The cytochrome P450-dependent metabolism of arachidonic acid

Microsomal cytochrome P-450 catalyzes the oxidative metabolism of arachidonic acid to a variety of products including cis-trans diene conjugated monohydroxy-acids (HETE's), all four isomeric cis-epoxyeicosatrienoic acids (EET's) as well as W- and W-1 oxidation products. The reaction utilizes oxygen and NADPH in a 1:1 stoichiometric ratio and oxydizes the fatty acid with a degree of regiospecificity which is dependent on the tissue source of microsomal hemeproteins. The reaction is inhibited by umolar concentrations of eicosatetraynoic acid (ETYA), indomethacin and aspirin. The cytochrome P-450 dependent arachidonic acid epoxygenase activity of rat liver microsomal functions has been reconstituted utilizing solubilized and purified components of the microsomal electron transport chain. Stereo-chemical analysis of the reaction products shows that 8,9-, 11,12- and 14,15-EET are formed with a high degree of enantiofacial selectivity (better than 80% formation of one enantiomer). The EET's are potent in vitro mediators for the release of several peptide hormones such as somatostatin from the median eminence, anterior and posterior pituitary hormones and the pancreatic hormones, insulin and glucagon. Preliminary evidence indicates that during the EET stimulated release of pituitary hormones there are changes in cellular Ca⁺⁺ mobilization and further oxygenation of the EET. By utilizing a combination of gas-chromatography-mass spectral analysis we have recently obtained physical evidence to demonstrate that the EET's are present as endogenous constituents of rat liver. This observation, in conjunction with the in vitro studies of the cytochrome P-450 dependent arachidonic acid oxygenase activity, expands the list of eicosanoids with potential physiological significance.