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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Substrate Selectivity of 5-Hydroxyeicosanoid Dehydrogenase and Its Inhibition by 5-Hydroxy-⁶-Long-Chain Fatty Acids

Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida (P.P., J.R.A., J.R.); and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada (C.C., K.-R.E., G.E.G., W.S.P.)

5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) is a metabolite of the 5-lipoxygenase (5-LO) product 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), formed by the microsomal enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). 5-oxo-ETE is a chemoattractant for neutrophils and eosinophils, both in vitro and in vivo. To examine the substrate selectivity of 5-HEDH and to search for potential inhibitors, we prepared a series of 5S-hydroxy fatty acids (C₁₂ to C₂₀ containing zero to four double bonds) by total chemical synthesis and examined their metabolism by microsomes from monocytic U937 cells. Although most of these fatty acids were oxidized to their 5-oxo metabolites by 5-HEDH, 5-HETE seemed to be the best substrate. However, substrates containing less than 16 carbons, a methylated -carboxyl group, or a hydroxyl group at the -end of the molecule were not substantially metabolized. Some of the fatty acids tested were fairly potent inhibitors of the formation of 5-oxo-ETE by 5-HEDH, in particular 5-hydroxy-6-octadecenoic acid and 5-hydroxy-6-eicosenoic acid. Both substances selectively inhibited 5-oxo-ETE formation by human peripheral blood mononuclear cells incubated with arachidonic acid and calcium ionophore without affecting the formation of leukotriene B₄, 12-HETE, or 12-hydroxy-5,8,10-heptadecatrienoic acid. We conclude that the requirements for appreciable metabolism by 5-HEDH include a chain length of at least 16 carbons, a free -carboxyl group, and a hydrophobic group at the -end of the molecule. 5-Hydroxy-⁶ C₁₈ and C₂₀ fatty acids selectively inhibit 5-HEDH without inhibiting 5-LO, leukotriene A₄ hydrolase, 12-lipoxygenase, or cyclooxygenase. Such compounds may be useful in defining the role of 5-oxo-ETE and its mechanism of synthesis.

Address correspondence to: William S. Powell, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain Street, Montreal, Quebec, Canada H2X 2P2. E-mail: william.powell{at}mcgill.ca