Mutagenicity and synthesis of alpha-substituted N-nitrosamines: derivatives with dithiocarbamic acid

Disulfiram (DSF) can considerably alter the organotropy of chemical carcinogens. For N-nitrosodimethylamine and for N-nitrosodiethylamine the organotropy is shifted from the liver to the nasal cavity or the oesophagus, respectively. Whereas the influence of DSF or its metabolites on enzyme systems has been studied, little is known about its interaction with the carcinogens at a molecular level. Therefore, postulated reaction products of a series of alpha-hydroxylated N-nitroso-dialkylamines and dithiocarbamate were synthesized and tested for mutagenicity in Salmonella typhimurium TA 1535. The results show that the compounds conjugated at a primary alpha-C-atom are not mutagenic, whereas those conjugated at a secondary alpha-C-atom are active. The primary N-nitroso-dithiocarbamates represent unique examples of inactivated dialkyl-nitrosamine derivatives. In addition, their formation in vitro was indirectly demonstrated. The possible role these inactivated compounds may play during the DSF-modulation of carcinogenesis will be discussed.