Effect of Substitution Site upon the Oxidation Potentials of Alkylanilines, the Mutagenicities of N-Hydroxyalkylanilines, and the Conformations of Alkylaniline−DNA Adducts

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Abstract
Carcinogenic arylamines typically undergo metabolic activation via N-hydroxylation followed in most instances by O-esterification. In this study, the ability of methyl-, dimethyl-, and ethylaniline constituents of tobacco smoke to undergo oxidation at the nitrogen atom was analyzed. In addition, the mutagenicity of the corresponding N-hydroxyalkylanilines and the conformational properties of the DNA adducts generated from their N-acyloxy derivatives were investigated. All the arylamines underwent irreversible electrochemical N-oxidation at potentials higher than those observed for the oxidation of carcinogenic polynuclear aromatic amines. There were minor differences in the oxidation potentials, which were consistent with the position and electron-donating abilities of the alkyl substituents; however, the differences appeared to be too small to account for the range of genotoxic effects among the alkylanilines. N-Hydroxyarylamines containing p-alkyl substituents had increased mutagenicities in Salmonella typhimurium TA100, which was attributed to their higher efficiencies of adduct formation. Increased mutagenicities were also observed upon o-alkyl substitution; however, this property was not related to a greater ability of the ortho-substituted species to form DNA adducts, which suggested that adducts from ortho-substituted alkylanilines may be intrinsically more mutagenic than their meta- and para-substituted analogues. In all instances, N-(acyloxy)-arylamines generated from the N-hydroxyarylamines reacted with dG, dG nucleotides, and DNA to yield C8-substituted dG derivatives as the major adducts. The alkylaniline-dG adducts displayed distinct conformational trends that were determined by the location of the alkyl substituents. Spectroscopic data indicated higher percentages of low-energy syn conformers in the adducts that contained alkyl groups ortho to the arylamine nitrogen as opposed to adducts not bearing ortho substituents. The data strongly suggest that the conformational properties of the DNA adducts, in particular their ability to adopt syn conformations, may be determinant factors for the genotoxic responses elicited by certain alkylanilines (e.g., 2-methylaniline and 2,6-dimethylaniline).

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