Characterization of cholestasis induced by estradiol-17 beta-D-glucuronide in the rat

Estradiol-17 beta-D-glucuronide induced an immediate, profound and reversible inhibition of bile flow after its i.v. administration in the rat. The degree of cholestasis was dose-dependent in the range of 8.5 to 21 mumol/kg i.v. A dose of 11 mumol/kg i.v. inhibited bile flow and bile acid secretory rate 65 to 70% within 15 to 30 min of its administration; bile flow and bile acid secretion had returned to near control values within 3 hr. Linear regression analysis of the relationship between bile flow and bile acid secretion indicated a substantial decrease in bile acid independent flow. In contrast, neither estradiol-17 beta, estradiol-3-glucuronide nor estradiol-3-sulfate-17 beta-D-glucuronide at an equimolar dose had any inhibitory effect on these parameters. After a dose of [3H]estradiol-17 beta-D-glucuronide, 79% of the administered radioactivity was excreted in the bile in 3 hr. Estradiol-3-sulfate-17 beta-D-glucuronide was tentatively identified as the predominant biliary metabolite with estradiol-17 beta-D-glucuronide also present in substantial amounts. These data indicate that estradiol-17 beta-D-glucuronide is toxicologically active and suggest the possibility that this estrogen metabolite may induce hepatic pathology in vivo.