Barbin A, Bartsch H
IARC Sci Publ. 1986(70):345-58.
Published results and work from this laboratory permit the characterization of the possible promutagenic lesions induced by chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), both known as bifunctional alkylating metabolites of vinyl chloride (VC). The mutagenic effectiveness of CEO and CAA in Escherichia coli, when compared to their nucleophilic selectivity, suggests that the critical target site in DNA bases is not an oxygen atom, and/or that the reaction mechanism of CEO and CAA is different from a simple alkylation. CEO-mutagenicity in E. coli is recA-independent, and CEO preferentially induces GC----AT transitions; accordingly, the mutagenicity of CEO in bacteria may result mainly from a miscoding guanosine or cytosine adduct. Two observations argue against the role of 1,N6-ethenoadenine (epsilon A) and 3,N4-ethenocytosine (epsilon C) in VC-induced mutagenesis/carcinogenesis: i) the lack of detection in double-stranded DNA in vivo and in vitro; ii) the inconsistency between mutational specificity of CEO and miscoding properties of epsilon A and epsilon C. The lack of miscoding properties of 7-(2-oxoethyl)guanine (oxet-G), the major in-vivo VC-DNA adduct, suggests a minor miscoding base adduct. Several lines of evidence point to N4-(2-chlorovinyl)cytosine as one possible putative promutagenic lesion produced by VC, but this compound has yet to be identified in DNA.
本实验室已发表的研究结果和工作，使得对环氧氯乙烷（CEO）和氯乙醛（CAA）诱导的潜在促诱变损伤进行表征成为可能，这两种物质均为氯乙烯（VC）的双功能烷基化代谢产物。与它们的亲核选择性相比，CEO和CAA在大肠杆菌中的诱变效力表明，DNA碱基中的关键靶位点不是氧原子，和/或CEO和CAA的反应机制不同于简单的烷基化。大肠杆菌中CEO的诱变作用不依赖recA，且CEO优先诱导GC→AT转换；因此，CEO在细菌中的诱变作用可能主要源于错误编码的鸟嘌呤或胞嘧啶加合物。有两个观察结果反对1,N⁶-乙烯基腺嘌呤（εA）和3,N⁴-乙烯基胞嘧啶（εC）在VC诱导的诱变/致癌作用中的作用：i）在体内和体外双链DNA中均未检测到；ii）CEO的突变特异性与εA和εC的错误编码特性之间不一致。7-(2-氧代乙基)鸟嘌呤（oxet-G）作为体内主要的VC-DNA加合物，缺乏错误编码特性，提示其为一种次要的错误编码碱基加合物。多条证据指向N⁴-(2-氯乙烯基)胞嘧啶是VC产生的一种可能的潜在促诱变损伤，但该化合物尚未在DNA中被鉴定出来。
