Auranofin stimulates LTA hydrolase and inhibits 5-lipoxygenasejlta synthase activity of isolated human neutrophils

Abstract The effect of auranofin on the 5-lipoxygenase pathway was studied in human neutrophils stimulated with either fMLP or A23187 (with or without arachidonic acid). The synthesis of leukotriene B 4 (LTB 4 ), 5-HETE and the all-trans isomers of LTB 4 was measured by HPLC. At low concentrations (0.5–2.0 μM), auranofin stimulated LT B4 synthesis, but inhibited it at higher concentrations (100% inhibition at μ M). In contrast auranofin caused dose-dependent inhibition of the synthesis of 5-HETE and the all-trans isomers of LTB 4 . Similar observations were made with each agonist. The stimulation of LTB 4 synthesis and inhibition of the trans isomer production suggests that auranofin at low concentrations stimulates LTA hydrolase—the enzyme that converts LTA 4 to LTB 4 , whereas the inhibition of synthesis of all lipoxygenase products at higher auranofin concentrations, suggests inhibition of 5-Iipoxygenase/LTA synthase.