Increased tight junction permeability: a possible mechanism of oestrogen cholestasis

Abstract

Ethynyl estradiol increased rat biliary permeability for 3H-inulin and 14C-sucrose, and significantly raised serum concentrations of bile acids after 3 and 7 days treatment (P < 0.0005) and bilirubin after 7 days (P < 0.05) but not after 3 days. Following i.v. infusion of bromsulphthalein or phenolphthalein, ethynyl estradiol-treated rats had elevated plasma concentrations of the 3 bile constituents, bromsulphthalein (P < 0.005 after 3 and 7 days), bromsulphthalein-glutathione conjugate (P < 0.005 after 3 days; P < 0.0005 after 7 days) and phenolphthalein glucuronide (P < 0.005 after 3 days; P < 0.0005 after 7 days), but the plasma concentration of unconjugated phenolphthalein, which was undetectable in bile, was unchanged. Similar changes followed partial biliary obstruction produced by bile cannula elevation. This pattern suggests that biliary constituents are refluxing from bile to plasma via the paracellular pathway, a concept further supported by structural changes in tight junction morphology in the estrogen-treated rats. Leakiness of canalicular tight junctions may explain the pathophysiology of estrogen-induced cholestasis.