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1 Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, and 2 Cell Biology and Anatomy, University of North Carolina, Chapel Hill 27599; 5 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; 3 Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201; and 4 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
The continuous
intragastric enteral feeding protocol in the rat was a major
development in alcohol-induced liver injury (ALI) research. Much of
what has been learned to date involves inhibitors or nutritional
manipulations that may not be specific. Knockout technology avoids
these potential problems. Therefore, we used long-term
intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome
P-450 (CYP)2E1 is induced
predominantly in hepatocytes by ethanol and could be one source of
reactive oxygen species leading to liver injury. We aimed to determine
if CYP2E1 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-dextrin 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 EA for 4 wk. However, EA stimulated rates 1.4-fold in
both groups. EA elevated serum aspartate aminotransferase levels
threefold to similar levels over control in both CYP2E1 +/+ and
/ mice. Liver histology was normal in control groups. In
contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between
the 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 presented here
are consistent with the hypothesis that oxidants from CYP2E1 play only
a small role in mechanisms of early ALI in mice. Moreover, this new
mouse model illustrates the utility of knockout technology in ALI research.
CYP2E1 knockout mouse; intragastric feeding
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