The long-term objective of the research described in this application is to determine the physiological and clinical relevance of soluble epoxide hydrolase (sEH) polymorphisms in humans. Numerous studies have shown that sEH is involved in the metabolism of exogenous and endogenous epoxide substrates. Exogenous substrates include mutagenic and carcinogenic epoxides found in our diet. Endogenous substrates include fatty acid epoxides, which regulate vascular tone, and sEH knockout mice have significantly lower blood pressure than do wild-type mice. sEH activity in humans varies by more than 500-fold, however, the mechanisms that underlie this variability remain unknown. Preliminary studies described in this application reveal the existence of at least 6 amino acid variants in the human sEH protein. Based on heterologous expression experiments, we show that at least 2 of these variant amino acids significantly alter the specific activity of the human sEH protein in vitro. These results suggest that sEH activity variability in humans may be partially due to genetic polymorphisms in the sEH gene, and that these polymorphisms may influence an individual's susceptibility or response to exogenous or endogenous epoxides. Based on these preliminary results, the specific aims of this application are to: 1. Construct and further characterize human sEH variant proteins using a heterologous protein expression system, 2. Compare sEH genotypes with sEH enzyme activity and amount in human liver samples, and, 3. Compare sEH genotypes in a group of hypertensive and normotensive humans.
These specific aims are designed to test the hypothesis that polymorphisms in the human sEH gene result in an altered sEH phenotype in vitro and in vivo. This work will provide a basis for understanding the mechanistic roles of sEH polymorphisms in determining human disease progression as related to exogenous and endogenous epoxide metabolism.
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