The effects of diethyldithiocarbamate on the hepatotoxic action and antitumor activity of N-methylformamide in mice.
The oral administration of diethyldithiocarbamate (DTC) prevented hepatic necrosis induced by N-methylformamide (NMF) in ddY-strain mice, in more susceptible BALB/c mice and in diethylmaleate-treated mice in which NMP-hepatotoxicity was potentiated, as evidenced by suppression of increases of plasma glutamic pyruvic transaminase activity and liver calcium content or by histological observations. Early depletion of liver glutathione following NMF administration was also prevented by DTC. DTC markedly delayed the in vivo metabolism of NMF as indicated by a prolonged retention of plasma and liver NMF levels and an enhancement of urinary excretion of NMF. These observations support a bioactivation mechanism for NMF hepatotoxicity, and the hepatoprotective action of DTC may be due to an inhibition of the metabolic activation of NMF. Hepatotoxic manifestations after repeated administration of NMF also tended to be ameliorated by simultaneous treatment with DTC. Cotreatment with DTC, however, decreased the antitumor activity of NMF against Ehrlich ascites tumors, and Sarcoma 180. This also implies the involvement of a bioactivation mechanism in the antitumor action of NMF, but further studies are necessary to confirm this point. The possible therapeutic value of DTC as a hepatoprotector may be diminished by the suppression of the antitumor activity of NMF.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004050:Ditiocarb / Q000494:pharmacology*; D005559:Formamides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D013045:Species Specificity; D013859:Thiocarbamates / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D005559:Formamides; D013859:Thiocarbamates; D004050:Ditiocarb; D005978:Glutathione; C002950:methylformamide