Inhibition of alveolar macrophage 5-lipoxygenase metabolism by auranofin

Abstract

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.