Hepatic macromolecular covalent binding of the hepatocarcinogen 2,6-dinitrotoluene and its 2,4-isomer in vivo: modulation by the sulfotransferase inhibitors pentachlorophenol and 2,6-dichloro-4-nitrophenol.
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 (DNT). Male F-344 rats were administered one of the sulfotransferase inhibitors (40 mu mol/kg i.p.) 45 min prior to oral administration of 28 mg/kg [ring-14C]-2,4-DNT or [3-3H]-2,6-DNT and killed 12 h 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%. Purification of hepatic DNA by hydroxylapatite chromatography indicated covalent binding of 2,4- and 2,6-DNT at levels 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%. 2,6-Dichloro-4-nitrophenol decreased the binding of 2,4-DNT to DNA by greater than 84% while the decrease due to pentachlorophenol was 33%. 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. 3H2O was detected in the urine of rats administered [3-3H]-2,6-DNT. Pentachlorophenol decreased 3H2O formation to the same extent as it decreased the total hepatic macromolecular covalent binding of 2,6-DNT, suggesting that 3H exchange at the 3 position of 2,6-DNT occurs following sulfate ester formation. These results are consistent with a nitrenium-carbonium ion resonance of the sulfate ester-derived reactive intermediate of 2,6-DNT.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002733:Chlorophenols / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004136:Dinitrobenzenes / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced; D046911:Macromolecular Substances; D008297:Male; D009578:Nitrobenzenes / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010416:Pentachlorophenol / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors*; D014316:Tritium
D002273:Carcinogens; D002733:Chlorophenols; D004136:Dinitrobenzenes; D046911:Macromolecular Substances; D009578:Nitrobenzenes; D009596:Nitrophenols; D014316:Tritium; C015802:2,6-dichloro-4-nitrophenol; C016403:2,4-dinitrotoluene; D004247:DNA; D010416:Pentachlorophenol; D013466:Sulfurtransferases; C023514:2,6-dinitrotoluene