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 hepatotoxicity. Male cyp2e1-/- and wild-type (cyp2e1+/+) mice were given a single i.p. injection of 1 ml/kg (= 1.59 g/kg) CCl4 and 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 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 exposure. In contrast, CCl4 treatment resulted in 442- 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 CCl4 exposure in these mice. In addition, a dramatic decrease in CYP2E1-catalyzed p-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice after CCl4 treatment, 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.
Wong
F W
FW
Department of Biochemistry, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Chan
W Y
WY
Lee
S S
SS
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency*; D004351:Drug Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects
D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1