Metabolism of chlorinated alkenes and alkanes as related to toxicity

The chlorine substitution in aliphatic compounds results, by its electron attracting effect, in a destabilization in alkanes and a stabilization in alkenes. Thus, with alkanes the main pathways of metabolic transformation to reactive intermediates are radical formation by C-C break or dechlorination, or dehydrochlorination. In alkenes, the stability of the molecule increases with the number of chlorine substitutions. In the series of chlorinated ethylenes, the first step of metabolic transformation is the oxidation to electrophilic oxiranes which may be hydrolized enzymatically or non-enzymatically, react with cellular nucleophiles, or rearrange to either chlorinated aldehydes or acyl chlorides. With tetra-, 1,2-cis- and trans-di-, 1,1-di-, and monochloroethylene, the metabolites identified in in vivo experiments are identical with the thermal rearrangement products of the respective oxiranes. An important exception is found with trichloroethylene, where the thermal rearrangement product is dichloroacetyl chloride; the metabolites in vivo, however, are entirely derived from trichloroacetaldehyde (chloral). The reason for this peculiar behavior is most probably a Lewis acid catalysis by the oxidizing enzyme system. Mutagenic and carcinogenic activities in the series of chlorinated ethylenes are determined by the stability of their oxiranes, which is higher in symmetrical than in unsymmetrical chlorine substitution: the relatively unstable and unsymmetric oxiranes of trichloroethylene, 1, 1,-dichloro-, and monochloroethylene are mutagenic in the Ames test; the more stable symmetric oxiranes of tetra-, 1,2-cis- and trans-dichloroethylenes are inactive.