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 met abolites (Powell and Gravelle (1988) J. Biol. Chem. 263, 2170-2177). I n the present study, we have shown that the first step in the formatio n of these dihydro metabolites is oxidation of the 5-hydroxyl group to a 5-oxo group, which is catalyzed by an NADP+-dependent microsomal de hydrogenase enzyme. All the dihydroxyeicosanoids we investigated which contained a 5(S)-hydroxyl group followed by a 6-trans double bond wer e 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)-hydro xy-6,8,11,14-eicosatetraenoic acid (5(S)-HETE), which has a K(m) of ab out 0.2 muM, compared to approx. 0.9 muM for 12-epi-6-trans-LTB4. In c ontrast to 5(S)-HETE, 5(R)-HETE as well as a variety of positional iso mers of 5(S)-HETE are not metabolized to significant extents by the PM NL 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 po tent chemotactic agents for human neutrophils, and raise intracellular calcium levels in these cells.