Inhibition of alveolar macrophage 5-lipoxygenase metabolism by auranofin.
We have examined the effect of the oral gold compound auranofin (AF) on calcium ionophore A23187-induced arachidonic acid metabolism in the rat alveolar macrophage. Both reverse-phase high performance liquid chromatographic and radioimmunoassay analyses revealed that AF dose-dependently inhibited leukotriene B4 and 5-hydroxyeicosatetraenoic acid synthesis in a parallel fashion with an IC50 approximately 4.3 micrograms/ml. At the same time, AF augmented A23187-induced arachidonate release and cyclooxygenase metabolism. A possible mechanism for the inhibition of 5-lipoxygenase was suggested by the capacity of AF to dose-dependently deplete ATP (IC50 approximately 5.9 micrograms/ml), a cofactor for 5-lipoxygenase. These data indicate that, at therapeutic concentrations, AF acts in vitro as a selective inhibitor of macrophage 5-lipoxygenase metabolism. This likely represents an important mechanism of action of AF in chronic inflammatory disorders.
Peters-Golden
M
M
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Shelly
C
C
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001310:Auranofin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000032:analysis; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D000001:Calcimycin; D001310:Auranofin; D000255:Adenosine Triphosphate; D001091:Arachidonate Lipoxygenases; D005978:Glutathione