Inhibitory effects of mixed disulfides from disulfiram on the metabolism and genotoxicity of N-nitrosodiethylamine.
Disulfiram (CAS 97-77-8, DSF), a potent anticarcinogenic compound, is known to form mixed disulfides with sulfhydryl group containing amino acids or proteins in vivo. In the present study the stabilities of two mixed disulfides which may arise in the metabolism of disulfiram, i.e. S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) and S-(N,N-diethyldithiocarbamoyl)-L-glutathione (GS-DDTC) in phosphate buffer (pH 7.2) and in rat liver subcellular fractions were investigated as well as their influences on the glutathione (GSH)-related detoxifying system, on the metabolism of [14C] N-nitrosodiethylamine (NDEA) and on the genotoxic activity of NDEA in rats. Both substances were stable in buffer and in microsomes but were degraded in cytosol showing a half life of 4.7 h (AC-DDTC) and 3.2 h (GS-DDTC). Addition of GSH to the incubation media accelerated the degradation of mixed disulfides in cytosol. In vivo administration of AC-DDTC and GS-DDTC (1.7 mmol/kg i.p.) led to an increase in hepatic GSH content and to an inhibition of the activity of NDEA deethylase. Both mixed disulfides inhibited the metabolism of NDEA. After a 28 mg/kg i.p. dose of [14C] NDEA only 0.4% was excreted unchanged in the urine. Pretreatment with AC-DDTC and GS-DDTC caused a 10 to 20 fold increase in the amount of NDEA excreted in the urine. The occurrence of DNA single strand breaks in rat liver cells induced by NDEA was completely neutralized by the pretreatment with AC-DDTC.
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects; D004052:Diethylnitrosamine / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004221:Disulfiram / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D016587:Antimutagenic Agents; D004277:DNA, Single-Stranded; D004220:Disulfides; D009153:Mutagens; D004052:Diethylnitrosamine; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D004221:Disulfiram