Recently, a new pathway for the oxidative metabolism of arachidonic acid mediated by cytochrome P-450 and utilizing NADPH and oxygen in a 1:1 stoichiometry has been described. The primary metabolites so far identified include hydroxyeicosatetraenoic acids (HETE's), Omega and Omega-1 oxidation products, epoxyeicosatrienoic acids (EET's), and vic-dihydroxyeicosatrienoic acids (DHET's). Significantly, both the identity and ratio of cytochrome metabolites are closely associated with the tissue source from which the cytochrome P-450 is isolated and on the conditions for cytochrome isoenzyme induction. Preliminary in vitro testing of the EET's has demonstrated that they are potent stimuli for the release of several hormones including estradiol, testosterone, stomatostatin, luteinizing hormone, prolactin, growth hormone, thyrotropin, oxytocin, vasopressin, insulin, and glucagon. Additionally, they have mild contractile activity on rat stomach strips and alter calcium release from canine aortic microsomes. These observations coupled with the almost universal distribution of cytochrome P-450 in mammalian tissues suggest an entirely new role for cytochrome P-450 in lipid metabolism which may prove vital to our understanding of eicosanoid production and to the role of these fatty acid metabolites in biological processes. The many urgent questions concerning the involvment of cytochrome P-450 in eicosanoid production and the physiological role of these metabolites will be addressed by (1) isolating and characterizing the oxidative 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 submittd for biological testing; (2) confirming structure assignments of novel metabolites by unambiguous total synthesis; (3) developing synthetic strategies and methodology to achieve a meaningful capability of producing by chemical synthesis sufficient quantities of minor or unstable metabolites for biological testing; and (4) elucidating the metabolic fate of physiologically significant cytochrome metabolites. This work will help to define the involvment of cytochrome P-450 in the production and possible further metabolism of eicosanoids and reveal new fatty acid metabolites with important implications for biology and medicine.
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