MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver.
beta-Estradiol 17beta-D-glucuronide (E(2)17G), an endogenous cholestatic metabolite of estradiol, has been identified as a substrate for both hepatic P-glycoprotein (P-gp) and the multispecific organic anion transporter (MOAT), the liver-specific homologue of the multidrug resistance protein. The aim of the present studies was to determine the role of hepatic P-gp and MOAT in E(2)17G-mediated cholestasis and its biliary excretion using the isolated perfused rat liver. A bolus dose of E(2)17G (2 micromol) alone decreased the bile flow maximally from 1.5 to 0.3 microl/min/g liver. In the presence of an infusion of 1.5 microM daunorubicin or 1.0 microM Taxol, P-gp substrates, E(2)17G cholestasis was blocked such that 2 micromol E(2)17G decreased the bile flow from 1.48 to 1.31 or from 1.70 to 1.31 microl/min/g liver, respectively. In the presence of 1 and 3 microM Taxol, the log dose-response curves for E(2)17G cholestasis were shifted to the right 2-fold and 5-fold, respectively, in a parallel manner. Taxol (10 and 50 microM) inhibited the ATP-dependent transport of 10 microM E(2)17G in canalicular plasma membrane vesicles by 46 and 81%, respectively. Daunorubicin (1.5 microM) also shifted the log dose-response curve for E(2)17G cholestasis to the right about 4-fold. Neither Taxol nor daunorubicin decreased the biliary excretion of E(2)17G. Infusion of cyclosporine (6 microM), an inhibitor of both P-gp and MOAT, significantly blocked both E(2)17G cholestasis and biliary excretion, such that 16 micromol E(2)17G decreased the bile flow only 15-20%. In contrast, bromosulfophthalein, a MOAT substrate, had no effect on either E(2)17G-mediated cholestasis or its biliary excretion. These data indicate that P-gp plays an essential role in E(2)17G-mediated cholestasis and suggest that MOAT functions to deliver high concentrations of E(2)17G to P-gp.
Department of Pharmacology, College of Medicine, Graduate Center for Toxicology, University of Kentucky, Lexington 40536, USA.
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Liu
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Huang
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Hoffman
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Gosland
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Vore
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D027321:Anion Transport Proteins; D001646:Bile / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology*; D002779:Cholestasis / Q000139:chemically induced / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D002352:Carrier Proteins; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D016572:Cyclosporine; D017239:Paclitaxel; D003630:Daunorubicin