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

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Abstract
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 esophagus, respectively. Whereas the influence of DSF or it metabolites on enzyme systems was studied, little is known about its interaction with the carcinogens at a molecular level. 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 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. Their formation in vitro was indirectly demonstrated. The possible role these inactivated compounds may play during the DSF-modulation of carcinogenesis will be discussed.