Reduced cholestatic potency of taurolithocholate during backward perfusion of the rat liver

Rat livers perfused backward are less susceptible to taurolithocholate (TLC) cholestasis than livers perfused forward. To understand this phenomenon, the uptake, metabolism, and excretion of TLC were studied in rat livers perfused forward and backward with TLC. Bolus injections of [3H]TLC were administered 20 minutes after the onset of unlabeled TLC infusion. Biliary bile acids were measured enzymatically and bile acid species were separated and quantified by thin-layer chromatography. Determination of radioactivity in each spot yielded the percentage distribution of various biliary bile acid metabolites. After perfusion, livers were examined by light and transmission electron microscopy. TLC infusion at 32 nmoles/minute/gm of liver reduced bile flow by 80% or more within 30 minutes of forward perfusion but not at all during backward perfusion. TLC uptake was over 95% regardless of perfusion direction. Although the distribution of biliary metabolites of TLC was the same during forward and backward perfusion, maximal rate of total biliary bile acid excretion was four-fold higher and total recovery of radioactivity in bile was six-fold higher during backward perfusion. Less than 6% of excreted radioactivity was in the form of unmetabolized TLC. Severe cholestasis induced by forward TLC perfusion was associated with extensive structural distortion of bile canalicular membranes almost exclusively in the periportal zone but with little hepatocellular necrosis. Livers perfused backward manifested no cholestasis. They showed cell necrosis in the pericentral zone which became extensive (10%) by 60 minutes, but the canalicular changes occurred only in a small proportion of canaliculi in the pericentral region. Bile canalicular membrane changes developed extensively only when very high doses of TLC were perfused backward. Even then, bile flow fell only 60%. We conclude: the lesser susceptibility to TLC cholestasis of livers perfused backward is in part related to the greater biotransformation and consequent excretion of TLC by pericentral hepatocytes. TLC-induced cholestasis is associated more closely with bile canalicular membrane changes than with extent of hepatocellular necrosis. The greater reduction of bile flow with periportal than with pericentral canalicular change is compatible with current concepts of biliary microanatomy which postulate a flow of bile from pericentral through periportal regions of the lobule into the bile ductules.