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 μmol/ kg i...

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Published in:Carcinogenesis (New York) 1984-09, Vol.5 (9), p.1199-1204
Main Authors: Kedderis, Gregory L., Dyroff, Martin C., Rickert, Douglas E.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biotransformation
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - metabolism
Chemical agents
Chlorophenols - pharmacology
Dinitrobenzenes - metabolism
Dinitrobenzenes - toxicity
DNA - metabolism
Liver - metabolism
Liver Neoplasms - chemically induced
Macromolecular Substances
Male
Medical sciences
Nitrobenzenes - metabolism
Nitrophenols - pharmacology
Pentachlorophenol - pharmacology
Rats
Rats, Inbred F344
Sulfurtransferases - antagonists & inhibitors
Tritium
Tumors
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Summary: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 μmol/ 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 heptaocarcinogen 2,6-DNT to hepatic DNA by >95%. 2,6-Dichloro-4-nitrophenol decreased the binding of 2,4-DNT to DNA by >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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/5.9.1199