Differential inhibitory effects of auranofin on leukotriene B 4 and leukotriene C 4 formation by human polymorphonuclear leukocytes

Abstract

Auranofin (AF) is a newly introduced oral gold compound having antirheumatic properties, and its efficacy in the treatment of bronchial asthma is now under investigation. In this study, we examined the effects of AF on leukotriene (LT) formation by human polymorphonuclear leukocytes (PMNs) stimulated with the calcium ionophore A23187. AF inhibited LTC 4 formation in a dose-dependent manner with an IC 50 (concentration required to produce 50% inhibition of control) of 3.2 μM. In contrast, LTB 4 formation was not prevented by AF at concentrations up to 6 μM, but it was reduced to 59 ± 4% (mean ± SE, N = 3) of control by an 8 μM concentration. As a next step, we explored the mechanisms of the differential inhibitory effects of AF using cell-free systems. When arachidonic acid (AA) and reduced glutathione (GSH) were used as substrates, AF inhibited LTC 4 synthesis more effectively (IC 50 = 14 μM) than LTB 4 synthesis (IC 50 = 100 μM). However, LTB 4 and LTC 4 syntheses from LTA 4 were affected only slightly by AF within the concentrations tested (3–100 μM). These results in the cell-free systems indicate that the inhibition of LT formation was caused by a reduction of LTA 4 synthesis and that the differential inhibitory effects can be ascribed to the higher K m value of glutathione S-transferase for LTA 4 than that of LTA 4 hydrolase in PMNs. In accordance with this hypothesis, LTC 4 synthesis was more dependent than LTB 4 synthesis on LTA 4 concentrations within 25–100μM, and AA-861, a 5-lipoxygenase inhibitor, caused similar differential inhibitory effects on the formation of LTs by intact PMNs. The inhibitory effect of AF on LT formation at physiological concentrations may play some role in the efficacy of this drug.