Cytochrome P450 metabolizes arachidonic acid to a rich variety of oxygenated eicosanoids including epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), and terminal alcohols. These new additions to the list of lipid mediators from the arachidonate cascade have been documented as endogenous constituents of several tissues, blood and urine. They stimulate hormone release, alter renal vascular physiology, modulate intracellular calcium, regulate ocular endothelium, and potentiate cell growth. The stereoselective incorporation of EETs into phospholipids including PI suggests a role in signal transduction. Other recently discovered pathways have expanded the structural diversity for eicosanoids, inter alai, dihydro-metabolites of LtB4 and HETEs, allene oxides and epoxy-alcohols from hydroperoxyeicosatetraenoic acids, and glutathione conjugates. The many urgent questions concerning the production and further metabolism of eicosanoids by these novel arachidonate cascade pathways, the physiological role of their metabolites, and their disposition will be addressed by (1) isolating and characterizing the metabolites of arachidonic acid and its congeners produced by purified enzymes, subcellular factions, and intact cells; (2) examining the factors which control or modulate the product profile; (3) developing analytical methodology for detecting and quantitating eicosanoids and relevant enzymes; (4) unambiguous total syntheses to confirm structure assignments and to provide sufficient material for biological evaluation; (5) continuing collaborative studies assessing the physiological role of eicosanoids in mammalian systems; and (6) elucidating the mode of action regulation, distribution, and metabolic fate of physiologically significant metabolites. Given the broad distribution of the new pathways 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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