Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

Abstract

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA), such as epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid, serve as second messengers of various hormones and growth factors and play pivotal roles in the regulation of vascular, renal and cardiac function. As discussed in the present review, virtually all of the major AA metabolizing CYP isoforms accept a variety of other polyunsaturated fatty acids (PUFA), including linoleic, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), as efficient alternative substrates. The metabolites of these alternative PUFAs also elicit profound biological effects. The CYP enzymes respond to alterations in the chain-length and double bond structure of their substrates with remarkable changes in the regio- and stereoselectivity of product formation. The omega-3 double bond that distinguishes EPA and DHA from their omega-6 counterparts provides a preferred epoxidation site for CYP1A, CYP2C, CYP2J and CYP2E subfamily members. CYP4A enzymes that predominantly function as AA ω-hydroxylases show largely increased (ω-1)-hydroxylase activities towards EPA and DHA. Taken together, these findings indicate that CYP-dependent signaling pathways are highly susceptible to changes in the relative bioavailability of the different PUFAs and may provide novel insight into the complex mechanisms that link essential dietary fatty acids to the development of cardiovascular disease.