致癌物硫酸二甲酯、甲磺酸乙酯、N-乙基-N-亚硝基脲和N-甲基-N-亚硝基脲对脱氧核糖核酸的烷基化作用。磷酸二酯位点胸苷酰（3'-5'）胸苷的相对反应活性。
Alkylation of deoxyribonucleic acid by carcinogens dimethyl sulphate, ethyl methanesulphonate, N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Relative reactivity of the phosphodiester site thymidylyl(3'-5')thymidine.
作者信息
Swenson D H, Lawley P D
出版信息
Biochem J. 1978 Jun 1;171(3):575-87. doi: 10.1042/bj1710575.
Abstract
- The ethyl phosphotriester of thymidylyl(3'-5')thymidine, dTp(Et)dT, was identified as a product from reaction of DNA with N-ethyl-N-nitrosourea, by procedures parallel to those reported previously for the methyl homologue produced by N-methyl-N-nitrosourea. 2. Enzymic degradation to yield alkyl phosphotriesters from DNA alkylated by these carcinogens and by dimethyl sulphate and ethyl methanesulphonate was studied quantitatively, and the relative yields of the triesters dTp(Alk)dT were determined. The relative reactivity of the phosphodiester group dTpdT to each of the four carcinogens was thus obtained, and compared with that of DNA overall, or with that of the N-7 atom of guanine in DNA. Relative reactivity of the phosphodiester group was lowest towards dimethyl sulphate, the least electrophilic of the reagents used, and was highest towards N-ethyl-N-nitrosourea, the most electrophilic reagent. 3. The nature of the alkyl group transferred also influenced reactivity of the phosphodiester site, since this site was relatively more reactive towards ethylation than would be predicted simply from the known Swain-Scott s values of the alkylating agents. It was therefore suggested that the steric accessibility of the weakly nucleophilic phosphodiester group on the outside of the DNA macromolecule favours its reaction with ethylating, as opposed to methylating, reagents. 4. Taking a value of the Swain-Scott nucleophilicity (n) of 2.5 for an average DNA nucleotide unit [Walles & Ehrenberg (1969) Acta Chem. Scand. 23, 1080-1084], a value of n of about 1 for the phosphodiester group was deduced, and this value was found to be 2-3 units less than that for the N-7 atom of guanine in DNA. 5. The reactivity of DNA overall was markedly high towards the alkylnitrosoureas, despite their relatively low s values. This was ascribed to an electrostatic factor that favoured reaction of the negatively charged polymer with alkyldiazonium cation intermediates.
摘要
- 通过与之前报道的由N-甲基-N-亚硝基脲产生的甲基同系物的方法平行的程序，胸苷酰基（3'-5'）胸苷的乙基磷酸三酯dTp(Et)dT被鉴定为DNA与N-乙基-N-亚硝基脲反应的产物。2. 对由这些致癌物以及硫酸二甲酯和甲磺酸乙酯烷基化的DNA进行酶促降解以产生烷基磷酸三酯进行了定量研究，并测定了三酯dTp(Alk)dT 的相对产率。由此获得了磷酸二酯基团dTpdT对四种致癌物中每一种致癌物的相对反应活性，并将其与DNA整体的反应活性或与DNA中鸟嘌呤的N-7原子的反应活性进行了比较。磷酸二酯基团的相对反应活性对硫酸二甲酯最低，硫酸二甲酯是所用试剂中亲电性最弱的，而对N-乙基-N-亚硝基脲最高，N-乙基-N-亚硝基脲是亲电性最强的试剂。3. 转移的烷基的性质也影响了磷酸二酯位点的反应活性，因为该位点对乙基化的反应活性相对较高，这比仅根据烷基化剂已知的斯温-斯科特s值所预测的要高。因此有人提出，DNA大分子外部亲核性较弱的磷酸二酯基团的空间可及性有利于其与乙基化试剂而非甲基化试剂反应。4. 假设平均DNA核苷酸单元的斯温-斯科特亲核性（n）值为2.5 [瓦莱斯和埃伦贝格（1969年）《化学学报》23卷，1080 - 1084页]，推断出磷酸二酯基团的n值约为1，并且发现该值比DNA中鸟嘌呤的N-7原子的n值小2 - 3个单位。5. 尽管烷基亚硝基脲的s值相对较低，但DNA整体对其反应活性明显较高。这归因于一个静电因素，该因素有利于带负电荷的聚合物与烷基重氮阳离子中间体反应。
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