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The effect of biotransformation of 2,4-dinitrotoluene on its mutagenic potential
D B Couch1, D J Abernethy, P F Allen
1Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Abstract:
Because both oxidative and reductive metabolism of the hepatocarcinogen 2,4-dinitrotoluene (2,4-DNT) can occur in vivo, we have examined the mutagenicity of compounds which can be formed from 2,4-DNT in an attempt to establish which metabolic pathways contribute to the formation of genotoxic products. A quantitative reversion assay using Salmonella typhimurium TA98 was used to evaluate the mutagenicity of these compounds. 2,4-Dinitrobenzyl alcohol, 2-amino-4-nitrotoluene and 2-nitroso-4-nitrotoluene were found to be more mutagenic to S. typhimurium than is 2,4-DNT and did not require metabolic activation by post-mitochondrial supernatants of Aroclor-induced rat liver homogenates (S9) for their effect. 2-Amino-4-nitrobenzoic acid was also mutagenic to S. typhimurium TA98 in the absence of S9, but its mutagenicity was enhanced when S9 was included in the incubation mixture. 2,4-Diaminotoluene required S9 for demonstration of mutagenicity and was approximately as effective, on a molar basis, as 2,4-DNT in inducing reversion to histidine prototrophy. These results suggest that both oxidative and reductive metabolism may be involved in production of mutagenic metabolites of 2,4-DNT.
Insights
Investigating the metabolism of 2,4-dinitrotoluene (2,4-DNT), this study found that several of its breakdown products are mutagenic. These findings suggest both oxidative and reductive pathways contribute to the formation of genotoxic compounds from 2,4-DNT.
Area of Science:
- Toxicology
- Metabolism
- Genotoxicity
Background:
- 2,4-dinitrotoluene (2,4-DNT) is a hepatocarcinogen with known oxidative and reductive metabolic pathways in vivo.
- Understanding the mutagenicity of 2,4-DNT metabolites is crucial for assessing its genotoxic risk.
Purpose of the Study:
- To evaluate the mutagenicity of potential metabolites formed from 2,4-DNT.
- To determine which metabolic pathways contribute to the formation of genotoxic products from 2,4-DNT.
Main Methods:
- Utilized a quantitative reversion assay with Salmonella typhimurium TA98 to assess mutagenicity.
- Tested the mutagenicity of 2,4-DNT and its potential metabolites, both with and without metabolic activation by rat liver homogenates (S9).
Main Results:
- 2,4-Dinitrobenzyl alcohol, 2-amino-4-nitrotoluene, and 2-nitroso-4-nitrotoluene were more mutagenic than 2,4-DNT and did not require S9 activation.
- 2-Amino-4-nitrobenzoic acid showed S9-enhanced mutagenicity.
- 2,4-Diaminotoluene required S9 activation and was similarly mutagenic to 2,4-DNT.
Conclusions:
- Both oxidative and reductive metabolic pathways of 2,4-DNT can produce mutagenic metabolites.
- The identified metabolites contribute to the overall genotoxic potential of 2,4-DNT.