Reduction of cyclophosphamide-induced toxicity by diethyldithiocarbamate and carbon disulfide and its possible mechanism.

The mechanism of reduction in cyclophosphamide (CPA)-induced toxicity by diethyldithiocarbamate (DTC) and carbon disulfide (CS2) was examined in relation to CPA metabolism in mice. Pretreatment with DTC (100 mg/kg) or CS2 (50 mg/kg), p.o. decreased the acute toxicity of CPA. Active metabolites of CPA in the plasma after the administration of CPA (100 or 450 mg/kg, i.p.) was lowered by DTC or CS2 treatment. The liver microsomal CPA oxidase activity decreased 1 h after the administration of DTC (25-100 mg/kg, p.o.) or CS2 (12.5-50 mg/kg, p.o.). These results suggested that the reduction of CPA-induced toxicity in mice pretreated with DTC or CS2 was due to the inhibition of activation of CPA and reduced formation of alkylating metabolites.