Hepatic transport of organic anions in taurolithocholate-induced cholestasis in rats

Abstract

The hepatic transport of organic anions was evaluated in taurolithocholate-induced cholestasis in rats. Taurolithocholate (3 mumol per 100 g body wt., i.v.) diminished bile flow by 61%, whereas biliary excretion of bile salts was normalized after 80 min. Tm studies of sulfobromophthalein revealed reduced biliary excretion (-58%) and increased hepatic 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 that, whereas hepatic uptake was unaltered, canalicular excretion was reduced and reflux from the liver into plasma was increased by the cholestatic agent. Studies on transport of phenol-3,6-dibromophthalein by isolated hepatocytes showed that while uptake was unaffected, the treatment reduced (-36%) the release from hepatocytes preloaded with the dye. Neither glutathione S-transferase activity nor binding of sulfobromophthalein to cytosolic proteins was altered when evaluated in vitro, suggesting that reduced conjugation and enhanced sinusoidal reflux were not due to an irreversible effect of taurolithocholate on this enzyme. In conclusion, taurolithocholate impairs the hepatic transport of organic anions by impairing canalicular excretion and intrahepatic conjugation, as well as by increasing transfer from the liver into the plasma.