Auranofin stimulates LTA hydrolase and inhibits 5-lipoxygenase/LTA synthase activity of isolated human neutrophils.
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 B4 (LTB4), 5-HETE and the all-trans isomers of LTB4 was measured by HPLC. At low concentrations (0.5-2.0 microM), auranofin stimulated LTB4 synthesis, but inhibited it at higher concentrations (100% inhibition at less than 10 microM). In contrast auranofin caused dose-dependent inhibition of the synthesis of 5-HETE and the all-trans isomers of LTB4. Similar observations were made with each agonist. The stimulation of LTB4 synthesis and inhibition of the trans isomer production suggests that auranofin at low concentrations stimulates LTA hydrolase--the enzyme that converts LTA4 to LTB4, whereas the inhibition of synthesis of all lipoxygenase products at higher auranofin concentrations, suggests inhibition of 5-lipoxygenase/LTA synthase.
Betts
W H
WH
Rheumatology Unit, Queen Elizabeth Hospital, Woodville, Adelaide, South Australia.
Hurst
N P
NP
Murphy
G A
GA
Cleland
L G
LG
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001091:Arachidonate Lipoxygenases / Q000378:metabolism*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007536:Isomerism; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008954:Models, Biological; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology*
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D001310:Auranofin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase