EXAMINATION OF ALPHA-CARBONYL DERIVATIVES OF NITROSODIMETHYLAMINE AND ETHYLNITROSOMETHYLAMINE AS PUTATIVE PROXIMATE CARCINOGENS
EXAMINATION OF ALPHA-CARBONYL DERIVATIVES OF NITROSODIMETHYLAMINE AND ETHYLNITROSOMETHYLAMINE AS PUTATIVE PROXIMATE CARCINOGENS
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DOI：
10.1093/carcin/14.6.1189
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发表时间：
1993-06-01
期刊：
影响因子：
4.7
通讯作者：
LIJINSKY, W
中科院分区：
文献类型：
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作者：
ELESPURU, RK;SAAVEDRA, JE;LIJINSKY, W
酶氧化产生的代谢物被认为是n -亚硝胺致突变性和致癌性的原因。虽然经常考虑α -羟基化合物，但这里研究了一种相关且更稳定的氧化产物- α -羰基化合物。合成了亚硝基二甲胺（NDMA）和乙基亚硝基somethy胺（在甲基或乙基氧化）的α -羰基衍生物。其衍生物为甲基亚硝基甲酰胺（MNFA）、乙基亚硝基甲酰胺（ENFA）和甲基亚硝基乙酰胺（MNAA）。这些化合物随后被研究为潜在的有毒、致突变和致癌中间体。这三种化合物对鼠伤寒沙门氏菌TA1535都是非常有效的直接作用诱变剂。在大肠杆菌中，MNFA和ENFA（但不包括MNAA）的突变指纹图谱与S(N)1型甲基化和乙基化化合物的突变指纹图谱相匹配。后一结果表明，这两种烷基亚硝基甲酰胺可能是母体亚硝胺致突变性的中间体。在动物实验中，假定的代谢物MNFA对F344大鼠的急性毒性比NDMA更大。在F344大鼠和叙利亚金仓鼠的慢性实验中，大多数动物（雌性仓鼠除外）在8个月内口服MNFA诱导前胃肿瘤。这些n -亚硝胺的氧化衍生物的性质与预期的近似致癌中间体一致。
Metabolites produced by enzymic oxidation are believed to be responsible for the mutagenicity and carcinogenicity of N-nitrosamines. Although alpha-hydroxy compounds are often considered, a related and more stable oxidation product, the alpha-carbonyl compound, was studied here. The alpha-carbonyl derivatives of nitrosodimethylamine (NDMA) and ethylnitrosomethylamine (oxidized at either the methyl or the ethyl group) were synthesized. The derivatives were methylnitrosoformamide (MNFA), ethylnitrosoformamide (ENFA) and methylnitrosoacetamide (MNAA). These compounds were then studied as potential toxic, mutagenic and carcinogenic intermediates. All three compounds were very potent directly acting mutagens to Salmonella typhimurium TA1535. Mutational Fingerprints in Escherichia coli of MNFA and ENFA (but not MNAA) matched those produced by S(N)1-type methylating and ethylating compounds respectively. The latter results indicate that the two alkylnitrosoformamides could be intermediates in the mutagenicity of the parent nitrosamines. In animal studies the putative metabolite MNFA was more acutely toxic than NDMA in F344 rats. In chronic experiments with MNFA in F344 rats and Syrian golden hamsters, tumors of the forestomach were induced by oral administration in most animals (except female hamsters) within 8 months. The properties of these oxidized derivatives of N-nitrosamines are consistent with expectations for proximate carcinogenic intermediates.