Metabolic activation of chlorinated ethylenes: dependence of mutagenic effect on electrophilic reactivity of the metabolically formed epoxides

Abstract

In chlorinated ethylenes, the chlorine substitution exerts, by its electron withdrawal effect, a stabilization of the molecule which increases with the number auf chlorine residues. All chlorinated ethylenes are metabolically transformed, in a first step reaction, to epoxides which may rearrange to aldehydes or acyl chlorides, respectively, undergo hydrolysis to diols, conjugate with glutathione, or react, by alkylation, with cellular macromolecules. The electrophilicity of the epoxides is high with those having an unsymmetric chlorine substitution, and comparatively low with the others bearing symmetric chlorine residues. According to in vitro mutagenicity testing in a modified Ames system, the following rule on structure/activity-relationship has been worked out: mutagenic potential is bound to unsymmetric substitution and high chemical reactivity (as with vinyl chloride, vinylidene chloride, and trichloroethylene), symmetric substitution results in lower chemical reactivity and non-mutagenicity. So far, the rule is substantiated by positive carcinogenic effects in animal experiments with vinyl chloride, vinylidene chloride and trichloroethylene.