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.