title: Inhibitory effect of exogenous arachidonic acid on alveolar macrophage 5-lipoxygenase metabolism. Role of ATP depletion.
abstract: Although a variety of agonists have the capacity to stimulate the release of endogenous arachidonic acid (AA) from macrophage lipids and its subsequent metabolism to both cyclooxygenase and 5-lipoxygenase eicosanoids, including leukotrienes (LT), previous work suggests that exogenously supplied arachidonate is metabolized preferentially to cyclooxygenase products and mono-hydroxyeicosatetranenoic acids rather than LT. We have compared the metabolism of endogenous and exogenous AA in cultured rat alveolar macrophages and have further examined the effect of exogenous fatty acids on eicosanoid synthesis stimulated by the calcium ionophore A23187 and the particulate agonist zymosan. As reported by others, exogenous AA was metabolized to large amounts of cyclooxygenase products, 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid, but far lesser amounts of all 5-lipoxygenase products. However, whereas exogenous AA augmented the synthesis of cyclooxygenase metabolites in both A23187- and zymosan-stimulated cells, it dose-dependently inhibited the synthesis of LT. Inasmuch as unsaturated fatty acids, including AA, uncouple oxidative phosphorylation, and because 5-lipoxygenase activity depends on ATP, we examined the possibility that ATP depletion was responsible for the inhibition of LT synthesis by exogenous AA. Arachidonate depleted cellular ATP in a dose-dependent fashion similar to its inhibition of LT synthesis. In addition, the other unsaturated fatty acids, linolenic and eicosatrienoic, but not the saturated fatty acids, palmitic or stearic, both depleted ATP and inhibited A23187-induced LT synthesis. These data suggest that the relative lack of synthesis of LT from exogenous AA is related to the ability of this unsaturated fatty acid to function as an inhibitor, as well as a substrate, of 5-lipoxygenase. Our results further suggest that this inhibition of 5-lipoxygenase may be mediated by ATP depletion.
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone; D005227:Fatty Acids / Q000494:pharmacology; D005260:Female; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011458:Prostaglandins E / Q000502:physiology; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001095:Arachidonic Acids; D005227:Fatty Acids; D016859:Lipoxygenase Inhibitors; D011458:Prostaglandins E; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone