title: Eicosapentaenoic acid is converted via ω-3 epoxygenation to the anti-inflammatory metabolite 12-hydroxy-17,18-epoxyeicosatetraenoic acid.
abstract: Eicosapentaenoic acid (EPA) has beneficial effects in many inflammatory disorders. In this study, dietary EPA was converted to 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) by ω-3 epoxygenation in the mouse peritoneal cavity. Mediator lipidomics revealed a series of novel oxygenated metabolites of 17,18-EpETE, and one of the major metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in murine zymosan-induced peritonitis. 12-OH-17,18-EpETE inhibited leukotriene B4-induced neutrophil chemotaxis and polarization in vitro in a low nanomolar range (EC50 0.6 nM). The complete structures of two natural isomers were assigned as 12S-OH-17R,18S-EpETE and 12S-OH-17S,18R-EpETE, using chemically synthesized stereoisomers. These natural isomers displayed potent anti-inflammatory action, whereas the unnatural stereoisomers were essentially devoid of activity. These results demonstrate that 17,18-EpETE derived from dietary EPA is converted to a potent bioactive metabolite 12-OH-17,18-EpETE, which may generate an endogenous anti-inflammatory metabolic pathway.
authors.affiliation: 1University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. marita@mol.f.u-tokyo.ac.jp.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kubota
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Isobe
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.forename: Tomomi
authors.initials: T
authors.lastname: Goto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity
chemical_list: D001095:Arachidonic Acids; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; D015054:Zymosan; D015118:Eicosapentaenoic Acid
keywords: bioactive lipid; metabolomics