BILIARY-EXCRETION OF ESTRADIOL-17-BETA-GLUCURONIDE IN THE RAT

Estradiol-17 beta-glucuronide (E(2)17G) is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestas is of pregnancy. In the current study, we examined the mechanism of th e biliary excretion tion of E(2)17G and estradiol metabolites in rats. Biliary excretion of tracer doses of [H-3] extradiol-17 beta-glucuron ide nide and [C-14]estradiol or [H-3]taurocholate and [(14)]vinblastin e, a P-glycoprotein (P-GP) substrate, intravenously administered as a bolus to bile drained control rats or EHBR was studied, Biliary excret ion of E(2)17G and estradiol metabolites in EHBR was markedly delayed, Analyses of biliary metabolites after estradiol injection showed less polar conjugates in EHBR, In contrast, the excretion of taurocholate and vinblastine (WB) was only slightly delayed in EHBR. Although pheno thiazine treatment to induce the expression of P-GP increased biliary vinblastine excretion, it did not affect biliary excretion of a tracer dose of [H-3]estradiol-17 beta-glucuronide, However, phenothiazine tr eatment inhibited the cholestasis induced by E(2)17G infused at the ra te of 0.075 mu mol/min/100 g for 20 minutes and increased biliary E(2) 17G excretion. Sulfobromophthalein infusion (0.2 mu mol/min/100 g body weight) markedly inhibited the biliary excretion of E(2)17G and estra diol metabolites, whereas dibromosulfophthalein (DBSP) at the same inf usion rate had no effect. These findings indicate that E(2)17G is excr eted into bile by a canalicular organic anion carrier for sulfobromoph thalein (BSP), not for DBSP, under physiological conditions, and that P-GP influences E(2)17G excretion only at a high dose.