DNA-ADDUCTS OF CHEMICAL CARCINOGENS
DNA-ADDUCTS OF CHEMICAL CARCINOGENS
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DOI：
10.1093/carcin/16.3.437
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发表时间：
1995-03-01
期刊：
影响因子：
4.7
通讯作者：
DIPPLE, A
中科院分区：
文献类型：
--
作者：
DIPPLE, A
在第一个纯化学致癌物（1）被发现后的30年左右时间里，不同化学类别的致癌物的作用机制中没有明显的共同因素或途径。也许正是由于这个原因，每一类致癌物质，如多环芳烃，芳香胺和亚硝胺，往往被审查和讨论分开。米莱尔和他们的同事发现代谢在致癌物活化中的作用（2），揭示了许多致癌物之间的共性，即对细胞大分子（如DNA）的化学反应性（3，4）。今天，DNA加合物的形成被认为是大多数强效致癌物的共同特性，并且这种加合物的形成是分子流行病学和生物监测中几种当前策略的基础。尽管许多化学致癌物的机制都有这一共同点，但代谢活化以及加合物形成的化学和立体化学的复杂性往往会在不同类别化合物形成DNA加合物的研究和文献综述中保持一定程度的区室化（5）。试图以强调不同化学类别共有特征的方式总结致癌物加合物的形成。这一观点是通过根据水溶液中DNA加合物形成的化学性质而不是化学结构对化学致癌物进行分类来实现的。采用这种方法，化学致癌物主要分为那些对DNA具有内在反应性的物质，如烷化剂，以及那些需要代谢活化的物质，如亚硝胺。例如，消失。虽然代谢活化的机制仍然是重要的问题，但DNA的烷基化是上述两种类型的试剂与DNA形成加合物的化学机制。事实上，对加合物形成文献的研究表明，大多数已知的致癌物通过三种一般类型的化学反应之一与DNA反应。这些涉及转移到DNA的：（i）烷基残基;（ii）芳基胺残基;或（iii）芳烷基残基。
During the 30 years or so following the identification of the first pure chemical carcinogen (1), no common factors or pathways in the mechanism of action of carcinogens from different chemical classes were evident. For this reason perhaps, each class of carcinogen, eg the polycyclic aromatic hydrocarbons, the aromatic amines and the nitrosamines, was often reviewed and discussed separately. The discovery by the Millers and their colleagues of the role of metabolism in carcinogen activation (2) revealed a commonality amongst many carcinogens, ie a chemical reactivity towards cellular macromolecules, such as DNA (3, 4). Today, DNA adduct formation is recognized as a common property of most potent carcinogens and the formation of such adducts is the basis of several current strategies in molecular epidemiology and biomonitoring. Despite this common aspect of mechanism for many chemical carcinogens, the complexities of metabolic activation and of the chemistry and stereochemistry of adduct formation have tended to keep some degree of compartmentalization in research and in literature reviews of DNA adduct formation by different classes of chemical compounds (5).In this article, an attempt is made to summarize carcinogen adduct formation in a fashion that emphasizes features that are common to different chemical classes. This perspective is achieved by classifying chemical carcinogens on the basis of the chemistry of DNA adduct formation in aqueous solution rather than on chemical structure. Adopting this approach, the major division of chemical carcinogens into those intrinsically reactive towards DNA, such as alkylating agents, and those requiring metabolic activation, such as nitrosamines for. example, disappears. While mechanisms of metabolic activation remain important concerns, alkylation-of-DNA is the chemical mechanism through which both types of agent, exemplified above, form adducts with DNA. Indeed, examination of the literature on adduct formation {reviewed in 5}, indicates that the majority of known carcinogens react with DNA through one of only three general types of chemical reaction. These involve the transfer to DNA of either:(i) an alkyl residue;(ii) an arylamine residue; or (iii) an aralkyl residue.