BISALLYLIC HYDROXYLATION AND EPOXIDATION OF POLYUNSATURATED FATTY-ACIDS BY CYTOCHROME-P450

Polyunsaturated fatty acids can be oxygenated by cytochrome P450 to hy droxy and epoxy fatty acids. Two major classes of hydroxy fatty acids are formed by hydroxylation of the omega-side chain and by hydroxylati on of bisallylic methylene carbons. Bisallylic cytochrome P450-hydroxy lases transform linoleic acid to 11-hydroxylinoleic acid, arachidonic acid to 13-hydroxyeicosa-5Z,8Z,11Z,14Z-tetraenoic acid, 10-hydroxyeico sa-5Z,8Z,11Z,14Z-tetraenoic acid and 7-hydroxyeicosa-5Z,8Z,11Z,14Z-tet raenoic acid and eicosapentaenoic acid to 16-hydroxyeicosa-5Z,8Z,11Z,1 4Z,17Z-pentaenoic acid, 13-hydroxyeicosa-5Z,8Z,11Z,14Z,17Z-pentaenoic acid and 10-hydroxyeicosa-5Z,8Z,11Z,14Z,17Z-pentaenoic acid as major m etabolites. The bisallylic hydroxy fatty acids are chemically unstable and decompose rapidly to cis-trans conjugated hydroxy fatty acids dur ing acidic extractive isolation. Bisallylic hydroxylase activity appea rs to be augmented in microsomes induced by the synthetic glucocortico id dexamethasone and by some other agents, but the P450 gene families of these hydroxylases have yet to be determined. The fatty acid epoxid es, which are formed by cytochrome P450, are chemically stable, but ar e hydrolyzed to diols by soluble epoxide hydrolases. Epoxidation of po lyunsaturated fatty acids is a prominent pathway of metabolism in the liver and the renal cortex and epoxygenase-activity appears to be unde r homeostatic control in the kidney. Many arachidonate epoxygenases ha ve 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 be en found to exert pharmacological effects on many cells.