Indexed: 11/30/2022]
Abstract
Gongronema latifolium fruit has wide application in ethnomedicine, especially in maintaining healthy living and general body healing. We therefore investigated the antioxidant, immunomodulatory activities, and safety of its ethanol extract and fractions. The in vitro antioxidant activities of the extract and fractions were determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) test while in vivo activities were determined using carbon tetrachloride (CCL4) induced oxidative stress. Cell and humoral mediated immune responses were also evaluated together with toxicity studies. The extract, ethyl acetate, and methanol fractions showed inhibition of DPPH radical with IC50s 120, 90, and 60 μg/mL, respectively. Methanol fraction at 200 mg/kg produced significant (P < 0.05) inhibition of lipid peroxidation (MDA conc. 1.2 μmol/L) compared to control (2.8 μmol/L). Both ethyl acetate and methanol fractions at 200 mg/kg produced significant (P < 0.05) phagocytic index of 0.021 and 0.025, respectively, compared with control (0.01). Significant (P < 0.05) elevations of white blood cells, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were noticed on the 91st day at higher doses. Generally, this study justified the traditional use of G. latifolium fruit for general body healing and maintenance of healthy living. Long term administration is safe on the haematological and biochemical systems especially at lower doses and its toxicity at higher doses is reversible.
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29
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Expression of multidrug resistance-associated protein 2 in human gallbladder carcinoma. BIOMED RESEARCH INTERNATIONAL 2013; 2013:527534. [PMID: 23841074 PMCID: PMC3697274 DOI: 10.1155/2013/527534] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 06/03/2013] [Indexed: 12/16/2022]
Abstract
Gallbladder carcinoma (GBCA) is one of the most aggressive malignancies. It is usually diagnosed at an advanced stage, and prognosis remains poor despite advances in imaging techniques and aggressive surgical treatment. Overexpression of multidrug resistance-associated proteins (MRPs) in tumor cells is a major cause of the intrinsic multidrug resistance phenotype. Despite the documented importance of MRP expression in many carcinomas, the prognostic significance of MRP2 expression in primary GBCA is not known. Immunostaining for MRP2 was performed on tissue samples obtained from 143 patients with GBCA. We examined the association between MRP expression and clinicopathological characteristics and outcome of patients with GBCA. GBCA demonstrated MRP2 immunoreactivity in the apicolateral membranes of epithelial cells. MRP2 expression was positive in 53.1% (76/143) of GBCA samples. Positive MRP2 expression was significantly associated with the presence of local recurrence (P = 0.038), lymphatic invasion (P = 0.038), vascular invasion (P = 0.023), and perineural invasion (P = 0.006). In addition, the median survival time of patients with MRP2-positive GBCA (15 months) was significantly shorter than that of patients with MRP2-negative GBCA (85 months, P = 0.011). We found that the expression of MRP2 in GBCA contributed to aggressive tumor behavior and poor prognosis, suggesting that MRP2 expression can be used as a potential prognostic biomarker of GBCA.
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Osselaere A, Li SJ, De Bock L, Devreese M, Goossens J, Vandenbroucke V, Van Bocxlaer J, Boussery K, Pasmans F, Martel A, De Backer P, Croubels S. Toxic effects of dietary exposure to T-2 toxin on intestinal and hepatic biotransformation enzymes and drug transporter systems in broiler chickens. Food Chem Toxicol 2013; 55:150-5. [PMID: 23313610 DOI: 10.1016/j.fct.2012.12.055] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 12/21/2012] [Accepted: 12/31/2012] [Indexed: 01/06/2023]
Abstract
The effects of the mycotoxin T-2 on hepatic and intestinal drug-metabolizing enzymes (cytochrome P450) and drug transporter systems (MDR1 and MRP2) in poultry were investigated during this study. Broiler chickens received either uncontaminated feed, feed contaminated with 68μg/kg or 752μg/kg T-2 toxin. After 3weeks, the animals were euthanized and MDR1, MRP2, CYP1A4, CYP1A5 and CYP3A37 mRNA expression were analyzed using qRT-PCR. Along the entire length of the small intestine no significant differences were observed. In the liver, genes coding for CYP1A4, CYP1A5 and CYP3A37 were significantly down-regulated in the group exposed to 752μg/kg T-2. For CYP1A4, even a contamination level of 68μg/kg T-2 caused a significant decrease in mRNA expression. Expression of MDR1 was not significantly decreased in the liver. In contrast, hepatic MRP2 expression was significantly down-regulated after exposure to 752μg/kg T-2. Hepatic and intestinal microsomes were prepared to test the enzymatic activity of CYP3A. In the ileum and liver CYP3A activity was significantly increased in the group receiving 752μg/kg T-2 compared to the control group. The results of this study show that drug metabolizing enzymes and drug transporter mechanisms can be influenced due to prolonged exposure to relevant doses of T-2.
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Affiliation(s)
- A Osselaere
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Belgium.
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31
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Li Y, Paxton JW. The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs. Expert Opin Drug Metab Toxicol 2013; 9:267-85. [PMID: 23289831 DOI: 10.1517/17425255.2013.749858] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION The flavonoids are a large group of dietary plant compounds with suggested health benefits. There is accumulating evidence that many of these flavonoids can interact with the major drug transporters (and metabolizing enzymes) in the body, leading to alterations in the pharmacokinetics of substrate drugs, and thus their efficacy and toxicity. AREAS COVERED This review summarizes and updates the reported in vitro and in vivo interactions between common dietary flavonoids and the major drug-effluxing ABC transporters; these include P-glycoprotein, breast cancer resistance protein and multidrug resistance proteins 1 and 2. In contrast to previous reviews, the ADME of flavonoids are considered, along with their glycosides and Phase II conjugates. The authors also consider their possible interactions with the ABC transporters in the oral absorption, distribution into pharmacological sanctuaries and excretion of substrate drugs. Electronic databases, including PubMed, Scopus and Google Scholar were searched to identify appropriate in vitro and in vivo ABC transporter-flavonoid interactions, particularly within the last 10 years. EXPERT OPINION Caution is advised when taking flavonoid-containing supplements or herbal remedies concurrently with drugs. Further clinical studies are warranted to explore the impact of flavonoids and their metabolites on the pharmacokinetics, efficacy and toxicity of drugs.
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Affiliation(s)
- Yan Li
- Auckland University of Technology, Faculty of Health and Environmental Sciences, Department of Interdisciplinary Studies, Auckland, New Zealand
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32
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Xiao L, Wang J, Jiang M, Xie W, Zhai Y. The emerging role of constitutive androstane receptor and its cross talk with liver X receptors and peroxisome proliferator-activated receptor A in lipid metabolism. VITAMINS AND HORMONES 2013; 91:243-58. [PMID: 23374719 DOI: 10.1016/b978-0-12-407766-9.00010-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The regulation of lipid metabolism is central to energy homeostasis in higher multicellular organisms. Lipid homeostasis depends on factors that are able to transduce metabolic parameters into regulatory events representing the fundamental components of the general control system. Nuclear receptors form a superfamily of ligand-activated transcription factors implicated in various physiological functions including energy metabolism. The constitutive androstane receptor (CAR, NR1I3), initially identified as a xenobiotic-sensing receptor, may also have roles in lipid homeostasis. The nuclear receptors liver X receptors (LXRs, NR1H2/3) and peroxisome proliferator-activated receptors (PPARs, NR1C) have been known for their roles in lipid metabolism. LXR is a sterol sensor that promotes lipogenesis, whereas PPARα controls a variety of genes in several pathways of lipid metabolism. This chapter focuses primarily on the role of CAR in lipid metabolism directly or through its cross talk with LXRs and PPARα.
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Affiliation(s)
- Lei Xiao
- Key Laboratory for Cell Proliferation and Regulation Biology, Ministry of Education, Biomedicine Research Institute and College of Life Sciences, Beijing Normal University, Beijing, China
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33
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Sivils JC, Ancrum TM, Bain LJ. LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal-status-specific manner. J Appl Toxicol 2012; 33:766-73. [PMID: 22522787 DOI: 10.1002/jat.2727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 12/29/2011] [Accepted: 12/29/2011] [Indexed: 12/24/2022]
Abstract
The multidrug resistance-associated protein1 (MRP1/ABCC1) is a member of the ABCC transporter subfamily that mediates the efflux of pharmaceuticals, xenobiotics and steroid hormones, typically as glutathione, glucuronide or sulfate conjugates. Since loss of one transporter can be compensated by increasing the expression of other transporters and conjugation enzymes, we sought to examine compensatory changes in phase I, II and III enzyme expression in extrahepatic tissues, including the kidney, lungs and small intestine of intact or castrated Mrp1(-/-) male mice. In the kidney, the expression of several P450s, sulfotransferase 1a1 (Sult), glucuronosyltransferases (Ugt) and Mrps2-4, were significantly changed owing to castration alone. The only time genotype mattered was between the castrated FVB and Mrp1 knockout mice. In contrast, expression of the Ugts, Sult 1a1 and Mrp3 in the lungs was significantly downregulated in the Mrp1 knockout mice, so based exclusively on genotype. In the small intestine, there were interactions between steroid hormone levels and genotype, as the expression differences were only found in mice lacking Mrp1, and were changed between intact and castrated animals. The mechanism behind this pattern of expression may be to due to Nrf2 regulation, as its expression mirrors that of the phase II and phase III enzymes. These results indicate that compensatory responses owing to the loss of Mrp1 vary dramatically, depending on the particular tissue. This information will aid in the understanding of how drug uptake, disposition and elimination can be influenced by both hormone status and the presence and magnitude of transporter expression.
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Affiliation(s)
- Jeffrey C Sivils
- Department of Biological Sciences, University of Texas at El Paso, 500 W. University Avenue, El Paso, TX 79910, USA
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34
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Gould NS, Min E, Martin RJ, Day BJ. CFTR is the primary known apical glutathione transporter involved in cigarette smoke-induced adaptive responses in the lung. Free Radic Biol Med 2012; 52:1201-6. [PMID: 22266045 PMCID: PMC3920665 DOI: 10.1016/j.freeradbiomed.2012.01.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 12/14/2011] [Accepted: 01/04/2012] [Indexed: 10/14/2022]
Abstract
One of the most abundant antioxidants in the lung is glutathione (GSH), a low-molecular-weight thiol, which functions to attenuate both oxidative stress and inflammation. GSH is concentrated in the epithelial lining fluid (ELF) of the lung and can be elevated in response to the increased oxidant burden from cigarette smoke (CS). However, the transporter(s) responsible for the increase in ELF GSH with cigarette smoke is not known. Three candidate apical GSH transporters in the lung are CFTR, BCRP, and MRP2, but their potential roles in ELF GSH transport in response to CS have not been investigated. In vitro, the inhibition of CFTR, BCRP, or MRP2 resulted in decreased GSH efflux in response to cigarette smoke extract. In vivo, mice deficient in CFTR, BCRP, or MRP2 were exposed to either air or acute CS. CFTR-deficient mice had reduced basal and CS-induced GSH in the ELF, whereas BCRP or MRP2 deficiency had no effect on ELF GSH basal or CS-exposed levels. Furthermore, BCRP or MRP2 deficiency had little effect on lung tissue GSH. These data indicate that CFTR is predominantly involved in maintaining basal ELF GSH and increasing ELF GSH in response to CS.
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Affiliation(s)
- Neal S. Gould
- Department of Medicine, National Jewish Health, Denver, CO
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - Elysia Min
- Department of Medicine, National Jewish Health, Denver, CO
| | - Richard J. Martin
- Department of Medicine, National Jewish Health, Denver, CO
- Department of Medicine, University of Colorado Denver, Aurora, CO
| | - Brian J. Day
- Department of Medicine, National Jewish Health, Denver, CO
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
- Department of Medicine, University of Colorado Denver, Aurora, CO
- Department of Immunology, University of Colorado Denver, Aurora, CO
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35
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Hardwick RN, Fisher CD, Street SM, Canet MJ, Cherrington NJ. Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis. Drug Metab Dispos 2012; 40:450-60. [PMID: 22112382 PMCID: PMC3286272 DOI: 10.1124/dmd.111.041095] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 11/23/2011] [Indexed: 01/21/2023] Open
Abstract
Ezetimibe (EZE) lowers serum lipid levels by blocking cholesterol uptake in the intestine. Disposition of EZE and its pharmacologically active glucuronide metabolite (EZE-GLUC) to the intestine is dependent on hepatobiliary efflux. Previous studies suggested that hepatic transporter expression and function may be altered during nonalcoholic steatohepatitis (NASH). The purpose of the current study was to determine whether NASH-induced changes in the expression and function of hepatic transporters result in altered disposition of EZE and EZE-GLUC. Rats fed a methionine- and choline-deficient (MCD) diet for 8 weeks were administered 10 mg/kg EZE either by intravenous bolus or oral gavage. Plasma and bile samples were collected over 2 h followed by terminal urine and tissue collection. EZE and EZE-GLUC concentrations were determined by liquid chromatography-tandem mass spectrometry. The sinusoidal transporter Abcc3 was induced in MCD rats, which correlated with increased plasma concentrations of EZE-GLUC, regardless of dosing method. Hepatic expression of the biliary transporters Abcc2 and Abcb1 was also increased in MCD animals, but the biliary efflux of EZE-GLUC was slightly diminished, whereas biliary bile acid concentrations were unaltered. The cellular localization of Abcc2 and Abcb1 appeared to be internalized away from the canalicular membrane in MCD livers, providing a mechanism for the shift to plasma drug efflux. The combination of induced expression and altered localization of efflux transporters in NASH shifts the disposition profile of EZE-GLUC toward plasma retention away from the site of action. This increased plasma retention of drugs in NASH may have implications for the pharmacological effect and safety of numerous drugs.
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Affiliation(s)
- Rhiannon N Hardwick
- University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona, USA
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36
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Fardel O, Kolasa E, Le Vee M. Environmental chemicals as substrates, inhibitors or inducers of drug transporters: implication for toxicokinetics, toxicity and pharmacokinetics. Expert Opin Drug Metab Toxicol 2011; 8:29-46. [DOI: 10.1517/17425255.2012.637918] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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37
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Li Y, Revalde JL, Reid G, Paxton JW. Interactions of dietary phytochemicals with ABC transporters: possible implications for drug disposition and multidrug resistance in cancer. Drug Metab Rev 2011; 42:590-611. [PMID: 20433315 DOI: 10.3109/03602531003758690] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Common foods, such as fruits and vegetables, contain a large variety of secondary metabolites known as phytochemicals, many of which have been associated with health benefits. However, there is a limited knowledge of the processes by which these, mainly charged, phytochemicals (and/or their metabolites) are absorbed into the body, reach their biological target, and how they are eliminated. Recent studies have indicated that some of these phytochemicals are substrates and modulators of specific members of the superfamily of ABC transporting proteins. In this review, we present the reported interactions between the different classes of phytochemicals and ABC transporters and the mechanism by which they modulate the activity of these transporters. We also discuss the implications that such interactions may have on the pharmacokinetics of xenobiotics and the possible role of phytochemicals in the reversal of multidrug resistance in cancer chemotherapy.
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Affiliation(s)
- Yan Li
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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38
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Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim Biophys Acta Mol Basis Dis 2011; 1812:867-78. [DOI: 10.1016/j.bbadis.2010.12.021] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 12/21/2010] [Accepted: 12/22/2010] [Indexed: 12/12/2022]
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39
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Tydén E, Bjornstrom H, Tjälve H, Larsson P. Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse. J Vet Pharmacol Ther 2011; 33:332-40. [PMID: 20646193 DOI: 10.1111/j.1365-2885.2009.01140.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The gene and protein expression and the cellular localization of the ABC transport proteins breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance-associated protein 2 (MRP2) have been examined in the intestines, liver and kidney in horse. High gene and protein expression of BCRP and MRP2 were found in the small intestines, with cellular localization in the apical membranes of the enterocytes. In the liver, MRP2 was present in the bile canalicular membranes of the hepatocytes, whereas BCRP was localized in the cytoplasm of hepatocytes in the peripheral parts of the liver lobuli. In the kidney both BCRP and MRP2 were predominantly present in the distal tubuli and in the loops of Henle. In most tissues, the gene and protein expression of MRP1 were much lower than for BCRP and MRP2. Immunostaining of MRP1 was detectable only in the intestines and with localization in the cytoplasm of enterocytes in the caecum and colon and in the cells of serous acini of Brunner's glands in the duodenum and the upper jejunum. The latter cells were also stained for BCRP, but not for MRP2. Many drugs used in horse are substrates for one or more of the ABC transport proteins. These transporters may therefore have important functions for oral bioavailability, distribution and excretion of substrate compounds in horse.
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Affiliation(s)
- E Tydén
- Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
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40
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Fan J, Maeng HJ, Du Y, Kwan D, Pang K. Transport of 5,5-diphenylbarbituric acid and its precursors and their effect on P-gp, MRP2 and CYP3A4 in Caco-2 and LS180 cells. Eur J Pharm Sci 2011; 42:19-29. [DOI: 10.1016/j.ejps.2010.10.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 08/19/2010] [Accepted: 10/01/2010] [Indexed: 01/16/2023]
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41
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Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev 2010; 62:1238-49. [PMID: 20727377 DOI: 10.1016/j.addr.2010.08.006] [Citation(s) in RCA: 288] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2010] [Revised: 08/09/2010] [Accepted: 08/10/2010] [Indexed: 12/24/2022]
Abstract
Drug-metabolizing enzymes (DMEs) and transporters play pivotal roles in the disposition and detoxification of numerous foreign and endogenous chemicals. To accommodate chemical challenges, the expression of many DMEs and transporters is up-regulated by a group of ligand-activated transcription factors namely nuclear receptors (NRs). The importance of NRs in xenobiotic metabolism and clearance is best exemplified by the most promiscuous xenobiotic receptors: pregnane X receptor (PXR, NR1I2) and constitutive androstane/activated receptor (CAR, NR1I3). Together, these two receptors govern the inductive expression of a largely overlapping array of target genes encoding phase I and II DMEs, and drug transporters. Moreover, PXR and CAR also represent two distinctive mechanisms of NR activation, whereby CAR demonstrates both constitutive and ligand-independent activation. In this review, recent advances in our understanding of PXR and CAR as xenosensors are discussed with emphasis placed on the differences rather than similarities of these two xenobiotic receptors in ligand recognition and target gene regulation.
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42
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Gu X, Manautou JE. Regulation of hepatic ABCC transporters by xenobiotics and in disease states. Drug Metab Rev 2010; 42:482-538. [PMID: 20233023 DOI: 10.3109/03602531003654915] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The subfamily of ABCC transporters consists of 13 members in mammals, including the multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and the cystic fibrosis transmembrane conductance regulator (CFTR). These proteins play roles in chemical detoxification, disposition, and normal cell physiology. ABCC transporters are expressed differentially in the liver and are regulated at the transcription and translation level. Their expression and function are also controlled by post-translational modification and membrane-trafficking events. These processes are tightly regulated. Information about alterations in the expression of hepatobiliary ABCC transporters could provide important insights into the pathogenesis of diseases and disposition of xenobiotics. In this review, we describe the regulation of hepatic ABCC transporters in humans and rodents by a variety of xenobiotics, under disease states and in genetically modified animal models deficient in transcription factors, transporters, and cell-signaling molecules.
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Affiliation(s)
- Xinsheng Gu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, 06269, USA
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Khan AA, Chow ECY, Porte RJ, Pang KS, Groothuis GMM. The role of lithocholic acid in the regulation of bile acid detoxication, synthesis, and transport proteins in rat and human intestine and liver slices. Toxicol In Vitro 2010; 25:80-90. [PMID: 20888898 DOI: 10.1016/j.tiv.2010.09.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 07/25/2010] [Accepted: 09/26/2010] [Indexed: 10/19/2022]
Abstract
The effects of the secondary bile acid, lithocholic acid (LCA), a VDR, FXR and PXR ligand, on the regulation of bile acid metabolism (CYP3A isozymes), synthesis (CYP7A1), and transporter proteins (MRP3, MRP2, BSEP, NTCP) as well as nuclear receptors (FXR, PXR, LXRα, HNF1α, HNF4α and SHP) were studied in rat and human precision-cut intestine and liver slices at the mRNA level. Changes due to 5 to 10 μM of LCA were compared to those of other prototype ligands for VDR, FXR, PXR and GR. LCA induced rCYP3A1 and rCYP3A9 in the rat jejunum, ileum and colon, rCYP3A2 only in the ileum, rCYP3A9 expression in the liver, and CYP3A4 in the human ileum but not in liver. LCA induced the expression of rMRP2 in the colon but not in the jejunum and ileum but did not affect rMRP3 expression along the length of the rat intestine. In human ileum slices, LCA induced hMRP3 and hMRP2 expression. In rat liver slices, LCA decreased rCYP7A1, rLXRα and rHNF4α expression, induced rSHP expression, but did not affect rBSEP or rNTCP expression; whereas in the human liver, a small but significant decrease was found for hHNF1α expression. These data suggests profound species differences in the effects of LCA on bile acid transport, synthesis and detoxification. An examination of the effects of prototype VDR, PXR, GR and FXR ligands showed that these pathways are all intact in precision cut slices and that LCA exerted VDR, PXR and FXR effects. The LCA-induced altered enzymes and transporter expressions in the intestine and liver would affect the disposition of drugs.
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Affiliation(s)
- Ansar A Khan
- Department of Pharmacy, University of Groningen, Groningen, The Netherlands
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Bosquillon C. Drug transporters in the lung--do they play a role in the biopharmaceutics of inhaled drugs? J Pharm Sci 2010; 99:2240-55. [PMID: 19950388 DOI: 10.1002/jps.21995] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The role of transporters in drug absorption, distribution and elimination processes as well as in drug-drug interactions is increasingly being recognised. Although the lungs express high levels of both efflux and uptake drug transporters, little is known of the implications for the biopharmaceutics of inhaled drugs. The current knowledge of the expression, localisation and functionality of drug transporters in the pulmonary tissue and the few studies that have looked at their impact on pulmonary drug absorption is extensively reviewed. The emphasis is on transporters most likely to affect the disposition of inhaled drugs: (1) the ATP-binding cassette (ABC) superfamily which includes the efflux pumps P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs), breast cancer resistance protein (BCRP) and (2) the solute-linked carrier (SLC and SLCO) superfamily to which belong the organic cation transporter (OCT) family, the peptide transporter (PEPT) family, the organic anion transporter (OAT) family and the organic anion transporting polypeptide (OATP) family. Whenever available, expression and localisation in the intact human tissue are compared with those in animal lungs and respiratory epithelial cell models in vitro. The influence of lung diseases or exogenous agents on transporter expression is also mentioned.
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Affiliation(s)
- Cynthia Bosquillon
- Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, United Kingdom.
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Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 2010; 62:1-96. [PMID: 20103563 PMCID: PMC2835398 DOI: 10.1124/pr.109.002014] [Citation(s) in RCA: 581] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.
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Affiliation(s)
- Curtis D Klaassen
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
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Yokooji T, Murakami T, Ogawa K, Yumoto R, Nagai J, Takano M. Modulation of intestinal transport of 2,4-dinitrophenyl-S-glutathione, a multidrug resistance-associated protein 2 substrate, by bilirubin treatment in rats. J Pharm Pharmacol 2010; 57:579-85. [PMID: 15901347 DOI: 10.1211/0022357056019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Abstract
The effect of bilirubin treatment on intestinal transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate of multidrug resistance-associated protein 2 (MRP2), after application of 1-chloro-2, 4-dinitrobenzene (CDNB), a precursor of DNP-SG, was examined in rat intestine by the in-vitro everted sac, in-situ re-circulating perfusion, and in-situ loop methods. CDNB was taken up rapidly by jejunum and ileum, and the consequent intestinal efflux of DNP-SG, a glutathione conjugated metabolite of CDNB, was significantly higher in jejunum than in ileum in the in-situ and in-vitro studies. Co-administration of bilirubin (100 μM), as well as probenecid (1 mM) or ciclosporin (100 μM), with CDNB decreased the DNP-SG efflux in jejunum significantly, but not in ileum. The suppression of DNP-SG efflux in jejunum was also observed after intravenous administration of bilirubin (85.5 μmol kg−1), in which plasma bilirubin glucuronide levels were approximately 100 μM. In the in-vitro metabolism study, bilirubin exerted no significant effect on CDNB metabolism in the intestinal S9 fraction (supernatant of 9000 g). These results suggested that the diseased states accompanied with hyperbilirubinaemia might have increased the intestinal absorption, or oral bioavailability, of MRP2 substrates by suppressing MRP2 function at the proximal intestinal region.
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Affiliation(s)
- Tomoharu Yokooji
- Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats. Toxicology 2010; 267:165-71. [DOI: 10.1016/j.tox.2009.11.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 11/05/2009] [Accepted: 11/06/2009] [Indexed: 11/21/2022]
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Paul KB, Hedge JM, DeVito MJ, Crofton KM. Short-term exposure to triclosan decreases thyroxine in vivo via upregulation of hepatic catabolism in Young Long-Evans rats. Toxicol Sci 2009; 113:367-79. [PMID: 19910387 DOI: 10.1093/toxsci/kfp271] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)-phenol) is a chlorinated phenolic antibacterial compound found in consumer products. In vitro human pregnane X receptor activation, hepatic phase I enzyme induction, and decreased in vivo total thyroxine (T4) suggest adverse effects on thyroid hormone homeostasis. Current research tested the hypothesis that triclosan decreases circulating T4 via upregulation of hepatic catabolism and transport. Weanling female Long-Evans rats received triclosan (0-1000 mg/kg/day) by gavage for 4 days. Whole blood and liver were collected 24 h later. Total serum T4, triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured by radioimmunoassay. Hepatic microsomal assays measured ethoxyresorufin-O-deethylase, pentoxyresorufin-O-deethylase (PROD), and uridine diphosphate glucuronyltransferase enzyme activities. The messenger RNA (mRNA) expression of cytochrome P450s 1a1, 2b1/2, and 3a1/23; UGTs 1a1, 1a6, and 2b5; sulfotransferases 1c1 and 1b1; and hepatic transporters Oatp1a1, Oatp1a4, Mrp2, and Mdr1b was measured by quantitative reverse transcriptase PCR. Total T4 decreased dose responsively, down to 43% of control at 1000 mg/kg/day. Total T3 was decreased to 89 and 75% of control at 300 and 1000 mg/kg/day. TSH did not change. Triclosan dose dependently increased PROD activity up to 900% of control at 1000 mg/kg/day. T4 glucuronidation increased nearly twofold at 1000 mg/kg/day. Cyp2b1/2 and Cyp3a1/23 mRNA expression levels were induced twofold and fourfold at 300 mg/kg/day. Ugt1a1 and Sult1c1 mRNA expression levels increased 2.2-fold and 2.6-fold at 300 mg/kg/day. Transporter mRNA expression levels were unchanged. These data denote important key events in the mode of action for triclosan-induced hypothyroxinemia in rats and suggest that this effect may be partially due to upregulation of hepatic catabolism but not due to mRNA expression changes in the tested hepatic transporters.
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Affiliation(s)
- Katie B Paul
- Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27514, USA
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Grover A, Benet LZ. Effects of drug transporters on volume of distribution. AAPS J 2009; 11:250-61. [PMID: 19399628 PMCID: PMC2691462 DOI: 10.1208/s12248-009-9102-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2009] [Accepted: 03/25/2009] [Indexed: 02/08/2023] Open
Abstract
Recently, drug transporters have emerged as significant modifiers of a patient's pharmacokinetics. In cases where the functioning of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity, as well as a change in half life independent of a change in clearance. Here, we review pharmacokinetic interactions at the transporter level that have been investigated in animals and humans and reported in literature, with a focus on the changes in distribution volume. We pay particular attention to the differing effects of changes in transporter function on the three measures of volume. Further, trends are discussed as they may be used to predict volume changes given the function of a transporter and the primary location of the interaction. Because the liver and kidneys express the greatest level and variety of transporters, we denote these organs as the primary location of transporter-based interactions. We conclude that the liver is a larger contributor to distribution volume than the kidneys, in consideration of both uptake and efflux transporters. Further, while altered distribution due to secondary interactions at tissues other than the liver and kidneys may have a pharmacodynamic effect, these interactions, at least at the blood-brain barrier, do not appear to significantly influence overall distribution volume. The analysis provides a framework for understanding potential pharmacokinetic interactions rooted in drug transporters as they modify drug distribution.
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Affiliation(s)
- Anita Grover
- Department of Biopharmaceutical Sciences, University of California, 533 Parnassus Ave, Room U-68, San Francisco, 94143-0912 CA USA
| | - Leslie Z. Benet
- Department of Biopharmaceutical Sciences, University of California, 533 Parnassus Ave, Room U-68, San Francisco, 94143-0912 CA USA
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Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol 2009; 156:7-27. [PMID: 19133988 DOI: 10.1111/j.1476-5381.2008.00030.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors including the farnesoid X receptor, pregnane X receptor, vitamin D receptor and constitutive androstane receptor, which target overlapping, although not identical, sets of genes. Because the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis, therapeutic targeting of these receptors via specific and potent agonists may further enhance the hepatic defence against toxic bile acids. Activation of these receptors results in repression of bile acid synthesis, induction of phases I and II bile acid hydroxylation and conjugation and stimulation of alternative bile acid export while limiting hepatocellular bile acid import. Furthermore, the use of nuclear receptor ligands may not only influence bile acid transport and metabolism but may also directly target hepatic fibrogenesis and inflammation. Many drugs already used to treat cholestasis and its complications such as pruritus (e.g. ursodeoxycholic acid, rifampicin, fibrates) may act via activation of nuclear receptors. More specific and potent nuclear receptor ligands are currently being developed. This article will review the current knowledge on nuclear receptors and their potential role in the treatment of cholestatic liver diseases.
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Affiliation(s)
- Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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