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.
Furusawa
S
S
Cancer Research Institute, Tohoku College of Pharmacy, Sendai, Japan.
Sasaki
K
K
Takayanagi
G
G
D000478:Alkylation; D000818:Animals; D002246:Carbon Disulfide / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism
D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; C039680:cyclophosphamide oxidase; D002246:Carbon Disulfide