Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450.
Epoxidation and hydroxylation of arachidonic acid (AA) are both catalyzed by cytochromes P450s (CYPs). The oxidized metabolites are known to be involved in the regulation of vascular tone and renal function. By using a panel of 15 human recombinant CYPs, this study demonstrates that other polyunsaturated long-chain fatty acids (PUFA-LC), especially the omega3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are also epoxidised. The regioselectivity of epoxidation of four PUFA-LC by CYPs was investigated. Among the several CYPs tested, CYP2C9/2C19 and 1A2 were the most efficient in EPA and DHA epoxidations. It ensued that 10muM of these two omega3 fatty acids decreased by more than 80% and 60%, respectively, the formation by CYP2C9 of AA-epoxidised derivatives. These findings suggest that some physiological effects of omega3 fatty acids may be due to a shift in the generation of active epoxidised metabolites of AA through CYP-mediated catalysis.
Fer
Maude
M
Laboratoire de Biochimie EA948, Faculté de Médecine, 22 Av Camille Desmoulins, CS 93837, 29238 BREST Cedex 3, France.
Dréano
Yvonne
Y
Lucas
Danièle
D
Corcos
Laurent
L
Salaün
Jean-Pierre
JP
Berthou
François
F
Amet
Yolande
Y
D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism; D001681:Biological Assay; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
D004852:Epoxy Compounds; D011994:Recombinant Proteins; D004281:Docosahexaenoic Acids; D003577:Cytochrome P-450 Enzyme System; D015118:Eicosapentaenoic Acid; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19