Formation of a 5-oxo metabolite of 5,8,11,14,17-eicosapentaenoic acid and its effects on human neutrophils and eosinophils.

We recently showed that human neutrophils convert arachidonic acid to its 5-oxo metabolite, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). 5-Oxo-ETE, which is synthesized by oxidation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by a highly specific microsomal dehydrogenase, is a potent stimulator of human neutrophils and eosinophils. The objective of the current investigation was to determine whether neutrophils can convert 5,8,11,14,17-eicosapentaenoic acid (EPA) to its 5-oxo metabolite, 5-oxo-6,8,11,14,17-eicosapentaenoic acid (5-oxo-EPE) and, if so, to compare the biological activities of 5-oxo-EPE and 5-oxo-ETE. The two major eicosanoids formed by neutrophils incubated with EPA in the presence of A23187 were 5-hydroxy-6,8,11,14,17-eicosapentaenoic acid (5-HEPE) and 5-oxo-EPE. Smaller amounts of LTB5 and 20-hydroxy-LTB5 were also formed. Phorbol myristate acetate stimulated the formation of 5-oxo-EPE from both EPA and 5-HEPE. 5-HEPE and 5-HETE were equally good substrates for 5-hydroxyeicosanoid dehydrogenase (Km, ca. 0.85 microM; Vmax, ca. 1.4 pmol/min per microgram protein). 5-Oxo-EPE mobilized calcium in neutrophils with an EC50 of 36 nM, about 10 times higher than that of 5-oxo-ETE. 5-Oxo-EPE was also about one-tenth as active as 5-oxo-ETE in stimulating the migration of both human neutrophils and human eosinophils. It is concluded that 5-oxo-EPE is readily formed from EPA via 5-HEPE. However, it is only about one-tenth as potent as 5-oxo-ETE in stimulating human neutrophils and eosinophils. These results support the contention that EPA can alleviate certain inflammatory diseases by reducing the contribution of arachidonate-derived eicosanoids.