Newbold R F, Warren W, Medcalf A S, Amos J
Nature. 1980 Feb 7;283(5747):596-9. doi: 10.1038/283596a0.
The carcinogenic potency of simple aliphatic alkylating agents such as the alkylnitrosamides and the alkylmethanesulphonates is positively correlated with their ability to alkylate the relatively weakly nucleophilic oxygen atoms in DNA, particularly the O6-atom of guanine. Differences in the spectrum of DNA alkylations produced by these agents can be rationalised on chemical grounds in that the electrophilic reactivity of the alkylating species determines the extent to which it will react at sites of weaker nucleophilicity. Alkylation of the more strongly nucleophilic ring nitrogen atoms of the purine bases, which is the main site of reaction with all these agents, appears to be much less important in alkylation carcinogenesis. O6-alkylation of guanine is likely to interfere with DNA base-pair hydrogen bonding and is possibly the major DNA modification responsible for the induction of GC yields AT transition mutations in bacteria and bacteriophage by alkylating agents. Here, we have studied the effects of three methylating agents of contrasting carcinogenic potency on mammalian (V79 Chinese hamster) cells in in culture. We report that the mutagenicity but not the cytotoxicity of each agent reflects its carcinogenicity and, furthermore, that the marked differences in mutagenicity are closely paralleled by differences in levels of O6-guanine methylation.
简单脂肪族烷基化剂（如烷基亚硝酰胺和烷基甲磺酸盐）的致癌效力与其烷基化DNA中相对亲核性较弱的氧原子（特别是鸟嘌呤的O6原子）的能力呈正相关。这些试剂产生的DNA烷基化谱的差异可以从化学角度进行合理说明，因为烷基化物种的亲电反应性决定了它在较弱亲核性位点的反应程度。嘌呤碱基中亲核性更强的环氮原子的烷基化是所有这些试剂的主要反应位点，但在烷基化致癌过程中似乎不太重要。鸟嘌呤的O6烷基化可能会干扰DNA碱基对的氢键形成，并且可能是导致烷基化剂在细菌和噬菌体中诱导GC突变为AT转换突变的主要DNA修饰。在这里，我们研究了三种致癌效力不同的甲基化剂对培养中的哺乳动物（V79中国仓鼠）细胞的影响。我们报告说，每种试剂的致突变性而非细胞毒性反映了其致癌性，此外，致突变性的显著差异与O6-鸟嘌呤甲基化水平的差异密切相关。
