Ukawa-Ishikawa S, Sawada A, Kasuya K, Mochizuki M
Kyoritsu College of Pharmacy, Shibakoen, Tokyo, Japan.
Mutat Res. 1998 Jan 13;412(1):99-107. doi: 10.1016/s1383-5718(97)00180-0.
Alkanediazohydroxides are common key intermediates in carcinogenesis and 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 to 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 non-enzymatic hydrolysis were also tested in comparison to that of the corresponding diazotates and other activated chemical species of N-nitrosamines. When the mutagenicity was assayed in three microbial strains, Salmonella typhimurium TA1535, and Escherichia coli WP2 and WP2 uvrA, 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 Salmonella strain and in E. coli strains, and this result could be explained by the efficiency of O6-alkylguanine-DNA alkyltransferase. In each bacterial strain, this effect of alkyl groups was similar in mutagenicity induced by (E)- and (Z)-diazotates, N-nitroso-N-alkylureas and other activated N-nitrosodialkylamines such as alpha-hydroxy nitrosamines. The geometrical isomerism affected the mutagenicity of (E)- and (Z)-potassium alkanediazotates, and the result suggested that alkanediazohydroxides react through diazonium ions in a cage rather than through free alkyldiazonium ions which have no geometrical isomerism. Our results confirmed that (E)-potassium alkanediazotates, (Z)-potassium alkanediazotates and N-nitroso-N-alkylureas all decomposed through diazohydroxides, and that alkanediazohydroxides are the active alkylating species of N-nitroso compounds, and also that the geometrical isomerism is important for carcinogenic N-nitroso compounds to show their biological activity.
链烷重氮氢氧化物是N-亚硝基化合物致癌和致突变过程中常见的关键中间体，N-亚硝基化合物在人类环境中广泛存在。对作为相应链烷重氮氢氧化物前体的（E）-和（Z）-链烷重氮酸钾的致突变性进行了评估，以研究几何异构的影响以及烷基对其生物活性的影响。还测试了非酶水解后自发产生链烷重氮氢氧化物的N-亚硝基-N-烷基脲的致突变性，并与相应的重氮酸盐和其他N-亚硝胺的活化化学物种进行了比较。当在三种微生物菌株（鼠伤寒沙门氏菌TA1535、大肠杆菌WP2和WP2 uvrA）中测定致突变性时，具有相同烷基的化合物的致突变效力顺序如下：（E）-重氮酸盐＞（Z）-重氮酸盐＞亚硝基脲。烷基对致突变效力的影响在沙门氏菌菌株和大肠杆菌菌株中有所不同，这一结果可以用O6-烷基鸟嘌呤-DNA烷基转移酶的效率来解释。在每种细菌菌株中，烷基的这种影响在由（E）-和（Z）-重氮酸盐、N-亚硝基-N-烷基脲以及其他活化的N-亚硝基二烷基胺（如α-羟基亚硝胺）诱导的致突变性中相似。几何异构影响了（E）-和（Z）-链烷重氮酸钾的致突变性，结果表明链烷重氮氢氧化物通过笼中的重氮离子反应，而不是通过没有几何异构的游离烷基重氮离子反应。我们的结果证实，（E）-链烷重氮酸钾、（Z）-链烷重氮酸钾和N-亚硝基-N-烷基脲均通过重氮氢氧化物分解，链烷重氮氢氧化物是N-亚硝基化合物的活性烷基化物种，并且几何异构对于致癌性N-亚硝基化合物表现其生物活性很重要。
