Acrylonitrile (AN) is widely used in the manufacture of resins, plastics, and polymers, where workers are exposed to it during its production, transportation, and application. After intake a portion of AN is converted to cyanoethylene oxide (CEO) by cytochrome P450 2E1. Both AN and CEO represent possible chemical carcinogens leading to DNA damage mainly in the form of the major 7-(2-oxoethyl)deoxyguanosine adduct. A kinetic model for its formation was devised and a corresponding second-order rate constant obtained from the experimental data on the reaction with CEO. A series of ab initio, density functional theory, and semiempirical calculations of activation free energies was then performed on the alkylation of nucleic bases with both CEO and AN. The combination of Hartree–Fock level of theory with the flexible 6-311++G(d,p) basis set and Langevin dipoles implicit solvation model gave the best agreement with the experimental activation barrier. It also predicted relative reactivities of all four nucleobases that are in agreement with the experimentally reported adduct yields. Moreover, this combination predicted higher reactivity of CEO than AN with all four nucleobases corroborating the experimental hypothesis that S_N2 substitution of CEO rather than direct Michael addition of AN is responsible for the genotoxic properties of AN. In a broader context this paper points to the applicability of quantum chemical methods to the studies of carcinogenesis.

中文翻译：

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丙烯腈和氰基环氧乙烷的核碱烷基化：计算研究

丙烯腈（AN）广泛用于制造树脂，塑料和聚合物，在生产，运输和使用过程中，工人会接触到丙烯腈。摄入后，一部分AN被细胞色素P450 2E1转化为氰基环氧乙烷（CEO）。AN和CEO均以主要的7-（2-氧代乙基）脱氧鸟苷加合物的形式代表可能导致DNA损伤的化学致癌物。设计了其形成的动力学模型，并从与CEO反应的实验数据中获得了相应的二阶速率常数。一系列从头开始然后，用CEO和AN对核酸碱基的烷基化进行密度泛函理论和活化能的半经验计算。Hartree-Fock理论水平与灵活的6-311 ++ G（d，p）基组和Langevin偶极隐式溶剂化模型的结合，与实验激活障碍达到了最佳一致性。它还预测了所有四个核碱基的相对反应性，与实验报道的加合物收率相符。此外，这种组合预测首席执行官与AN在所有四个核苷碱基上的反应性都高于AN，从而证实了S _N的实验假设。2替换CEO而不是直接添加AN是Michael的遗传毒性特性。在更广泛的背景下，本文指出了量子化学方法在致癌研究中的适用性。