Mechanisms of action of carcinogenic aromatic amines: an investigation using mutagenesis in bacteria.

The mutagenicities of groups of N-acetoxy-N-arylacetamides, nitroarenes, arylamides and arylamines were determined in the Salmonella typhimurium tester stains TA98, TA1538, TA100, TA1535 and TA1537. Three broad classes of mutagenic activity were found, interpreted as follows: class A, including 2-naphthylamine, produced essentially only base-pair substitution without induction of error-prone repair; class B, including 4-aminobiphenyl, caused consideration induction of error-prone repair, accompanied by a lower level of frame shifting; class C, including N-acetoxy-2-acetamidofluorene, produced high levels of frame shifting, with some induction of error-prone repair. Correlation of these results with known reactions of certain aromatic amine derivatives with nucleosides and nucleic acids, and with molecular orbital calculations, suggests that the effect of class A is produced by small aromatic groups attached to extranuclear heteroatoms in DNA bases, the effect of class B is caused by large aromatic groups attached to extranuclear heteroatoms or by arylamines attached to C-8 of guanine, while the effect of class C is caused by arylamides attached to C-8 of guanine, probably rotating into the helix, as proposed by others. The data also suggest that the N-acetoxy-N-arylacetamides are generally useful models for ultimate metabolites derived in vivo, even if the in vivo metabolites do not carry an acetyl group. Finally, there is a rough correlation between the sum of reversions induced in TA98 and TA100 by the N-acetoxy-N-arylacetamides and their previously determined local carcinogenicities. There is a poor correlation between mutagenicity in any one tester strain and carcinogenicity.