Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450

Abstract

family 1 to 3 are mainly epoxygenases, whereas CYP isoforms from family 4 are mainly -hydroxylases ( 4, 5 ).CYP epoxygenases convert arachidonic acid (AA) to four epoxyeicosatrienoic acid regioisomers (5,8,11,and 14, that function as lipid mediators. EETs produce vascular relaxation, have antiinfl ammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain [for review, see ( 6-8 )]. CYP epoxygenases also convert the 3-PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to epoxy-derivatives ( 9 ), which are potent dilators of coronary arterioles ( 10-12 ) or pulmonary artery ( 13 ) and inhibit platelet aggregation ( 14 ). The EPA-derived epoxides account for fi ve epoxyeicosatetraenoic acids (5,8,11,14,and 17,, whereas the DHA-derived epoxides account for six epoxydocosapentaenoic acids (4,7,10,13,16,and 19,. A high regio-and stereoselectivity has been observed when testing the effects of chemically synthesized epoxides from AA and EPA. For example, in the rat, renal arteries were dilated by 11(R),12(S)-EET but not by 11(S),12(R)-EET or 14,15-EET enantiomers ( 15 ). Also in rats, among all EETeTr enantiomers, only the 17(R),18(S)-enantiomer, not 17(S),18(R), was effective on calcium-activated potassium (BK) channels in isolated cerebral arteries ( 11 ). However, in porcine coronary microvessels, all regioisomeric EETeTrs had similar Cytochromes P450 (CYPs) belong to a protein superfamily among which some members metabolize polyunsaturated long-chain fatty acids (PUFA-LC) to several classes of oxygenated metabolites. The product profi les depend on the involved CYP isoforms and may consist of a series of regio-and stereo-isomeric epoxides and hydroxylated compounds ( 1-3 ). In humans, CYP isoforms from

Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin

“…Additionally, the vasoprotective benefits of n-3 PUFAs may be enhanced further by TCDD, since TCDD significantly increases levels of 17,and 10,16,[17][18][19]20-EDP in the liver and plasma. The increases in 17,18-EEQ and 19,20-EDP likely result from induction of CYP1A1 and 1A2, since recombinant enzyme studies of CYP1A1 and 1A2 show that they generate these 2 epoxides with high efficiency and stereospecificity (Fer et al, 2008;Lucas et al, 2010;Schwarz et al, 2004). The P450s responsible for the increases of 10,11-and 16,17-EDP by TCDD are uncertain.…”

Squalene monooxygenase – a target for hypercholesterolemic therapy

“…5,6-Oxidosqualene and 10,11-oxidosqualene are not observed in the reaction catalyzed by SE (van Duuren and Schmitt , 1960 ;Abe et al , 2007 ). Oxidation of the terminal double bonds is characteristic for other enzymatic reactions (Lucas et al , 2010 ). Zeaxanthin epoxidase oxidizes double bonds only at the ends of zeaxantin, despite the fact that this substrate, like squalene, contains several internal double bonds which could be potentially epoxidized (Hieber et al , 2000 ).…”

ω3 and ω6 CYP450 Eicosanoid Derivatives: Key Lipid Mediators in the Regulation of Pulmonary Hypertension

“…www.intechopen.com (Fer et al, 2008, Arnold et al, 2010, Lucas et al, 2010. Several epoxygenases have been identified in lung tissues, including 2J2, 2C8 2C9 and 1B1 (Fer et al, 2008).…”

“…Epoxy-docosapentaenoic acids are CYP450-dependent DHA metabolites (Fig. 1C) (Fer et al, 2004, Arnold et al, 2010, Lucas et al, 2010 and recent studies have demonstrated that these metabolites display potent vasodilatory activities on coronary arteries (Konkel et al, 2011, Wang et al, 2011. Metabolic pathways and chemical structures of CYP450-dependent AA, EPA and DHA metabolites known to modulate vascular tone are illustrated in Figure 1 A-C.…”