Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis
Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resista...
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Published in | Molecular pharmacology Vol. 90; no. 1; pp. 23 - 34 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
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United States
01.07.2016
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Abstract | Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK1 cells were stably transfected with human Na(+)-taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3. |
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AbstractList | Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK1 cells were stably transfected with human Na(+)-taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3. |
Author | Locher, Kaspar P Synal-Hermanns, Uta Yoker, Aylin Stieger, Bruno Mahdi, Zainab M |
Author_xml | – sequence: 1 givenname: Zainab M surname: Mahdi fullname: Mahdi, Zainab M organization: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.) – sequence: 2 givenname: Uta surname: Synal-Hermanns fullname: Synal-Hermanns, Uta organization: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.) – sequence: 3 givenname: Aylin surname: Yoker fullname: Yoker, Aylin organization: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.) – sequence: 4 givenname: Kaspar P surname: Locher fullname: Locher, Kaspar P organization: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.) – sequence: 5 givenname: Bruno surname: Stieger fullname: Stieger, Bruno email: bruno.stieger@uzh.ch organization: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.M.M., U.S.-H., A.Y., B.S.); and Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland (K.P.L.) bruno.stieger@uzh.ch |
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SubjectTerms | Animals Antifungal Agents - adverse effects ATP Binding Cassette Transporter, Sub-Family B - metabolism ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Azoles - pharmacology Bile Acids and Salts - metabolism Biological Transport - drug effects Blotting, Western Chemical and Drug Induced Liver Injury - metabolism Cholagogues and Choleretics - metabolism Cholestasis - chemically induced Cholestasis - metabolism Humans LLC-PK1 Cells Phospholipids - metabolism Reproducibility of Results Swine Taurocholic Acid - metabolism |
Title | Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis |
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