HEPATIC TRANSPORT OF ORGANIC-ANIONS IN TAUROLITHOCHOLATE-INDUCED CHOLESTASIS IN RATS

The hepatic transport of organic anions was evaluated in taurolithocho late-induced cholestasis in rats. Taurolithocholate (3 mu mol per 100 g body wt., i.v.) diminished bile how by 61%, whereas biliary excretio n of bile salts was normalized after 80 min. Tm studies of sulfobromop hthalein revealed reduced biliary excretion (-58%) and increased hepat ic content of the dye (+75%). Conjugation pattern in bile showed that free sulfobromophthalein was increased by 57%, suggesting that hepatic conjugation was also impaired. This finding, however, could not fully explain the reduced sulfobromophthalein excretion since Tm of its non -metabolizable analog phenol-3,6-dibromophthalein was also decreased ( -41%). Compartmental analysis of plasma decay of both dyes revealed th at, whereas hepatic uptake was unaltered, canalicular excretion was re duced and reflux from the liver into plasma was increased by the chole static agent. Studies on transport of phenol-3,6-dibromophthalein by i solated hepatocytes showed that while uptake was unaffected, the treat ment reduced (-36%) the release from hepatocytes preloaded with the dy e. Neither glutathione S-transferase activity nor binding of sulfobrom ophthalein to cytosolic proteins was altered when evaluated in vitro, suggesting that reduced conjugation and enhanced sinusoidal reflux wer e not due to an irreversible effect of taurolithocholate on this enzym e. In conclusion, taurolithocholate impairs the hepatic transport of o rganic anions by impairing canalicular excretion and intrahepatic conj ugation, as well as by increasing transfer from the liver into the pla sma. (C) Journal of Hepatology.