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.