EFFECT OF OXYPURINOL, A XANTHINE-OXIDASE INHIBITOR, ON HEPATIC-INJURYIN THE BILE DUCT-LIGATED RAT

Oxidant stress has been implicated as playing a role in the pathogenes is of cholestatic liver injury. The objective of this study was to det ermine whether the xanthine oxidase/xanthine dehydrogenase enzyme syst em was involved in this oxidant stress. Adult Sprague-Dawley rats were treated with the xanthine oxidase inhibitor, oxypurinol, and randomiz ed to bile duct ligation or sham surgery; vehicle-treated, sham-operat ed rats served as controls. After 5 d of bile duct ligation, serum asp artate aminotransferase, alanine aminotransferase, alkaline phosphatas e, and total and direct bilirubin concentrations were significantly el evated, and increased lipid peroxidation of hepatic mitochondria and m icrosomes was present. Treatment with oxypurinol reduced the aspartate aminotransferase, alanine aminotransferase, and bilirubin values by 2 6-47% but did not alter the increased lipid peroxidation of mitochondr ia and microsomes. Serum vitamin E:total lipids ratio was also reduced in both bile duct-ligated groups, consistent with oxidant injury. The se data show that inhibition of xanthine oxidase reduces biochemical e vidence of hepatocellular injury during bile duct ligation without aff ecting oxidant damage to intracellular hepatocyte organelles. Thus, in this model a component of cholestatic injury appears to have been cau sed by oxidant stress from a source outside of the hepatocyte.