Resistance to Carbon Tetrachloride-Induced Hepatotoxicity in Mice Which Lack CYP2E1 Expression

Abstract

CYP2E1 knockout mice (cyp2e1−/−) were used to investigate the involvement of CYP2E1 in the development of carbon tetrachloride (CCl4)-induced hepatotoxicity. Malecyp2e1−/−and wild-type (cyp2e1+/+) mice were given a single ip injection of 1 ml/kg (=1.59 g/kg) CCl4and 24 h later liver injury was assessed by elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. No significant increases in serum ALT and AST activities were observed incyp2e1−/−mice when compared to wild-type counterparts after CCl4exposure. No detectable abnormality in liver histology was found incyp2e1−/−mice after CCl4exposure. In contrast, CCl4treatment resulted in 422- and 125-fold increases in serum ALT and AST activities, respectively, in wild-type mice. Consistent with the results of serum ALT and AST activities, severe hepatic damage was noted in livers of wild-type mice, indicating the importance of CYP2E1 in mediating the hepatic damage following CCl4exposure in these mice. In addition, a dramatic decrease in CYP2E1-catalyzedp-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice after CCl4treatment, suggesting that CYP2E1 was degraded during the process of CCl4-induced hepatotoxicity. These studies conclusively demonstrate that CYP2E1 is the major factor involved in the CCl4-induced hepatotoxicity in mice.