Recently, a new branch of the arachidonate cascade has been described whereby cytochrome P-450 metabolizes arachidonic acid to a rich variety of oxygenated eicosanoids including hydroxyeicosatetraenoic acids (HETEs), w/w-1 oxidation products, and epoxy-eicosatrienoic acids (EETs). The metabolite profile is dependent on the development stage and tissue source of the cytochrome P-450. Further metabolism of these producet by cytochrome P-450, glutathione transferases, esterases, hydroleses, and other enzyme systems has been documented. The EETs are potent in vitro stimuli for the release of several steroid and peptide hormones and can dramatically influence cellular calcium mobilization and sodium/potassium flux. The EETS have been confirmed as endogenous constituents of mammalian production, ductus arteriosus contraction and transformations of eicosanoids produced by other branches of arachidonate cascade. Most of the cytochrome derived eicosanoids are available in only minute amounts from natural sources and in many instances have not been fully characterized. The many urgent questions concerning the involvement of cytochrome P-450 in the production and further metabolism of eicosanoids, the physiological role of these metabolites and their ultimate disposition will be addressed by (1) isolating and characterizing the metabolites of arachidonic and related fatty acids produced by cytochrome P-450 utilizing purified cytochrome P-450, subcellular fractions, and intact cells (previously unknown metabolites will be submitted for biological testing); (2) examining the factors which control or modulate the product profile; (3) investigating the competency of cytochrome P-450 to oxidize eicosanoids produced by other branches of the arachidonate cascade and determining the structure of the products; (4) confirming structure and sterochemical assignments of novel metabolites by unambiguous total syntheses; (5) continuing collaborative studies assessing the physiological role of cytochrome derived metabolites, and (6) elucidating the mode of action, regulation, distributing, and metabolic fate of pharmacologically significant metabolites and analogues. In light of the almost universal distribution of cytochrome P-450 in mammalian tissues, this work will have profound implications for our understanding of fatty acid metabolism and its relationship to homeostasis.
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