MUTAGENICITY OF ISOMERIC ALKANEDIAZOTATES, PRECURSORS FOR ULTIMATE ALKYLATING SPECIES OF CARCINOGENIC N-NITROSO COMPOUNDS

Alkanediazohydroxides are common key intermediates in carcinogenesis a nd mutagenesis of N-nitroso compounds, which are widely found in human environment. Mutagenicity of (E)- and (Z)-potassium alkanediazotates, as precursors of corresponding alkanediazohydroxides were evaluated t o investigate the effect of geometric isomerism and also the effect of alkyl groups on their biological activity. Mutagenicity of N-nitroso- N-alkylureas which spontaneously produce alkanediazohydroxides after n on-enzymatic hydrolysis were also tested in comparison to that of the corresponding diazotates and other activated chemical species of N-nit rosamines. When the mutagenicity was assayed in three microbial strain s, Salmonella typhimurium TA1535, and Escherichia coli WP2 and WP2 wrA , the order of mutagenic potency of the compounds with the same alkyl group was as follows; (E)-diazotates > (Z)-diazotates > nitrosoureas. The effect of alkyl groups on the mutagenic potency was different in S almonella strain and in E. coli strains, and this result could be expl ained by the efficiency of O-6-alkylguanine-DNA alkyltransferase. In e ach bacterial strain, this effect of alkyl groups was similar in mutag enicity induced by (E)- and (Z)-diazotates, N-nitroso-N-alkylureas and other activated N-nitrosodialkylamines such as alpha-hydroxy nitrosam ines. The geometrical isomerism affected the mutagenicity of (E)- and (Z)-potassium alkanediazotates, and the result suggested that alkanedi azohydroxides react through diazonium ions in a cage rather than throu gh free alkyldiazonium ions which have no geometrical isomerism. Our r esults confirmed that (E)-potassium alkanediazotates, (Z)-potassium al kanediazotates and N-nitroso-N-alkylureas all decomposed through diazo hydroxides, and that alkanediazohydroxides are the active alkylating s pecies of N-nitroso compounds, and also that the geometrical isomerism is important for carcinogenic N-nitroso compounds to show their biolo gical activity. (C) 1998 Elsevier Science B.V.