title: Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products.
abstract: Dietary fish oil containing omega 3 highly unsaturated fatty acids has cardioprotective and anti-inflammatory effects. Prostaglandins (PGs) and thromboxanes are produced in vivo both from the omega 6 fatty acid arachidonic acid (AA) and the omega 3 fatty acid eicosapentaenoic acid (EPA). Certain beneficial effects of fish oil may result from altered PG metabolism resulting from increases in the EPA/AA ratios of precursor phospholipids. Here we report in vitro specificities of prostanoid enzymes and receptors toward EPA-derived, 3-series versus AA-derived, 2-series prostanoid substrates and products. The largest difference was seen with PG endoperoxide H synthase (PGHS)-1. Under optimal conditions purified PGHS-1 oxygenates EPA with only 10% of the efficiency of AA, and EPA significantly inhibits AA oxygenation by PGHS-1. Two- to 3-fold higher activities or potencies with 2-series versus 3-series compounds were observed with PGHS-2, PGD synthases, microsomal PGE synthase-1 and EP1, EP2, EP3, and FP receptors. Our most surprising observation was that AA oxygenation by PGHS-2 is only modestly inhibited by EPA (i.e. PGHS-2 exhibits a marked preference for AA when EPA and AA are tested together). Also unexpectedly, TxA(3) is about equipotent to TxA(2) at the TP alpha receptor. Our biochemical data predict that increasing phospholipid EPA/AA ratios in cells would dampen prostanoid signaling with the largest effects being on PGHS-1 pathways involving PGD, PGE, and PGF. Production of 2-series prostanoids from AA by PGHS-2 would be expected to decrease in proportion to the compensatory decrease in the AA content of phospholipids that would result from increased incorporation of omega 3 fatty acids such as EPA.
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Wada
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: DeLong
authors.forename: Yu H
authors.initials: YH
authors.lastname: Hong
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Rieke
authors.forename: Inseok
authors.initials: I
authors.lastname: Song
authors.forename: Ranjinder S
authors.initials: RS
authors.lastname: Sidhu
authors.forename: Chong
authors.initials: C
authors.lastname: Yuan
authors.forename: Mark
authors.initials: M
authors.lastname: Warnock
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
authors.forename: Chieko
authors.initials: C
authors.lastname: Yokoyama
authors.forename: Emer M
authors.initials: EM
authors.lastname: Smyth
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.forename: R Michael
authors.initials: RM
authors.lastname: Garavito
authors.forename: De Xin
authors.initials: de X
authors.lastname: Sui
authors.forename: John W
authors.initials: JW
authors.lastname: Regan
authors.forename: William L
authors.initials: WL
authors.lastname: Smith
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000737:chemistry*; D002460:Cell Line; D015118:Eicosapentaenoic Acid / Q000737:chemistry*; D005395:Fish Oils / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry; D051379:Mice; D010743:Phospholipids / Q000737:chemistry; D053657:Platelet-Rich Plasma / Q000378:metabolism; D011453:Prostaglandins / Q000737:chemistry*; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism; D013931:Thromboxanes / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005395:Fish Oils; D007295:Inositol Phosphates; D010743:Phospholipids; D011453:Prostaglandins; D013931:Thromboxanes; D016718:Arachidonic Acid; D013928:Thromboxane A2; C039903:thromboxane A3; D015118:Eicosapentaenoic Acid