Mechanism for the potentiation of oxygen toxicity by disulfiram

Abstract

Rats given disulfiram (200 mg/kg) or diethyldithiocarbamate (200 mg/kg) by intraperitoneal injection were exposed to 2 atmospheres absolute oxygen in a hyperbaric chamber or kept in normoxia. By 12 hr of hyperoxia exposure, none of the control but 30% of the disulfiram-treated and 87% of the diethyldithiocarbamate-treated rats had died. Both disulfiram and diethyldithiocarbamate administration decreased lung cytosolic superoxide dismutase activity, but the pharmacokinetics were different. At 1 hr postinjection of diethyldithiocarbamate superoxide dismutase activity was 40% decreased but returned to control activity within 13 hr (4 hr, 18% inhibited). In contrast, disulfiram administration produced a greater decrease at 4 hr (31%) than at 1 hr (16%) and was still effective at 13 hr (28% less than control). Although disulfiram did not produce as great a decrease at 1 hr as did diethyldithiocarbamate, it's effect was more persistent. In vitro, diethyldithiocarbamate inactivated superoxide dismutase at 10(-4) M, although 10(-3) M disulfiram did not cause any reduction in enzymatic activity. The contrast between the inhibition by disulfiram of lung superoxide dismutase activity in vivo and its lack of effect in vitro suggests metabolism of disulfiram to diethyldithiocarbamate. It is likely that disulfiram administration potentiates oxygen toxicity via in vivo reduction to diethyldithiocarbamate and subsequent inhibition of superoxide dismutase.