Mutagenic and promutagenic properties of DNA adducts formed by vinyl chloride metabolites.

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.