title: Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily.
abstract: CYP2C enzymes epoxidize arachidonic acid (AA) to metabolites involved in the regulation of vascular and renal function. We tested the hypothesis that eicosapentaenoic acid (EPA), a n-3 polyunsaturated fatty acid, may serve as an alternative substrate. Human CYP2C8 and CYP2C9, as well as rat CYP2C11 and CYP2C23, were co-expressed with NADPH-CYP reductase in a baculovirus/insect cell system. The recombinant enzymes showed high EPA and AA epoxygenase activities and the catalytic efficiencies were almost equal comparing the two substrates. The 17,18-double bond was the preferred site of EPA epoxidation by CYPs 2C8, 2C11, and 2C23. 17(R),18(S)-Epoxyeicosatetraenoic acid was produced with an optical purity of about 70% by CYPs 2C9, 2C11, and 2C23 whereas CYP2C8 showed the opposite enantioselectivity. These results demonstrate that EPA is an efficient substrate of CYP2C enzymes and suggest that n-3 PUFA-rich diets may shift the CYP2C-dependent generation of physiologically active eicosanoids from AA- to EPA-derived metabolites.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa-Sicard
authors.forename: Marija
authors.initials: M
authors.lastname: Markovic
authors.forename: Horst
authors.initials: H
authors.lastname: Honeck
authors.forename: Baghat
authors.initials: B
authors.lastname: Christ
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D020033:Protein Isoforms / Q000145:classification / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018411:Spodoptera; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: C000717351:Cyp2c23 protein, rat; D020033:Protein Isoforms; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D015118:Eicosapentaenoic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase