Steroid D-ring glucuronides: characterization of a new class of cholestatic agents in the rat

Estriol-17 beta(beta-D-glucuronide) (E317G), estriol-16 alpha(beta-D-glucuronide) (E316G) and testosterone-17 beta(beta-D-glucuronide) (TG) produced an immediate, reversible and dose-dependent inhibition of bile flow after their i.v. administration in the rat. Within 15 to 30 min of their administration, bile flow was inhibited by 50% at doses of 13.2, 20.0 and 31.6 mumol/kg of E317G, TG and E316G, respectively. A plot of the logarithm of the dose of each agent vs. the maximal percentage of inhibition of bile flow yielded straight lines which were parallel. E317G, TG and E316G were 0.68, 0.40 and 0.29 times as potent, respectively, as estradiol-17 beta(beta-D-glucuronide), a previously identified cholestatic steroid glucuronide. Maximal inhibition of bile acid secretory rate was similar to that of bile flow for all three agents. Calculation of the bile acid vs. bile flow regression lines indicated substantial inhibition of bile acid independent flow by E317G and TG but only slight inhibition by E316G. In contrast, estriol-3(beta-D-glucuronide) at doses of 11 and 33 mumol/kg increased bile flow. After an i.v. dose (44 mumol/kg) of [3H]E316G, 53% of the dose was recovered in the bile in 3 hr. Unchanged [3H]E316G and a minor metabolite tentatively identified as [3H]estriol-3-sulfate-16 alpha(beta-D-glucuronide) were the predominant compounds recovered in the bile. These data present evidence for a new class of cholestatic compounds, the steroid D-ring glucuronides, and suggest a means by which endogenous or exogenous steroids may produce hepatobiliary dysfunction.