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 anti-inflammatory 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.
James
M J
MJ
Morialta Trust Rheumatology Research Laboratory, Royal Adelaide Hospital, Australia.
Cleland
L G
LG
Gibson
R A
RA
D016718:Arachidonic Acid / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007536:Isomerism; D007975:Leukotriene B4 / Q000096:biosynthesis*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D001310:Auranofin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D015118:Eicosapentaenoic Acid; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase