Cholestatic Properties of Steroid Glucuronides
Subsequent animal studies demonstrated that pregnancy and both synthetic and natural estrogens were effective in decreasing the biliary excretion of several organic anions, including BSP (9), dibromosulfophthalein, and the glucuronide conjugate metabolites of phenytoin and morphine (10-15). Ethinylestradiol, at dosages of 0.5-1 mg/day for 5-10 days, also decreased basal bile flow and the maximal taurocholate secretory capacity (1~19). Both pregnancy and treatment of rats with estradiol or ethinylestradiol decrease the uptake of taurocholate and several steroid glucuronides in isolated hepatocytes (20, 21), indicating inhibition of basolateral as well as canalicular transport processes. Indeed, ethinylestradiol treatment decreases both Na +/taurocholate cotransport in basolateral membrane vesicles and ATPdependent taurocholate transport in canalicular membrane vesicles (22). The decrease in Na+ /taurocholate cotransport is accompanied by a decrease in steady-state mRNA levels for Na+ /taurocholate cotransporter (23, 24 ). The effects of pregnancy, however, are less pronounced. While the Vmu for Na+ftaurocholate cotransport is decreased in isolated hepatocytes from pregnant rats (25), this value is not different in hepatic basolateral membrane vesicles isolated from pregnant versus nonpregnant rats (26, 27), consistent with the lack of effect of pregnancy on the expression of mRNA (26, 28) and protein (27) for the Na+ /taurocholate cotransporter.