Abstract
A comparative genetic study was undertaken with structurally related N‐methyl‐4‐aminoazobenzenes of varied chemical reactivities and carcinogenicities, including the parent N, N‐dimethyl azo dye (butter yellow) and model compounds of its suspected metabolites. The mutagenic activity of each compound was examined with respect to the specific effects on the heterochromatic bobbed (bb) and Minute (M) loci, relative to general mutability as indicated by the overall response of the X‐chromosome (recessive lethals and visibles) in the same treated genome.
The intrinsically non‐reactive compounds, such as the parent dye and its 3′‐methyl derivative, were inactive with respect to the general X‐chromosome mutations (mainly euchromatic genes) and the large heterochromatic M deletions, but were decisively active on the r‐RNA sites (yielding bb's), particularly in mature sperm. The N‐substituted reactive derivatives (amino‐oxy esters and chloroethylamines) were effective to various degrees for all mutational classes, but the reactivation of the ring methyl groups–as with the 3′‐chloromethyl compound–proved to be mutagenically ineffective.
Differential mutagenic effects were discernible among the tested azo dyes, with respect both to the affected genes and to the response of the germ cell stages. However, a close similarity occurred between the mutational spectra of the parent azo dye and its N‐benzoyloxy ester, both exerting maximal activity on the bb loci in mature sperm. This is in line with the biochemical evidence that metabolic activation of azo dyes probably proceeds via the formation of amino‐oxy esters.
The mutagenic activity and/or selectivity on the bb loci among the tested azo dyes appeared to be correlated with their carcinogenic potential. Specificity for these genes occurred with the hepatocarcinogenic parent dye and its 3′‐methyl derivative, and a high level of selectivity for these sites was also manifested by the N‐benzoyloxy ester which could be regarded as a precursor of the N‐hydroxy intermediate metabolite. The chloroethylamino derivatives produced a level of bb selectivity compatible with their possible in vivo conversion to alkylating carcinogens.
The genetic properties of the azo dyes were similar to those of other aromatic amines with comparable oncological activities and were in harmony with the concept that molecular deletions within the r‐RNA loci might be significant in cancer initiation.