Nonsteroidal anti-inflammatory drugs stimulate 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes.

[14C]Arachidonic acid metabolism in human polymorphonuclear (PMN) leukocytes proceeds predominantly through the 5- and 15-lipoxygenase pathways. The major products are 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and 15-HETE. Three nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit 5-HETE production. Concentrations of drugs required for 50% inhibition of 5-lipoxygenase were 0.17mM for indomethacin, 0.60mM for ibuprofen, and 3.4mM for aspirin. A surprising result was that the human PMN leukocyte 15-lipoxygenase/leukotriene pathway was selectively activated by 1mM to 5mM ibuprofen. Metabolites were identified by gas chromatography/mass spectrometry or by retention times on high-performance liquid chromatography in comparison with authentic standards. The major product was 15-HETE; in all 19 human donors tested, 15-HETE formation was stimulated up to twentyfold by 5mM ibuprofen. Other identified products include 5,15-DiHETE, 8,15-DiHETE, and 12-HETE. This ibuprofen-induced activation of 15-HETE formation occurred even in the presence of 10% serum. When the effects of aspirin, indomethacin, and ibuprofen were compared in PMN leukocytes from six donors, ibuprofen caused an average ninefold stimulation of 15-lipoxygenase, whereas aspirin and indomethacin exhibited an average 150% and 200% enhancement, respectively. Results suggest that ibuprofen acts at the postphospholipase stage and may mimic an endogenous activator, initiate a physiologic activation process, or displace a naturally occurring inhibitor of the 15-lipoxygenase. The capacity of NSAIDs to activate the 15-lipoxygenation of arachidonic acid provides a novel mechanism for the stimulation of 15-HETE production, which may indirectly stimulate the generation of leukotrienes by tissue mast cells.