title: Diaminotoluenes induce intrachromosomal recombination and free radicals in Saccharomyces cerevisiae.
abstract: The carcinogenicity of aniline-based aromatic amines is poorly reflected by their activity in short-term mutagenicity assays such as the Salmonella typhimurium reverse mutation (Ames) assay. More information about the mechanism of action of such carcinogens is needed. Here we report the effects on DEL recombination in Saccharomyces cerevisiae of the carcinogen 2,4-diaminotoluene and its structural isomer 2,6-diaminotoluene, which is reported to be non-carcinogenic. Both compounds are detected as equally mutagenic in the Salmonella assay. In the absence of any external metabolizing system both compounds were recombinagenic in the DEL assay with the carcinogen being a more potent inducer of deletions than the non-carcinogen. In the presence of Aroclor-induced rat liver S9, however, the carcinogen 2,4-diaminotoluene became a 2-fold more potent inducer of deletions, and the non-carcinogen 2,6-diaminotoluene was rendered less toxic and no induced recombination was observed. 2,4-Diaminotoluene is distinguished from its non-carcinogen analog in the DEL assay, therefore, on the basis of a preferential activation of the carcinogen in the presence of a rat liver microsomal metabolizing system. Free radical species are produced by several carcinogens and have been implicated in carcinogenesis. We further investigated whether exposure of yeast to either 2,4-diaminotoluene or 2,6-diaminotoluene resulted in a rise in intracellular free radical species. The effects of the free radical scavenger N-acetylcysteine on toxicity and recombination induced by the two compounds and intracellular oxidation of the free radical-sensitive reporter compound dichlorofluorescin diacetate were studied. Both 2,4- and 2,6-diaminotoluene produced tree radical species in yeast, indicating that the reason for the differential activity of the compounds for induced deletions is not reflected in any difference in the production of free radical species.
authors.affiliation: Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA 02115-6012, USA. brennan@mbcrr.harvard.edu
authors.forename: R J
authors.initials: RJ
authors.lastname: Brennan
authors.forename: R H
authors.initials: RH
authors.lastname: Schiestl
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000494:pharmacology*; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D010655:Phenylenediamines / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011995:Recombination, Genetic / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D004271:DNA, Fungal; D016166:Free Radical Scavengers; D005609:Free Radicals; D009153:Mutagens; D010655:Phenylenediamines; C025235:2,6-diaminotoluene; C010914:2,4-diaminotoluene; D000111:Acetylcysteine