Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer 344 rats by pretreatment with pentachlorophenol

Abstract

The organochlorine pesticide, pentachlorophenol, a potent sulfotransferase inhibitor, reportedly reduces the binding of 2,6-dinitrotoluene, an industrial hepatocarcinogen to hepatic DNA by 95% after a single i.p. injection. Activation of 2,6-dinitrotoluene to genotoxic metabolites involves enzymes in both the liver and the intestinal flora. Since pentachlorophenol also has bactericidal activity and induces hepatic mixed function oxidase activity after longer treatment, the effect of pentachlorophenol on intestinal enzyme activity and the biotransformation of 2,6-dinitrotoluene to genotoxic metabolites was studied after 1, 2, 4, and 5 weeks of treatment. Male Fischer 344 rats were dosed daily, by gavage, with either 20 mg/kg pentachlorophenol or the peanut oil vehicle. After 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 for 24 hr and tested for mutagenic activity by the Ames Salmonella typhimurium reversion assay. At 2 and 4 weeks, six control and six treated animals were sacrificed and nitroreductase, azo reductase, β-glucuronidase, dechlorinase, and dehydrochlorinase activities were analyzed in homogenates of the small intestine, large intestine, and cecum. At 5 weeks, hepatic DNA adduct formation was assayed by the 32P-postlabeling of DNA. Results from this study indicated that pentachlorophenol accelerated the biotransformation of 2,6-dinitrotoluene to genotoxic metabolites and potentiated the formation of 2,6-dinitrotoluene-induced DNA adducts in the liver. This is the first report of a chemical interaction leading to increased DNA adduct formation and indicates that chemical interactions could be important to risk assessment since they alter the relationship between exposure, dose, and the effect of genotoxicants.