Metabolism and relative carcinogenic potency of chloroethanes: a quantum chemical structure-activity study

Using the all-valence electron, semiempirical molecular orbital method, MNDO, properties have been identified and calculated for eight chloroethanes which can serve as indicators of their extent of transformation to alcohols by cytochrome P450 and the subsequent formation of aldehydes by loss of HCl from these alcohols. The assumption was made that these aldehydes are the active carcinogens of the chloroethanes and that they act as electrophiles in adduct formation with DNA bases. Electrophilic properties of these putative ultimate carcinogens have been calculated which are indicators of the rank order of carcinogenic activity of the parent compounds in susceptible species. Particularly relevant in this respect are (a) the electron affinity of aldehydes as measured by the energy of their electron accepting (lowest energy virtual) orbital, and (b) the net charge on the C alpha carbon, adjacent to the carbonyl carbon, which can participate in electrophilic attack on nucleophilic sites of DNA bases. The molecular properties identified in this study as indicators of rank order or carcinogenic activity of the parent chloroethanes are consistent with the importance of cytochrome P450 in transforming halohydrocarbons to active carcinogens and of acylchlorides and chloroaldehydes as the active form. Their validity and usefulness can be further tested in screening unknown and more complex chlorohydrocarbons for carcinogenic activity.