Increase in biliary permeability subsequent to intrahepatic cholestasis by estradiol valerate in rats

To clarify the role of biliary permeability in estrogen-induced intrahepatic cholestasis, long-term experiments were performed in rats using estradiol 17 beta-valerate. Bile flow, secretion of taurocholate, biliary clearance of [14C]sucrose and [14C]inulin, and phosphate concentration in bile were determined in hemoglobin-free perfused livers excised from male rats pretreated for different time periods. Basal and taurocholate-stimulated bile flow were already reduced during the first 7-10 days of treatment and remained at the lower level for more than 12 wk. In contrast, the concentration of taurocholate in bile was elevated at 7 and 10 days but was lower than in controls after 3 wk. An increase in [14C]sucrose clearance after 3 wk indicated a moderate increase in the permeability of a paracellular pathway. The concentration of phosphate in bile was also increased after 3 wk. Detailed analysis of biliary sucrose and inulin clearances revealed that the diffusion permeability coefficient (k = 0.14) did not increase during the first 10 days of treatment but did increase to greater than 0.4 after 3 wk of treating rats with estradiol 17 beta-valerate. From the temporal sequence of the cholestatic responses it is concluded that the altered permeability of the biliary tree is not the primary event but occurs subsequent to the cholestasis induced by estrogens.