Comparison of DNA adduct formation between 2,4 and 2,6-dinitrotoluene by 32P-postlabelling analysis.
Using 32P-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 isomer-specific 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 10(6) 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.
La
D K
DK
Department of Environmental Health Sciences, School of Public Health, University of California, Los Angeles 90024.
Froines
J R
JR
D000818:Animals; D001345:Autoradiography; D002273:Carcinogens / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D002855:Chromatography, Thin Layer; D004247:DNA / Q000378:metabolism*; D004136:Dinitrobenzenes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D010761:Phosphorus Radioisotopes; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004136:Dinitrobenzenes; D010761:Phosphorus Radioisotopes; C016403:2,4-dinitrotoluene; D004247:DNA; C023514:2,6-dinitrotoluene