Citation:

Chadwick, R., S. George, J. Chang, M. Kohan, J. Dekker, J. Long, M. Duffy, AND R. Williams. POTENTIATION OF 2,6-DINITROTOLUENE GENOTOXICITY IN F-344 RATS BY PRETREATMENT WITH PENTACHLOROPHENOL. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-91/047 (NTIS PB91191544), 1991.

Description:

The organochlorine pesticide, pentachlorophenol (PCP), a potent sulfotranferase inhibitor, reduces binding of the hepatocarcinogen. 2,6-dinitrotoluene (DNT), to hepatic DNA by 95% after a single i.p. injection. ctivation of DNT to genotoxic metabolites involves enzymes in both the liver and the intestinal flora. ince PCP also has bactericidal activity and induces hepatic mixed function oxidase activity after longer treatment, the effect of PCP on intestinal enzyme activity and the biotransformation of DNT to genotoxic metabolites, after 1, 2, 4, and 5 weeks of treatment was studied. ale Fischer 344 rats were dosed daily, by gavage, with either 20 mg/kg PCP or the peanut oil vehicle. fter 1, 2, 4, and 5 weeks, select control and treated animals were injected p.o. with 75 mg/kg 2,6 dinitrotoluene and transferred to metabolism cages, where urine was collected and tested for mutagenic activity. t 2 and 4 weeks, 6 control and 6 treated animals were sacrificed and nitroreductase, azo reductase, glucuronidase, dechlorinase and dehydrochlorinase activities were analyzed in homogenates of the small intestine, large intestine, and cecum. t 5 weeks, hepatic DNA adduct formation was assayed by the 32Ppostlabeling of DNA. Results of this study indicated that PCP accelerated the biotransformation of DNT to geneotoxic metabolites and potentiated the formation of DNT - induced DNA adducts in the liver. his is the first report of a chemical interaction leading to increased DNA adduct formation and may be important in risk assessment since it alters the relationship between exposure, dose and the effect of genotoxicants.

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