Estradiol-l7&~-glucuronide (E-l7G), a metabolite of natural estrogen, is a potent cholestatic agent in uivo. We, therefore, studied the mechanisms of E-17G cholestasis using in vitro perfused rat liver system. Furthermore, since it has been postulated that sodium taurocholate (TC) may interfere with either uptake or biliary excretion of other steroid agents, we tested whether E-17G cholestasis could be modified by TC administration. During a constant infusion of TC at a physiological rate (0.50 pmole per min), a dose-dependent decrease of bile flow was observed after E-17G addition from 1.5 to 5 x M. E-17G decreased bile acid excretory rate but not bile acid concentration in bile. In separate experiments, TC was infused at different rates (0, 0.25, 0.50, and 0.75 pmole per min) into the perfusate over the entire experimental period, and E-17G was added at 1.75 x M. In this setting, E-17G cholestasis was diminished by increasing TC infusion rate and was prevented by TC at 0.75 Hmole per min. Infusion of sodium dehydrocholate (0.75 pmole per min), a nonmicelle-forming bile acid, did not prevent E-17G cholestasis. During E-17G cholestasis, an increased biliary permeability to ''C-sucrose was observed. This effect was also prevented by TC, but not by sodium dehydrocholate which was infused at 0.75 pmole per min. The perfusate disappearance curves of 3H-E-17G at the different TC infusion rates showed no changes in the initial uptake phase, but a profound dose-dependent difference in the excretory phase. The amount of E-17G left in perfusate at the end of experiments was 34% when no TC was infused and decreased to 28%; 22 and 7% at 0.25; 0.50 and 0.75 pmole per rnin TC rate, respectively. Measurement of 3H-E-17G excreted in bile as well as its biliary concentration in the four TC groups showed that TC significantly increased E-17G excretion. Small amounts of E-17G were recovered in liver plasma membranes. However, these amounts were directly proportional to changes of bile flow induced by estrogen at different TC infusion rates. In these same liver membrane preparations, neither Na+,K+nor Mg++-ATPases were altered. The data suggest that alterations of canalicular membrane permeability may be critical in the development of E-17G cholestasis. Prevention of E-17G cholestasis by TC infusion may occur through increased micellar solubilization and facilitated biliary excretion of the estrogen thus avoiding its membrane-altering action.
Intrahepatic cholestasis induced by estrogens is characterized by modification of hepatic membrane lipids, reduction in the bile acid-independent component of bile flow, alteration of the membrane-bound Na+,K+-and