| Interactions | The influence of diets varying in pectin content on intestinal microfloral metabolic capacity of rats has been investigated as a possible mechanism for the alteration of toxicity of 2,6-DNT produced by these diets. Male F-344 rats were fed a purified diet (AIN)-76A), AIN-76A plus 5% or 10% citrus pectin, or either of 2 cereal-based diets that vary in pectin content, NIH-07 or Purina Chow 5002. After 28 days, rats were given tritium-labeled 2,6-DNT (10 or 75 mg/kg per os) and killed 12 hr later. Total hepatic macromolecular covalent binding was determined by exhaustive extraction. The macromolecular covalent binding of 2,6-DNT was independent of diet at 10 mg/kg. At 75 mg/kg, marcomolecular covalent binding was increased 40% by feeding 5% pectin in the purified diet and 90% by feeding 10% pectin in the purified diet. Animals fed Purina 5002 and NIH-07 had 135 and 150% higher macromolecular covalent binding, respectively, than animals fed the purified diet alone and significantly greater macromolecular covalent binding than animals fed the pectin supplemented diets. Elevated (2 to 3-fold) beta-glucuronidase and nitroreductase activities, microfloral enzymes proposed to be involved in the activation of 2,6-DNT to toxicant, were found in the cecal contents of animals fed the pectin-containing diets which correlated with a 2 to 3-fold increase in total number of cecal anaerobes.Pectin-induced changes in microflora have been shown to elevate the covalent binding of 2,6-DNT-related materials to total rat hepatic macromolecules. Therefore, the effect of diets varying in pectin content on the induction of foci and hepatic tumors induced by 2,6-DNT was studied in male F344 rats. 2,6-DNT (3.0-3.5 and 0.6-0.7 mg/kg/day) was incorporated into NIH-07, an open formula cereal-based diet high in pectin content, AIN-76A, a purified pectin-free diet, or AIN-76A supplemented with 5% pectin. Hepatic foci were scored after histochemical staining for gamma-glutamyl transpeptidase, canalicular adenosine triphosphatase or glucose-6-phosphatase following administration of test diets for 3,6 and 12 months. The number of foci per cu m of liver increased in a dose and time dependent manner following incorporation of 2,6-DNT into test diets with NIH-07 > pectin greater than AIN-76A. In the NIH-07 diet, 2,6-DNT did not alter the phenotypic distribution of foci. Animals fed control or 2,6-DNT-containing AIN-76 and pectin diets had few or no gamma-glutamyl transpeptidase foci throughout the study. Hepatocellular carcinomas and neoplastic nodules were observed only in rats fed NIH-07 containing 2,6-DNT. The concentrations of 2,6-DNT-related material covalently bound to hepatic macromolecules after a single oral dose of radiolabeled 2,6-DNT given after 12 months on the diets increased in control rats and in rats receiving low dose 2,6-DNT in the diet with AIN-76A < pectin < NIH-07. The results suggest that diet-induced alterations in the covalent binding of 2,6-DNT are not the sole factor in determining the carcinogenic response to 2,6-DNT.The sulfotransferase inhibitors 2,6-dichloro-4-nitrophenol and pentachlorophenol were used to investigate the role of sulfate ester formation during the in vivo bioactivation of 2,4- and 2,6-dinitrotoluene. Male F-344 rats were administered one of the sulfotransferase inhibitors (40 umol/kg ip) 45 min prior to oral administration of 28 mg/kg ring-(14)C-2,4-DNT or 3-(3)H-2,6-DNT and killed 12 hr later. Pentachlorophenol had no significant effect on the urinary excretion of the benzyl glucuronide or benzoic acid metabolites of 2,6-DNT. The sulfotransferase inhibitors decreased the total hepatic macromolecular covalent binding of 2,4-DNT by 33%, and of 2,6-DNT by 69%. Hepatic DNA showed covalent binding of 2,4- and 2,6-DNT of 45 and 94 pmol equivalents/mg DNA, respectively. The sulfotransferase inhibitors decreased the binding of the hepatocarcinogen 2,6-DNT to hepatic DNA by greater than 95%. These results suggest that sulfation is important in the biotransformation of 2,4- and 2,6-DNT to reactive metabolites which covalently bind to DNA. (3)H2O was detected in the urine of rats administered 3-(3)H-2,6-DNT. Pentachlorophenol decreased (3)H2O formation to the same extent as it decreased the total hepatic macromolecular covalent binding of 2,6-DNT, suggesting that (3)H exchange at the 3 position of 2,6-DNT occurs following sulfate ester formation.To determine what effect 2,4,5-trichlorophenoxyacetic acid had on 2,6-dinitrotoluene metabolism, intestinal enzymes, microbial populations, and urine mutagenicity were examined during 2,4,5-trichlorophenoxyacetic acid treatment. Weanling Fischer 344 male rats were treated daily with 54.4 mg/kg 2,4,5-trichlorophenoxyacetic acid by gavage for 4 wk. One, two, and four wk after the initial 2,4,5-trichlorophenoxyacetic acid dose, rats were administered (orally) 2,6-dinitrotoluene (75 mg/kg) and urine was collected for 24 hr in metabolism cages. Azo reductase, nitroreductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase activities were examined concurrently. Treatments of rats for 1 wk reduced the transformation of 2,6-dinitrotoluene to mutagenic urinary metabolites. This was accompanied by a decrease in the fecal anaerobic microorganisms. The elimination of Lactobacillus ermentum from the small intestine and cecum of treated animals accompanied a significant increase in oxygen-tolerant lactobacilli and other unidentified aerobic microorganisms. However, there were no significant alterations in the intestinal enzyme activities examined. By 2 wk of 2,4,5-trichlorophenoxyacetic acid treatment, microbiota and urine genotoxicity returned to the levels observed in control animals. This trend continued for the duration of the experiment. After 2 wk, while cecal nitroreductase and azo reductase activities increased, small intestinal beta-glucuronidase activity decreased. By 4 wk, treated and untreated animal intestinal enzyme activities were indistinguishable. The transient increase in azo reductase and nitroreductase after treatment with 2,4,5-trichlorophenoxyacetic acid for 2 wk may have been counteracted by the reduced beta-glucuronidase activity, thus resulting in no change in 2,6-dinitrotoluene-derived urin mutagenicity. However, other environmental chemicals, unaffected by beta-glucuronidase, potentially could be activated by 2,4,5-trichlorophenoxyacetic acid exposure.For more Interactions (Complete) data for 2,6-DINITROTOLUENE (6 total), please visit the HSDB record page. |
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