Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily.
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.
Barbosa-Sicard
Eduardo
E
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Markovic
Marija
M
Honeck
Horst
H
Christ
Baghat
B
Muller
Dominik N
DN
Schunck
Wolf-Hagen
WH
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
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