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 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.
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.).
Zainab M
ZM
Mahdi
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.).
Uta
U
Synal-Hermanns
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.).
Aylin
A
Yoker
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.).
Kaspar P
KP
Locher
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.
Bruno
B
Stieger
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects*; D001393:Azoles / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D018374:LLC-PK1 Cells; D010743:Phospholipids / Q000378:metabolism; D015203:Reproducibility of Results; D013552:Swine; D013656:Taurocholic Acid / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D001393:Azoles; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D010743:Phospholipids; D013656:Taurocholic Acid; C095122:multidrug resistance protein 3