Bisallylic hydroxylation and epoxidation of polyunsaturated fatty acids by cytochrome P450.

Polyunsaturated fatty acids can be oxygenated by cytochrome P450 to hydroxy and epoxy fatty acids. Two major classes of hydroxy fatty acids are formed by hydroxylation of the omega-side chain and by hydroxylation of bisallylic methylene carbons. Bisallylic cytochrome P450-hydroxylases transform linoleic acid to 11-hydroxylinoleic acid, arachidonic acid to 13-hydroxyeicosa-5Z,8Z,11Z,14Z-tetraenoic acid, 10-hydroxyeicosa-5Z,8Z,11Z,14Z-tetraenoic acid and 7-hydroxyeicosa-5Z,8Z,11Z,14Z-tetraenoic acid and eicosapentaenoic acid to 16-hydroxyeicosa-5Z,8Z,11Z,14Z,17Z-pent aenoic acid, 13-hydroxyeicosa-5Z,8Z,11Z,14Z,17Z-pent aenoic acid and 10-hydroxyeicosa-5Z,8Z,11Z,14Z,17Z-pent aenoic acid as major metabolites. The bisallylic hydroxy fatty acids are chemically unstable and decompose rapidly to cis-trans conjugated hydroxy fatty acids during acidic extractive isolation. Bisallylic hydroxylase activity appears to be augmented in microsomes induced by the synthetic glucocorticoid dexamethasone and by some other agents, but the P450 gene families of these hydroxylases have yet to be determined. The fatty acid epoxides, which are formed by cytochrome P450, are chemically stable, but are hydrolyzed to diols by soluble epoxide hydrolases. Epoxidation of polyunsaturated fatty acids is a prominent pathway of metabolism in the liver and the renal cortex and epoxy-genase activity appears to be under homeostatic control in the kidney. Many arachidonate epoxygenases have been identified belonging to the CYP2C gene subfamily. Epoxygenases have also been found in the central nervous system, endocrine organs, the heart and endothelial cells. Epoxides of arachidonic acid have been found to exert pharmacological effects on many cells.