Effect of dihomogammalinolenic acid and its 15-lipoxygenase metabolite on eicosanoid metabolism by human mononuclear leukocytes in vitro: selective inhibition of the 5-lipoxygenase pathway.
The purpose of the present study was to determine the effect of the n-6 fatty acid, dihomogammalinolenic acid (DGLA, 20: 3, n-6) on arachidonic acid (AA) (C20: 4) metabolism by human peripheral mononuclear leukocytes (HPML). After incubation of HPML with A23187 (5 microM) and DGLA, the cyclooxygenase (CO) and lipoxygenase (LO) products were separated and quantified by reversed-phase high-performance liquid chromatography (RP-HPLC) combined with radioimmunoassay. DGLA led to no change in PGE2 formation, but at similar concentrations there was a dose-dependent decrease in LTB4 formation (IC50 = 45.0 microM). The inhibition of LTB4 formation by DGLA was associated with a dose-dependent increase in its 15-LO metabolite 15-hydroxyeicosatraenoic acid (15-HETrE) and its CO metabolite prostaglandin E1 (PGE1). Incubation of HPLM with 15-HETrE (0-1.5 microM) alone did not result in a change in PGE2 formation, whereas 15-HETrE was a much more potent inhibitor of LTB4 formation (IC50 = 0.5 microM) than DGLA. These results show that the addition of DGLA to HPML results in a selective inhibition of LTB4 formation, presumably via its metabolite (15-HETrE).
Iversen
L
L
Department of Dermatology, Marselisborg Hospital, University of Aarhus, Denmark.
Fogh
K
K
Kragballe
K
K
D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*
D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D015126:8,11,14-Eicosatrienoic Acid; D015232:Dinoprostone