Mutagenicity of nitracrine analogues in Salmonella typhimurium: mutational specificity and activation by bacterial enzymes and rat-liver S9.
The mutagenic potential of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-(nitracrine), 2-, 3- and 4-nitro derivatives was studied in several strains of Salmonella typhimurium, using a plate-incorporation assay. In view of the potential importance of DNA binding and nitro group reduction, binding constants and redox potentials were determined. The parent compound was mutagenic only in the frameshift tester strain TA1537, and this effect was not enhanced by the plasmid pKM101. Each of the nitroarenes showed significant activity in S. typhimurium strains TA1537 and TA1538, and this mutagenicity was enhanced by the presence of plasmid pKM101. All caused reversion of the base-pair substitution allele in hisG46 in strain TA100 and this effect was either largely or totally dependent upon the plasmid. The frameshift mutagenic effects of the 3-nitro and 4-nitro compounds appeared to be little dependent upon the classical nitroreductase which is deficient in strain TA98NR, or transacetylase enzyme lacking in strain TA98/1,8-DNP6, whereas the activity of the 1-nitro compound depended partly on that nitroreductase enzyme, and that of the 2-nitro compound on having both activities present. In the latter two cases, the mutagenic effects of the compounds could not be restored by the addition of an S9 mix of mammalian enzymes. Mutagenicity data were compared with physicochemical parameters. The results do not distinguish between the view that the orientation of the nitro group with respect to the aromatic plane dictates mutagenic potential, and the earlier view that the nitro group redox potential is important. However, the extraordinary mutagenic potency of the 1-NO2 derivative is not explainable by its physicochemical properties alone.
D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D008099:Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000494:pharmacology; D009564:Nitracrine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D009601:Nitroreductases / Q000378:metabolism; D010957:Plasmids / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D000609:Aminoacridines; D009153:Mutagens; C024890:C 137; D009564:Nitracrine; D009601:Nitroreductases