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J Biol Chem, Vol. 274, Issue 34, 23963-23968, August 20, 1999
From the Laboratory of Metabolism, Microsomal epoxide hydrolase (mEH) is a conserved
enzyme that is known to hydrolyze many drugs and carcinogens, and a few endogenous steroids and bile acids. mEH-null mice were produced and
found to be fertile and have no phenotypic abnormalities thus indicating that mEH is not critical for reproduction and physiological homeostasis. mEH has also been implicated in participating in the
metabolic activation of polycyclic aromatic hydrocarbon carcinogens. Embryonic fibroblast derived from the mEH-null mice were unable to
produce the proximate carcinogenic metabolite of
7,12-dimethylbenz[a]anthracene (DMBA), a widely
studied experimental prototype for the polycylic aromatic
hydrocarbon class of chemical carcinogens. They were also resistant to
DMBA-mediated toxicity. Using the two-stage initiation-promotion skin
cancer bioassay, the mEH-null mice were found to be highly resistant to
DMBA-induced carcinogenesis. In a complete carcinogenesis bioassay, the
mEH mice were totally resistant to tumorigenesis. These data establish
in an intact animal model that mEH is a key genetic determinant in DMBA
carcinogenesis through its role in production of the ultimate
carcinogenic metabolite of DMBA, the 3,4-diol-1,2-epoxide.
Targeted Disruption of the Microsomal Epoxide Hydrolase Gene
MICROSOMAL EPOXIDE HYDROLASE IS REQUIRED FOR THE CARCINOGENIC
ACTIVITY OF 7,12-DIMETHYLBENZ[a]ANTHRACENE
,, Laboratory of Molecular
Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland
20892
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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