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J Biol Chem, Vol. 273, Issue 33, 20951-20959, August 14, 1998

Calcium/Calmodulin-dependent Conversion of 5-Oxoeicosanoids to 6,7-Dihydro Metabolites by a Cytosolic Olefin Reductase in Human Neutrophils

Kiflu Berhane, Andrew A. Ray, Subhash P. Khanapure^§, Joshua Rokach^§, and William S. Powell

From the  Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada and the ^§ Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901-6988

We previously showed that 6-trans isomers of leukotriene B₄ but not leukotriene B₄ itself are converted to dihydro metabolites by human neutrophils. The first step in the formation of these metabolites is oxidation of the 5-hydroxyl group by 5-hydroxyeicosanoid dehydrogenase. The objective of the present investigation was to characterize the second step in the formation of the dihydro metabolites, reduction of an olefinic double bond. We found that the olefin reductase reduces the 6,7-double bond of 5-oxoeicosanoids, is localized in the cytosolic fraction of neutrophils, and requires NADPH as a cofactor. Neutrophil cytosol converts a variety of both 5-oxo- and 15-oxoeicosanoids to dihydro products. However, conversion of 5-oxoeicosanoids to their 6,7-dihydro metabolites is inhibited by EGTA and a calmodulin antagonist and stimulated by the addition of calcium and calmodulin, whereas the reduction of 15-oxoeicosanoids to their 13,14-dihydro metabolites is slightly inhibited by calcium. Furthermore, eicosanoid ⁶- and ¹³-reductases could be separated by chromatography on DEAE-Sepharose. 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is converted by the ⁶-reductase to 6,7-dihydro-5-oxo-ETE, which is 1000 times less potent than 5-oxo-ETE in mobilizing calcium in neutrophils. We conclude that neutrophils contain both 5-oxoeicosanoid ⁶-reductase and prostaglandin ¹³-reductase. Metabolism of 5-oxo-ETE by the ⁶-reductase results in loss of its biological activity.

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