VITAMIN-E REDUCES OXIDANT INJURY TO MITOCHONDRIA AND THE HEPATOTOXICITY OF TAUROCHENODEOXYCHOLIC ACID IN THE RAT

Background & Aims: Hydrophobic bile acids have been implicated in the pathogenesis of cholestatic liver injury. The hypothesis that hydropho bic bile acid toxicity is mediated by oxidant stress in an in vivo rat model was tested in this study. Methods: A dose-response study of bol us intravenous (IV) taurochenodeoxycholic acid (TCDC) in rats was cond ucted. Rats were then pretreated with parenteral alpha-tocopherol, and its effect on IV TCDC toxicity was evaluated by liver blood tests and by assessing mitochondrial lipid peroxidation. Results: Four hours af ter an IV bolus of TCDC (10 mu mol/100 g weight), serum aspartate amin otransferase (AST) and alanine aminotransferase (ALT) revers peaked, h epatic mitochondria showed evidence of increased lipid peroxidation, a nd serum bile acid analysis was consistent with a cholestatic injury. Liver histology at 4 hours showed hepatocellular necrosis and swelling and mild portal tract inflammation. Treatment with parenteral a-tocop herol was associated with a 60%-70% reduction in AST and ALT levels, i mproved histology, and a 60% reduction in mitochondrial lipid peroxida tion in rats receiving TCDC. Conclusions: These data show that hepatoc yte injury and oxidant damage to mitochondria caused by IV TCDC can be significantly reduced by pretreatment with the antioxidant vitamin E. These in vivo findings support the role for oxidant stress in the pat hogenesis of bile acid hepatic toxicity.