Inhibition of human neutrophil leukotriene B₄ synthesis by combination auranofin and eicosapentaenoic acid

It has been demonstrated that both auranofin and eicosapentaenoic acid (EPA) have antiinflammatory properties and both inhibit neutrophil leukotriene B₄ (LTB₄) synthesis. In the present study, we examined interactions between auranofin and EPA with regard to inhibition of human neutrophil LTB₄ synthesis. Auranofin inhibited A23187-stimulated LTB₄ synthesis, but the dose required for inhibition of LTB₄ was greater than that required for inhibition of other 5-lipoxygenase metabolites; namely, the all-trans isomers of LTB₄ and 5-hydroxyeicosatetraenoic acid. These results were explained after a comparison of the rates of synthesis of these 5-lipoxygenase metabolites in the presence and absence of added arachidonic acid which led to the conclusion that leukotriene A hydrolase, the enzyme catalysing the formation of LTB₄, was saturated with substrate and rate-limiting for LTB₄ synthesis during A23187 stimulation. In combination, auranofin and EPA had a simple additive effect on inhibition of the 5-lipoxygenase pathway. Favorable drug/EPA combinations have the potential to provide a beneficial anti-inflammatory effect with lower levels of each component than are required when used individually.