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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity

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

The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G protein-coupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C₁₂ and C₁₄ analogs were without appreciable activity, whereas the C₁₆ 5-oxo-dienoic acid was a weak partial agonist. In contrast, the corresponding C₁₈ analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C₂₀ analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead acid (5Z,8Z,11Z-eicosatrienoic acid), which accumulates in dietary essential fatty acid deficiency, by neutrophils. The main Mead acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B₃. We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty acid deficiency.

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