Prevention of lithocholate--induced cholestasis by cycloheximide, an inhibitor of protein synthesis

Our previous investigations have shown that lithocholic acid (LCA)-induced cholestasis is associated with an increased synthesis of microsomal cholesterol which is transported with LCA and incorporated in the bile canalicular membrane. As the significance of these changes remains unknown the effect of interference with microsomal protein synthesis and/or with the cellular transport of cholesterol was studied. Male Wistar rats were injected i.p. with cycloheximide at the dose of 15 micrograms/100 g BW 3 times over a 24-hour period. After cannulating the common bile duct and collecting bile for one hour, the animals were either injected i.v. with 12 mumoles C14-LCA/100 g BW or with a 7.5% albumin solution and bile was collected for another hour. LCA injection in untreated animals reduced bile flow by more than 90% of control values. In contrast, bile flow in the group treated with cycloheximide and LCA was normal and did not differ from that of animals given cycloheximide alone. Bile salt secretion rate was increased in the cycloheximide-LCA group over the control groups. This was mainly due to the secretion of more than 80% of the injected LCA and was confirmed by the distribution of the radioactivity. By electron microscopy, the liver in the cycloheximide-LCA group did not show any of the well defined changes associated with LCA-induced cholestasis. These data suggest that microsomes play an important role in the pathogenesis of LCA cholestasis and that inhibition of microsomal protein synthesis can prevent its development.