Cholestasis induced by estradiol-17 beta-D-glucuronide: mechanisms and prevention by sodium taurocholate.
Estradiol-17 beta-D-glucuronide (E-17G), a metabolite of natural estrogen, is a potent cholestatic agent in vivo. We, therefore, studied the mechanisms of E-17G cholestasis using in vitro perfused rat liver system. Furthermore, since it has been postulated that sodium taurocholate (TC) may interfere with either uptake or biliary excretion of other steroid agents, we tested whether E-17G cholestasis could be modified by TC administration. During a constant infusion of TC at a physiological rate (0.50 mumole per min), a dose-dependent decrease of bile flow was observed after E-17G addition from 1.5 to 5 X 10(-5) M. E-17G decreased bile acid excretory rate but not bile acid concentration in bile. In separate experiments, TC was infused at different rates (0, 0.25, 0.50, and 0.75 mumole per min) into the perfusate over the entire experimental period, and E-17G was added at 1.75 X 10(-5) M. In this setting, E-17G cholestasis was diminished by increasing TC infusion rate and was prevented by TC at 0.75 mumole per min. Infusion of sodium dehydrocholate (0.75 mumole per min), a nonmicelle-forming bile acid, did not prevent E-17G cholestasis. During E-17G cholestasis, an increased biliary permeability to 14C-sucrose was observed. This effect was also prevented by TC, but not by sodium dehydrocholate which was infused at 0.75 mumole per min. The perfusate disappearance curves of 3H-E-17G at the different TC infusion rates showed no changes in the initial uptake phase, but a profound dose-dependent difference in the excretory phase.(ABSTRACT TRUNCATED AT 250 WORDS)
D000251:Adenosine Triphosphatases / Q000032:analysis; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced* / Q000517:prevention & control; D003685:Dehydrocholic Acid / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000494:pharmacology*
D001647:Bile Acids and Salts; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D013656:Taurocholic Acid; D000251:Adenosine Triphosphatases; D003685:Dehydrocholic Acid