CHARACTERIZATION OF OMEGA HYDROXYLASE P450 GENE FAMILY

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The long term objective of this research is to determine the health related effects of induction of the Omega fatty acid hydroxylase gene family (P4501V) by hypolipidemic non-genotoxic tumor promoters. The metabolism of fatty acids, cholesterol and eicosanoids, mediators of paracrine and cellular regulation, by P45OIV members suggest that the regulation of this family may be of importance in inborn errors of fatty acid metabolism, hypercholesteremia, and the inflammation process. The present objective of this grant is to (1) define the size and complexity of the human omega fatty acid hydroxylase P-450 gene family (P4501V), (2) determine the substrate specificities of each P-450 member and whether selective isozymes and activities are polymorphic in the human population, and (3) to define and characterize those genetic elements which function in the expression of these genes and are responsive to induction by tumor promoting hypolipideamic drugs, peroxisomal proliferating agents as well as during starvation and diabetes. Data from these studies will provide insight into the mechanisms of transcriptional activation of omega fatty acid metabolizing P4501V gene family by hypolipideamic drugs, as well as during starvation, and drug induced diabetes. Characterization of the substrate catalytic activities of human P4501V gene will help to determine their function in the omega oxidation of fatty acids, prostaglandins and leukotrines. These data will identify the functional roles these P-450s play in fatty acid cholesterol and eicosanoid metabolism. Results may also have their importance in the human population with respect to inborn errors of fatty acid metabolism, the inflammatory response and their functional role during tumor promotion by non-genotoxic peroxisomal proliferating agents.