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) a nd its metabolite, diethyldithiocarbamate (DDTC). Diallyldithiocarbama te 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 dithiocarbama tes (SDTCs) were prepared using glucose, cellobiose, and lactose as gl ycosyl donors and DDTC and diallyldithiocarbamate as accepters. All th e S-glycoside bonds of SDTCs were very stable under physiological cond itions in vitro. At low nitrosamine concentrations, glucose-DDTC inhib ited microsomal nitrosamine dealkylases in vitro. In vivo these enzyme s were also inhibited 4 h after ip administration of glucose-DDTC or l actose-DDTC to rats (1.7 mmol/kg); after 24 h, the values had returned to control levels. Glucose-DDTC induced the activity of glutathione-r elated enzymes. Concomitant treatment of rats with glucose-DDTC and N- nitrosodiethylamine (NDEA) led to a depression of the oxidative metabo lism of [C-14]NDEA to (CO2)-C-14 but increased the elimination of unch anged [C-14]NDEA in the urine. Furthermore, glucose-DDTC totally inhib ited the formation of DNA single-strand breaks induced by NDEA. All th ese effects may contribute to possible antimutagenic and anticarcinoge nic actions of the dithiocarbamates investigated.