Microsomal epoxide hydrolase (mEH) is a key biotransformation enzyme, active in the metabolism of many environmental toxins. Its primary, but not exclusive role appears to be one of detoxification, whereby potentially deleterious chemical epoxide derivatives are converted to less reactive and more polar dihydrodiol intermediates. In certain cases, for example in the conversion of procarcinogenic polyaromatic compounds, mEH may also support a bioactivation role, providing a catalytic pathway for the, formation of highly electrophilic bay-region diol-epoxide metabolites. Altered levels of expression of epoxide hydrolase in humans have been postulated as a critical risk factor for various birth defects and cancers. In our laboratory, we have succeeded in isolating and sequencing the complete gene for human microsomal epoxide hydrolase, and have delineated several genetic polymorphisms that appear to result in a functional alteration in expression profiles within human cells. The major thrust of this research program is to characterize the molecular nature of human microsomal epoxide hydrolase, including its structure, regulation, and genetic variability. Our central hypothesis is that mEH genes and regulatory modes exist polymorphically in humans, resulting in heritable differences in epoxide-metabolizing capacity, contributing toward differential susceptibility or risk of toxicity from certain environmentally-linked chemical exposures.
The specific aims of our study are to use molecular toxicological techniques to: 1) characterize mEH genetic alleles in the population with respect to their structure and factional impact on enzymatic activity, 2) delineate 5'-flanking regions of the human mEH gene required for control of constitutive and induced levels of transcriptional activity, and, 3) identify post-transcriptional regulatory pathways that effect the expression levels of mEH in human cells. Information gained from these studies will provide a firm basis for conducting future genetic epidemiological investigations examining the potential association between specific mEH allelic patterns with levels of mEH expression and with smoking-related cancer incidence. Through analysis of human mEH genetic diversity and regulation of expression, it should be feasible to develop biomonitoring, diagnostic, and perhaps, therapeutic approaches that will enable effective identification and intervention strategies for individuals at risk from altered mEH expression for toxic outcomes related to particular chemical exposures.
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