Abstract |
The organochlorine pesticide, pentachlorophenol (PCP), a potent sulfotransferase inhibitor, reduces binding of the hepatocarcinogen, 2,6-dinitrotoluene (DNT), to hepatic DNA by 95% after a single i.p. injection. Activation of DNT to genotoxic metabolites involves enzymes in both the liver and the intestinal flora. Since 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. Male Fischer 344 rats were dosed daily, by gavage, with either 20 mg/kg PCP 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 and tested for mutagenic activity. At 2 and 4 weeks, 6 control and 6 treated animals were sacrificed and nitroreductase, azo reductase, beta-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 (32)P-postlabeling of DNA. Results of the study indicated that PCP accelerated the biotransformation of DNT to genotoxic metabolites and potentiated the formation of DNT - induced DNA adducts in the liver. |