Sugar-linked dithiocarbamates as modulators of metabolic and genotoxic properties of N-nitroso compounds.
A series of putative anticarcinogenic and antimutagenic compounds was synthesized on the basis of tetraethylthiuram disulfide (disulfiram) and its metabolite, diethyldithiocarbamate (DDTC). Diallyldithiocarbamate was synthesized in order to combine the anticarcinogenic properties of diallyl sulfide, a known inhibitor of chemical carcinogenesis from Allium species, and those of DDTC. Several sugar-linked dithiocarbamates (SDTCs) were prepared using glucose, cellobiose, and lactose as glycosyl donors and DDTC and diallyldithiocarbamate as acceptors. All the S--glycoside bonds of SDTCs were very stable under physiological conditions in vitro. At low nitrosamine concentrations, glucose-DDTC inhibited microsomal nitrosamine dealkylases in vitro. In vivo these enzymes were also inhibited 4 h after i.p. administration of glucose-DDTC or lactose-DDTC to rats (1.7 mmol/kg); after 24 h, the values had returned to control levels. Glucose-DDTC induced the activity of glutathione-related enzymes. Concomitant treatment of rats with glucose-DDTC and N-nitrosodiethylamine (NDEA) led to a depression of the oxidative metabolism of [14C]NDEA to 14CO2 but increased the elimination of unchanged [14C]NDEA in the urine. Furthermore, glucose-DDTC totally inhibited the formation of DNA single-strand breaks induced by NDEA. All these effects may contribute to possible antimutagenic and anticarcinogenic actions of the dithiocarbamates investigated.
Lee
B H
BH
Division of Molecular Toxicology, German Cancer Research Center, Heidelberg.
Bertram
B
B
Schmezer
P
P
Frank
N
N
Wiessler
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004052:Diethylnitrosamine / Q000378:metabolism; D004050:Ditiocarb / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006031:Glycosylation; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009603:Nitroso Compounds / Q000378:metabolism / Q000633:toxicity*; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D002241:Carbohydrates; D004277:DNA, Single-Stranded; D006027:Glycosides; D009603:Nitroso Compounds; D011355:Prodrugs; D013859:Thiocarbamates; D004052:Diethylnitrosamine; D004050:Ditiocarb