CYP2E1 is not involved in early alcohol-induced liver injury

The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what h as been learned to date involves inhibitors or nutritional manipulations th at may not be specific. Knockout technology avoids these potential problems . Therefore, we used long-term intragastric cannulation in mice to study ea rly ALI. Reactive oxygen species are involved in mechanisms of early ALI; h owever, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is indu ced predominantly in hepatocytes by ethanol and could be one source of reac tive oxygen species leading to liver injury. We aimed to determine if CYP2E 1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dex trin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/ - mice after acute ethanol administration to naive mice or mice receiving E A for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevat ed serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in con trol groups. In contrast, mice given ethanol developed mild steatosis, slig ht inflammation, and necrosis; however, there were no differences between t he CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data pr esented here are consistent with the hypothesis that oxidants from CYP2E1 p lay only a small role in mechanisms of early ALI in mice. Moreover, this ne w mouse model illustrates the utility of knockout technology in ALI researc h.