title: Mutagenicity of halogenated and other substituted dinitrobenzenes in Salmonella typhimurium TA100 and derivatives deficient in glutathione (TA100/GSH-) and nitroreductase (TA100NR).
abstract: In a previous study, it was shown that 1-chloro-2,4-dinitrobenzene (CDNB) was less mutagenic in a glutathione (GSH)-deficient derivative of Salmonella typhimurium TA100 (TA100/GSH-) than in TA100 itself, suggesting that the mutagenicity of the compound is dependent on GSH, possibly mediated by the action of a bacterial nitroreductase(s) on the CDNB-GSH conjugate. In the present study a series of mutagenicity tests were performed to determine how CDNB could be activated after reaction with GSH. In liquid preincubation assays, strains TA100, TA100/GSH- and TA100NR, a nitroreductase-deficient derivative of TA100, were treated with CDNB and its fluoro and bromo analogues (FDNB and BDNB), further with its GSH conjugate (S-GSH-DNB) and possible metabolic products, such as S-cysteine-dinitrobenzene (S-Cys-DNB) and S-methyl-dinitrobenzene (S-methyl-DNB), and with 2 more analogues, O-methyl-dinitrobenzene (O-methyl-DNB) and dinitrobenzene (DNB). CDNB, FDNB and BDNB were found to be mutagenic in TA100 and TA100NR, while TA100/GSH- was much less sensitive to the mutagenic action of these halogenated dinitrobenzenes. DNB, O-methyl-DNB, S-methyl-DNB and S-Cys-DNB induced equal numbers of His+ revertants in TA100 and TA100/GSH-, but were not mutagenic in TA100NR. S-GSH-DNB showed no mutagenic activity in any of the 3 strains under the present experimental conditions. These results suggest that the halogenated aromatics may react with bacterial DNA and produce pre-mutagenic alterations according to 2 mechanisms: direct attack on the DNA through nucleophilic substitution (SN2) of the halogen atoms; activation through GSH conjugation and subsequent nitroreduction of the conjugate or its metabolic products to more reactive intermediates.
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects*; D004136:Dinitrobenzenes / Q000378:metabolism / Q000494:pharmacology*; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology*; D009601:Nitroreductases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004136:Dinitrobenzenes; D009578:Nitrobenzenes; D010088:Oxidoreductases; D009601:Nitroreductases; D005980:Glutathione Reductase