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.
Powell
W S
WS
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Gravel
S
S
Gravelle
F
F
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism* / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects*; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000001:Calcimycin; D015118:Eicosapentaenoic Acid; D000429:Alcohol Oxidoreductases; C099244:5-hydroxyeicosanoid dehydrogenase; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium