Adaptive response to increased bile acids: induction of MDR1 gene expression and P-glycoprotein activity in renal epithelial cells.
Cholestatic liver disease and increased serum bile acid concentrations are known to trigger various adaptive responses including the induction of hepatic, intestinal and renal bile acid transport proteins, but renal P-glycoprotein (Pgp, multidrug resistance protein 1, MDR1) remained uninvestigated in this context. We show that treatment of Madin Darby canine kidney (MDCK) cells with pathophysiologically relevant concentrations of chenodeoxycholic acid (CDCA; 100 microM) for 12 h induces MDR1 transcript levels in vitro more than twofold. CDCA and deoxycholic acid pre-treatment for 24-96 h (100 microM) also increased Pgp activity measured as rhodamine efflux, while cholic acid and taurocholic acid were not effective in concentrations up to 600 microM. CDCA pre-treatment (100 microM, 72 h) also resulted in a doubling of rhodamine123 secretion across an epithelium-like monolayer grown on Transwell filters and decreased the sensitivity towards the kidney toxic drugs cyclosporine A and paclitaxel. These findings predict physiologically as well as pharmacologically relevant consequences of liver disease for Pgp substrate transport and toxicity in the kidneys.
Kneuer
Carsten
C
Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. kneuer@uni-leipzig.de
Honscha
Walther
W
Gäbel
Gotthold
G
Honscha
Kerstin U
KU
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D019826:Cholic Acid / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D013656:Taurocholic Acid / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D020112:Rhodamine 123; D013656:Taurocholic Acid; D016572:Cyclosporine; D019826:Cholic Acid; D017239:Paclitaxel