Barbin A, Bartsch H, Leconte P, Radman M
Nucleic Acids Res. 1981 Jan 24;9(2):375-87. doi: 10.1093/nar/9.2.375.
1,N6-Ethenoadenine (epsilon A) and 3,N4-ethenocytosine (epsilon C) are formed when electrophilic vinyl chloride (VC) metabolites, chloroethylene oxide (CEO) or chloroacetaldehyde (CAA) react with adenine and cytosine residues in DNA. They were assayed for their miscoding properties in an in vitro system using Escherichia coli DNA polymerase I and synthetic templates prepared by reaction of poly(dA) and poly(dC) with increasing concentrations of CEO or CAA. Following the introduction of etheno groups, an increasing inhibition of DNA synthesis was observed. dGMP was misincorporated on CAA- or CEO-treated poly(dA) templates and dTMP was misincorporated on CAA- or CEO-treated poly(dC) templates, suggesting that epsilon A and epsilon C may miscode. The error rates augmented with the extent of reaction of CEO or CAA with the templates. Base-pairing models are proposed for the epsilon A.G. and epsilon C.T pairs. The potentially miscoding properties of epsilon A and epsilon C may explain why metabolically-activated VC and its reactive metabolites specifically induce base-pair substitution mutations in Salmonella typhimurium. Promutagenic lesions may represent one of the initial steps in VC- or CEO-induced carcinogenesis.
当亲电子性氯乙烯(VC)代谢产物环氧氯乙烷(CEO)或氯乙醛(CAA)与DNA中的腺嘌呤和胞嘧啶残基反应时,会形成1,N6-乙烯基腺嘌呤(εA)和3,N4-乙烯基胞嘧啶(εC)。在体外系统中,使用大肠杆菌DNA聚合酶I和通过使聚(dA)和聚(dC)与浓度不断增加的CEO或CAA反应制备的合成模板,对它们的错配特性进行了测定。引入乙烯基基团后,观察到DNA合成的抑制作用增强。在经CAA或CEO处理的聚(dA)模板上,dGMP发生错掺入;在经CAA或CEO处理的聚(dC)模板上,dTMP发生错掺入,这表明εA和εC可能会发生错配。错误率随着CEO或CAA与模板的反应程度而增加。提出了εA.G和εC.T碱基对的碱基配对模型。εA和εC潜在的错配特性可能解释了为什么经代谢活化的VC及其活性代谢产物会在鼠伤寒沙门氏菌中特异性诱导碱基对替代突变。前诱变损伤可能代表了VC或CEO诱导致癌作用的初始步骤之一。