LARGE INTRAVENOUS BILIRUBIN LOADS INCREASE THE CYTOTOXICITY OF BILE AND LOWER THE RESISTANCE OF THE CANALICULAR MEMBRANE TO CYTOTOXIC INJURY AND CAUSE CHOLESTASIS IN PIGS

Background: Large intravenous bilirubin loads cause loss of hepatic ca nalicular membrane microvilli and cholestasis. This study examines whe ther these untoward effects might be due to canalicular membrane injur y from cytotoxic bile. Methods: The cytotoxicity of bile was assayed a gainst pig erythrocytes before and throughout 4.5-h intravenous infusi on of 170 mu g kg(-1) body weight of bilirubin in anaesthetized pigs. The capacity to generate canalicular bile flow was tested before and a fter bilirubin infusion by means of short-term intraportal cholic acid infusion. Results: Bilirubin infusion increased the cytotoxicity of h epatic bile, reduced biliary phospholipid secretion by 90%, and caused cholestasis. Cholic acid infusion before bilirubin also increased the cytotoxicity of bile but increased bile how and doubled biliary phosp holipid output. Conclusion: Large intravenous bilirubin infusions incr ease the cytotoxicity of bile, suppress biliary phospholipid secretion , and render hepatic canalicular membrane microvilli susceptible to in jury from cytotoxic bile so that cholestasis occurs.