Metabolism and biologic effects of 5-oxoeicosanoids on human neutrophils.
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a recently discovered metabolite of arachidonic acid that activates human neutrophils by a mechanism independent of the receptor for leukotriene B4 (LTB4). The objectives of this study were to identify the major metabolites of 5-oxo-ETE in neutrophils and to compare the biologic activities of 5-oxo-ETE with those of its metabolites and other 5-oxoeicosanoids. Neutrophils rapidly converted 5-oxo-ETE to its omega-oxidation product, 5-oxo-20-hydroxy-6E,8Z,11Z,14Z- eicosatetraenoic acid. This compound was nearly 100 times less potent than 5-oxo-ETE in elevating cytosolic calcium levels in neutrophils. Methylation of the carboxyl group of 5-oxo-ETE resulted in a 20-fold loss of potency, whereas replacement of the 8,9-cis double bond by a trans double bond reduced potency by about sixfold. Similar results were obtained for the effects of the above compounds on neutrophil migration. 5-Oxo-20-hydroxy-6E,8Z,11Z,14Z- eicosatetraenoic acid, 5-oxo-8-trans-ETE, and 5-oxo-ETE methyl ester desensitized neutrophils to 5-oxo-ETE. 5-Oxo-ETE-induced calcium mobilization was inhibited by pretreatment of the cells with pertussis toxin. 5-Oxo metabolites of 6-trans-LTB4 and 12-epi-6-trans-LTB4 had weak stimulatory effects on calcium levels and migration that appeared to be mediated primarily by stimulation of LTB4 receptors. These studies indicate that the 5-oxo group, the omega-end of the molecule, and the carboxyl group are all important for the biologic activity of 5-oxo-ETE, which may be mediated by a G protein-linked receptor. The biologic activity of 5-oxo-ETE can be terminated by omega-oxidation.
Powell
W S
WS
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
MacLeod
R J
RJ
Gravel
S
S
Gravelle
F
F
Bhakar
A
A
D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D037342:Pertussis Toxin; D013237:Stereoisomerism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001095:Arachidonic Acids; D010566:Virulence Factors, Bordetella; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D007975:Leukotriene B4; D037342:Pertussis Toxin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium