Subcellular Pathology of Rat Liver in Cholestasis and Choleresis Induced by Bile Salts. 1. Effects of Lithocholic, 3beta-hydroxy-5-cholenoic, Cholic, and Dehydrocholic Acids

Cholestasis or choleresis was induced in the rat by intravenous infusion (0.05 to 0.2 mumole per minute per 100 grams of body weight) of sodium taurolithocholate, 3beta-hydroxy-5-cholenoate, taurocholate, and dehydrocholate either singly or in combination after or without cannulation of the common bile duct. Bile flow was monitored and ultrastructural changes were examined by scanning and transmission electron microscopy up to 3 hours after bile salt administration. Taurolithocholate induced acute cholestasis and ultrastructural alterations consisting primarily of dilation of bile canaliculi, loss of canalicular microvilli, and lamellar transformation of the canalicular membrane. Occasionally, crystalline precipitates were present within the canalicular lumen and in the pericanalicular region of hepatocytes. 3beta-Hydroxy-5-cholenoate caused similar but less severe ultrastructural changes than those induced by taurolithocholate. Dehydrocholate had a greater choleretic effect than taurocholate, but neither induced noteworthy ultrastructural change. When infused simultaneously with taurolithocholate, taurocholate reversed cholestasis and largely prevented development of the ultrastructural changes induced by taurolithocholate. In contrast, simultaneous infusion of dehydrocholate prevented neither cholestasis nor development of the ultrastructural changes induced by taurolithocholate, which were more striking than those caused by taurolithocholate or 3beta-hydroxy-5-cholenoate alone. In addition, structural changes associated with cholestasis induced by these bile salts either singly or in combination were more pronounced and frequent in the periportal zone than elsewhere in the hepatic lobule. These results suggest that both taurolithocholate and 3beta-hydroxy-5-cholenoate induce cholestasis by affecting the structural and functional integrity of the bile canalicular membrane and also, in part, by forming untransportable precipitates. The contrasting effects of taurocholate and dehydrocholate on taurolithocholate-induced changes suggest that taurocholate overcomes the effect of taurolithocholate by solubilizing it into mixed micelles, but dehydrocholate and its metabolites have little or no such effect. The intralobular variation in severity of ultrastructural changes probably reflects the accumulation of bile salts in greater concentrations in hepatocytes near the portal triads.