The relation between the structure of vicinal dihalogen compounds and their mutagenic activation via conjugation to glutathione.

Abstract

Vicinal dihalogen compounds may be activated to mutagenic 2-halogenothioethers by conjugation to glutathione. The objective of this investigation was to determine this type of metabolic activation in vitro in relation to the chemical structure of such compounds. The specific activity of rat liver glutathione transferases catalyzing the conjugation of a series of vicinal dihalogen compounds with glutathione was determined. The results were employed to define optimal conditions for the assessment of the relative mutagenic activity of these compounds towards Salmonella typhimurium TA 100 in the presence of rat liver 100,000 g supernatant. To further our understanding of the factors governing the mutagenic activity of the intermediate 2-halogenothioethers, a series of model intermediates, N-acetyl-S-2-halogenoalkyl-L-cysteine methyl esters, was synthesized and their mutagenic activity was determined in Salmonella strain TA 100. Alkyl substitution at the halogen-bearing carbon atoms reduces both glutathione transferase activity and mutagenicity of vicinal dihalogen compounds considerably. In the case of phenyl-substitution, glutathione transferase activity is increased without concomitant enhancement of the mutagenic activity. Introduction of alkyl-substituents into the model conjugates also results in a lower mutagenic activity. The specific activity of the glutathione transferases follows the halide order for leaving group ability, i.e. I > Br > Cl. For the mutagenic activity, however, a different result is obtained: the diiodo and dichloro derivatives are less active than the corresponding chloro-bromo and dibromo compounds. The 2-chloroethylthioether is most mutagenic, the 2-bromoethyl- somewhat less, while the 2-iodoethylthioether is the least mutagenic compound. A major factor in determining the mutagenicity of such intermediates is presumably their stability in aqueous solutions, the more reactive compound having a shorter life-time and thus a lower probability to reach genetically relevant macromolecules.