Differential inhibitory effects of auranofin on leukotriene B4 and leukotriene C4 formation by human polymorphonuclear leukocytes.
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 LTC4 formation in a dose-dependent manner with an IC50 (concentration required to produce 50% inhibition of control) of 3.2 microM. In contrast, LTB4 formation was not prevented by AF at concentrations up to 6 microM, but it was reduced to 59 +/- 4% (mean +/- SE, N = 3) of control by an 8 microM 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 LTC4 synthesis more effectively (IC50 = 14 microM) than LTB4 synthesis (IC50 = 100 microM). However, LTB4 and LTC4 syntheses from LTA4 were affected only slightly by AF within the concentrations tested (3-100 microM). These results in the cell-free systems indicate that the inhibition of LT formation was caused by a reduction of LTA4 synthesis and that the differential inhibitory effects can be ascribed to the higher Km value of glutathione S-transferase for LTA4 than that of LTA4 hydrolase in PMNs. In accordance with this hypothesis, LTC4 synthesis was more dependent than LTB4 synthesis on LTA4 concentrations within 25-100 microM, 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.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001310:Auranofin / Q000494:pharmacology*; D005978:Glutathione / Q000097:blood; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D013189:SRS-A / Q000096:biosynthesis / Q000097:blood* / Q000494:pharmacology
D001095:Arachidonic Acids; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D001310:Auranofin; D005978:Glutathione