CHARACTERIZATION OF CHOLESTASIS INDUCED BY ESTRADIOL-17 BETA-D-GLUCURONIDE IN THE RAT

Abstract

Estradiol-17.beta.-D-glucuronide induced an immediate, profound and reversible inhibiton of bile flow after its i.v. administration in the rat. The degree of cholestasis was dose-dependent in the range of 8.5-21 .mu.mol/kg i.v. A dose of 11 .mu.mol/kg i.v. inhibited bile flow and bile acid secretory rate 65-70% within 15-30 min of its administration; bile flow and bile acid secretion had returned to near control values within 3 h. Linear regression analysis of the relationship between bile flow and bile acid secretion indicated a substantial decrease in bile acid independent flow. Estradiol-17.beta., estradiol-3-glucuronide or estradiol-3-sulfate-17.beta.-D-glucuronide at an equimolar dose did not inhibit parameters. After a dose of [3H]estradiol-17.beta.-D-glucuronide, 79% of the administered radioactivity was excreted in the bile in 3 h. Estradiol-3-sulfate-17.beta.-D-glucuronide was tentatively indentified as the predominant biliary metabolite with estradiol-17.beta.-D-glucuronide present in substantial amounts. Estradiol-17.beta.-D-glucuronide is toxicologically active and this estrogen metabolite may induce hepatic pathology in vivo.