METABOLISM AND BIOLOGIC EFFECTS OF 5-OXOEICOSANOIDS ON HUMAN NEUTROPHILS

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a recently discov ered metabolite of arachidonic acid that activates human neutrophils b y a mechanism independent of the receptor for leukotriene B-4 (LTB(4)) . 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. Ne utrophils rapidly converted 5-oxo-ETE to its omega-oxidation product, 5-oxo-20-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, This compound wa s nearly 100 times less potent than 5-oxo-ETE in elevating cytosolic c alcium levels in neutrophils, Methylation of the carboxyl group of 5-o xo-ETE resulted in a 20-fold loss of potency, whereas replacement of t he 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 c ompounds on neutrophil migration, 5-Oxo-20-hydroxy-6E,8Z,11Z,14Z-eicos atetraenoic acid, 5-oxo-8-trans-ETE, and 5-oxo-ETE methyl ester desens itized neutrophils to 5-oxo-ETE, 5-Oxo-ETE-induced calcium mobilizatio n was inhibited by pretreatment of the cells with pertussis toxin, 5-O xo metabolites of 6-trans-LTB(4) and 12-epi-6-trans-LTB(4) had weak st imulatory effects on calcium levels and migration that appeared to be mediated primarily by stimulation of LTB(4) receptors, These studies i ndicate that the 5-oxo group, the omega-end of the molecule, and the c arboxyl group are all important for the biologic activity of 5-oxo-ETE , which may be mediated by a G protein-linked receptor, The biologic a ctivity of 5-oxo-ETE can be terminated by omega-oxidation.