Inhibition of Cytochrome P450 2E1 Expression by Oleanolic Acid: Hepatoprotective Effects Against Carbon Tetrachloride-induced Hepatic Injury

The protective effects of oleanolic acid on carbon tetrachloride-induced hepatotoxicities and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with oleanolic acid prior to the administration of carbon tetrachloride significantly prevented the increase in serum alanine aminotransferase and lactate dehydrogenase activity and liver lipid peroxidation in a dose-dependent manner. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with oleanolic acid alone but pretreatment with oleanolic acid protects carbon tetrachloride-induced depletion of hepatic glutathione levels. The effects of oleanolic acid on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were investigated. Treatment of mice with oleanolic acid resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. These results show that the protective effects of oleanolic acid against the carbon tetrachloride-induced hepatotoxicity may, at least in part, be due to its ability to block bioactivation of carbon tetrachloride mainly by the inhibition of expression and activities of P450 2E1.