Substrate Selectivity of 5-Hydroxyeicosanoid Dehydrogenase and Its Inhibition by 5-Hydroxy-Δ6-Long-Chain Fatty Acids

• Published in: The Journal of pharmacology and experimental therapeutics 2009-04, Vol.329 (1), p.335
• Main Authors: Pranav Patel, Chantal Cossette, Jaganmohan R. Anumolu, Karl-Rudolf Erlemann, Gail E. Grant, Joshua Rokach, William S. Powell
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.143453

5-Oxo-6 E ,8 Z ,11 Z ,14 Z -eicosatetraenoic acid (5-oxo-ETE) is a metabolite of the 5-lipoxygenase (5-LO) product 5 S -hydroxy-6 E ,8 Z ,11 Z ,14 Z -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 5 S -hydroxy fatty acids (C 12 to C 20 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 α-carboxyl group, or a hydroxyl group at the ω-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 B 4 , 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 α-carboxyl group, and a hydrophobic group at the ω-end of the molecule. 5-Hydroxy-Δ 6 C 18 and C 20 fatty acids selectively inhibit 5-HEDH without inhibiting 5-LO, leukotriene A 4 hydrolase, 12-lipoxygenase, or cyclooxygenase. Such compounds may be useful in defining the role of 5-oxo-ETE and its mechanism of synthesis.