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Comparison of DNA adduct formation between 2,4 and 2,6-dinitrotoluene by32P-postlabelling analysis

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Abstract

Using32P-postlabelling, we examined DNA binding by 2,4 and 2,6-dinitrotoluene (DNT) in Fischer-344 rats. DNA binding between the two compounds was compared to determine if differences in adduct formation and persistence could partly explain the known isomerspecific hepatocarcinogenicity of DNTs. The differences in cytotoxicity between the two isomers were also assessed. Both 2,4 and 2,6-DNT induced adduct formation in hepatic DNA. Three distinct adducts were detected following single i.p. administration of 2,4-DNT, while the 2,6-isomer produced four different adducts. Depending on the concentration administered, the two compounds differed in their relative yields. 2,6-DNT produced a greater total adduct yield relative to the 2,4-isomer at low concentrations. Following administration of high concentrations, however, 2,4-DNT predominated. The maximum adduct levels measured were 3.0 and 1.8 adducted nucleotides per 106 nucleotides for 2,4 and 2,6-DNT, respectively. Substantial amounts of adducts from both compounds were found to persist over time. After 2 weeks, the mean persistence for 2,4 and 2,6-DNT induced adducts were 42% and 46%, respectively. Qualitative examination for liver toxicity showed 2,6-DNT to be more cytotoxic, inducing extensive hemorrhagic centrilobular necrosis. Rats treated with 2,4-DNT did not show any observable signs of hepatocellular necrosis. Under the conditions of this study, the differences between 2,4 and 2,6-DNT in adduct formation and persistence do not appear to be sufficient to account for their differences in carcinogenicity. The toxicity of 2,6-DNT may be a determining factor in the potent carcinogenicity observed with this compound.

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  1. Department of Environmental Health Sciences and UCLA Center for Occupational and Environmental Health, School of Public Health, University of California, 90024, Los Angeles, CA, USA

    David K. La & John R. Froines

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  1. David K. La
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  2. John R. Froines
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La, D.K., Froines, J.R. Comparison of DNA adduct formation between 2,4 and 2,6-dinitrotoluene by32P-postlabelling analysis. Arch Toxicol 66, 633–640 (1992). https://doi.org/10.1007/BF01981502

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  • DOI: https://doi.org/10.1007/BF01981502

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