title: Disulfiram is a potent inhibitor of rat 5-lipoxygenase activity.
abstract: The effect of disulfiram on the 5-lipoxygenase activity from rat polymorphonuclear leukocyte cell-free lysates was determined and compared with that of other thiocarbamoyl and aryl disulfides. Disulfiram was a potent inhibitor of the soluble 5-lipoxygenase causing 50% inhibition at submicromolar concentrations (0.4-0.7 microM). The inhibition by disulfiram was similar to that of bis(diisopropylthiocarbamoyl) disulfide with both compounds being about 100-fold more potent as inhibitors than the structurally related bis(4-methyl-1-homopiperazinylthiocarbonyl) disulfide analog. The potency of 5-lipoxygenase inhibition by disulfiram was comparable to that of diphenyldisulfide (IC50 = 0.2-0.4 microM), in the same range or better than most typically used inhibitors. However, the degree of inhibition by disulfiram was more sensitive to thiols than that of diphenyldisulfide, as shown by the selective protection against disulfiram inhibition by low concentrations of thiols. Diethyldithiocarbamate, the reduction product of disulfiram, was a less potent inhibitor of the 5-lipoxygenase activity, causing only a partial inhibition (40-60%) over a wide range of concentrations (2-30 microM). The results demonstrate that disulfiram is a potent inhibitor of 5-lipoxygenase in vitro and provide the basis for further investigations on the effect of the drug on leukotriene biosynthesis inhibition and its contribution to the ethanol-disulfiram reaction. They also indicate that disulfiram represents a sensitive reagent to characterize the thiol requirement of the 5-lipoxygenase reaction.
authors.affiliation: Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire-Dorval, Qué.
authors.forename: L Y
authors.initials: LY
authors.lastname: Choo
authors.forename: D
authors.initials: D
authors.lastname: Riendeau
mesh_terms: D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D004220:Disulfides / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D004220:Disulfides; D016859:Lipoxygenase Inhibitors; D013438:Sulfhydryl Compounds; D001091:Arachidonate Lipoxygenases; D004221:Disulfiram