Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression

CYP2E1 knockout mice (cyp2e1(-/-)) were used to investigate the involvement of CYP2E1 in the development of carbon tetrachloride (CCl4)-induced hepato toxicity. Male cyp2e1(-/-) and wildtype (cyp2e1(+/+)) mice were given a sin gle ip injection of 1 ml/kg (=1.59 g/kg) CCl4 and 24 h later liver injury w as assessed by elevations of serum alanine aminotransferase (ALT) and aspar tate aminotransferase (AST) activities and histopathology. No significant i ncreases in serum ALT and AST activities were observed in cyp2e1(-/-) mice when compared to wild-type counterparts after CCl4 exposure. No detectable abnormality in liver histology was found in cyp2e1(-/-) mice after CCl4 exp osure. In contrast, CCl4 treatment resulted in 422- and 125-fold increases in serum ALT and AST activities, respectively, in wild-type mice. Consisten t with the results of serum ALT and AST activities, severe hepatic damage w as noted in livers of wild-type mice, indicating the importance of CYP2E1 i n mediating the hepatic damage following CCl4 exposure in these mice. In ad dition, a dramatic decrease in CYP2E1-catalyzed p-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice afte r CCl4 treatment, suggesting that CYP2E1 was degraded during the process of CCl4-induced hepatotoxicity, These studies conclusively demonstrate that C YP2E1 is the major factor involved in the CCl4-induced hepatotoxicity in mi ce. (C) 1998 Academic Press.