Inhibition of leukotriene B4 biosynthesis by disulfiram and A-64077 during carrageenan-induced pleurisy in the rat.
1. The effect of disulfiram and A-64077 on leukotriene B4 biosynthesis was investigated using human polymorphonuclear leukocyte preparations and an in vivo rat pleurisy assay. 2. Disulfiram inhibited the calcium ionophore-induced release of LTB4 by human leukocytes in vitro with an IC50 of 4.6 +/- 0.3 microM, a value similar to that observed with the 5-lipoxygenase inhibitor A-64077 (IC50 = 1.2 +/- 0.3 microM). These inhibitors were at least 100-fold more potent than diethyldithiocarbamate, the primary metabolite of disulfiram. 3. In a rat pleurisy model, the administration of A-64077 (p.o., 2 hr pretreatment) caused a marked decrease in LTB4 levels measureable after ionophore stimulation at doses of 3 and 10 mg kg (67 and 96% inhibition, respectively). Disulfiram was about a 100-fold less potent, inhibiting LTB4 release by 65% at 300 mg kg (p.o., 6 hr pretreatment). 4. In contrast to A-64077, the inhibitory effect of disulfiram on LTB4 production by isolated leukocytes from the pleural cavity was reduced by the addition of the cell-free pleural exudate, suggesting that protein binding or conversion of disulfiram to inactive species contributes to diminish the potency of the drug. 5. The results indicate that disulfiram, after oral administration in rats, causes an inhibition of leukotriene biosynthesis in the pleural cavity and further illustrate the limited specificity of this drug as an inhibitor of aldehyde dehydrogenase at doses generally used to inhibit this enzyme in vivo.
Riendeau
D
D
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Guay
J
J
Foster
A
A
Wolfe
S
S
Chan
C C
CC
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D002351:Carrageenan; D003093:Colitis, Ulcerative / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology*; D005122:Exudates and Transudates / Q000502:physiology; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D008297:Male; D010998:Pleurisy / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D002351:Carrageenan; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram; C063449:zileuton; D006918:Hydroxyurea