title: Oxygenation of omega-3 fatty acids by human cytochrome P450 4F3B: effect on 20-hydroxyeicosatetraenoic acid production.
abstract: Cytochrome P450 (CYP) omega-oxidases convert arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a lipid mediator that modulates vascular tone. We observed that a microsomal preparation containing recombinant human CYP4F3B, which converts AA to 20-HETE, converted eicosapentaenoic acid (EPA) to 20-OH-EPA. Likewise, docosahexaenoic acid (DHA) was converted to 22-OH-DHA, indicating that human CYP4F3B also can oxidize 22-carbon omega-3 fatty acids. Consistent with these findings, addition of 0.5-5 microM EPA, DHA or omega-3 docosapentaenoic acid (DPA) to incubations containing 0.5 microM [3H]AA inhibited [3H]20-HETE production by 15-65%. [3H]20-OH-EPA was rapidly taken up by COS-7 cells, and almost all of the incorporated radioactivity remained as unmodified 20-OH-EPA. The 20-OH-EPA stimulated luciferase activity in COS-7 cells that express peroxisome proliferator-activated receptor alpha, indicating that this EPA metabolite may function as a lipid mediator. These findings suggest that some functional effects of omega-3 fatty acid supplementation may be due to inhibition of 20-HETE formation or the conversion of EPA to the corresponding omega-oxidized product.
authors.affiliation: Department of Biochemistry, Carver College of Medicine, 4-403 BSB, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Harmon
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.forename: Terry L
authors.initials: TL
authors.lastname: Kaduce
authors.forename: Shanming
authors.initials: S
authors.lastname: Hu
authors.forename: V
authors.initials: V
authors.lastname: Raj Gopal
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Spector
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D013058:Mass Spectrometry / Q000379:methods; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D006893:Hydroxyeicosatetraenoic Acids; D011994:Recombinant Proteins; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D015118:Eicosapentaenoic Acid; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human; D010100:Oxygen