Effect of lovastatin on cholestatic liver injury induced by bile duct ligation in rats

Abstract

The involvement of bile acids in hepatic damage under cholestasis and the effect of lowering bile acid level through the inhibition of microsomal 3- hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by lovastatin was studied. Rats were divided into five groups: Sham operated control (group 1), common bile duct (CBD) ligation alone (group 2), choledococaval shunt operation (group 3), CBD ligation plus taurocholic acid injection (group 4), and CBD ligation plus lovastatin injection (group 5). Markers which reflect hepatic injury in serum in group 3 showed a greater increase than that in group 1. Serum total bile acid, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, 5'-nucleotidase and total bilirubin levels in group 4 showed greater increases than those in group 2. The levels of serum alanine aminotransferase, aspartate aminotransferase and cytosolic total bile acid in group 5 were lower than those in group 2. Serum total bile acid and microsomal HMG-CoA reductase levels in group 5 were not significantly lower than those in group 2. Rats in group 3 showed focal areas of hepatic necrosis associated with some infiltration of a few inflammatory cells. The abnormalities of the light microscopic structures of the liver of rats were more evident in group 4 than in group 2, and were preserved in group 5. According to the results, the choledococaval shunt operated rats resulted in hepatic damages. More hepatic amage was caused by administration of taurocholic acid under the cholestasis. Lovastatin, an inhibitor of HMG-CoA reductase, prevented the hepatic damage under the cholestasis. These experiments demonstrate that bile acid is one of the major factors which contribute to the damages observed in cholestasis, and that lowering cytosolic bile acid level through inhibition of HMG-CoA reductase is helpful in protecting the cholestatic damage.