Metabolism of 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human neutrophils.
We have previously shown that human polymorphonuclear leukocytes (PMNL) convert 6-trans isomers of leukotriene B4 (LTB4) to 6,11-dihydro metabolites (Powell and Gravelle (1988) J. Biol. Chem. 263, 2170-2177). In the present study, we have shown that the first step in the formation of these dihydro metabolites is oxidation of the 5-hydroxyl group to a 5-oxo group, which is catalyzed by an NADP(+)-dependent microsomal dehydrogenase enzyme. All the dihydroxyeicosanoids we investigated which contained a 5(S)-hydroxyl group followed by a 6-trans double bond were good substrates for this reaction. However, LTB4, which contains a 6-cis double bond, was not metabolized to any detectable 5-oxo products. The preferred substrate for the dehydrogenase reaction is 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5(S)-HETE), which has a Km of about 0.2 microM, compared to approx. 0.9 microM for 12-epi-6-trans-LTB4. In contrast to 5(S)-HETE, 5(R)-HETE as well as a variety of positional isomers of 5(S)-HETE are not metabolized to significant extents by the PMNL dehydrogenase. 5-Oxo-ETE and 5-oxo-15-hydroxy-ETE, which are formed from 5(S)-HETE and 5,15-diHETE, respectively, by this pathway, are potent chemotactic agents for human neutrophils, and raise intracellular calcium levels in these cells.
Meakins-Christie Laboratories, Dept of Medicine, McGill University, Montreal, Quebec, Canada.
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Powell
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Gravelle
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Gravel
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Hashefi
D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity
D001095:Arachidonic Acids; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D010088:Oxidoreductases