Metabolism and Carcinogenicity of Nitrotoluenes

  • Douglas E. Rickert
  • John P. Chism
  • Gregory L. Kedderis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


Technical grade dinitrotoluene (DNT) is a mixture of isomers (76.4% 2,4-DNT, 18.8% 2,6-DNT and 4.7% other isomers) of demonstrated hepatocar-cinogenicity in Fischer-344 rats. The incidence of neoplasia is higher in males than in females and is primarily associated with 2,6-DNT. The sex and isomer specificity of DNT is reflected in an in vivo-in vitro hepatocyte unscheduled DNA synthesis assay for potential genotoxicity, as less DNA synthesis is seen in hepatocytes from female rats than those from male rats treated with DNT, and 2,6-DNT is approximately 10-fold more active than 2,4-DNT. Detailed studies of the metabolism of 2,4- and 2,6-DNT indicate that each isomer is converted to a dinitrobenzyl alcohol in a cytochrome P-450-dependent process. The alcohols are then conjugated with glucuronic acid and excreted in the bile and urine. Male rats excrete more of the glucuronide conjugates in the bile than do female rats. Intestinal microflora hydrolyze the glucuronide and reduce at least one nitro group of the aglycone. The resulting aminonitrobenzyl alcohols are reabsorbed and converted to active metabolites in the liver (reviewed in Rickert et al., 1984a). Based on the ability of sulfotransferase inhibitors to decrease the covalent binding of 2,6-DNT to hepatic DNA, we postulated that 2-amino-6-nitrobenzyl alcohol was N-hydroxylated to yield 2-hydroxylamino-6-nitrobenzyl alcohol and conjugated with sulfate to yield an unstable N,O-sulfate which decomposed to an electrophilic nitrenium ion capable of reacting with hepatic DNA (Kedderis et al., 1984).


Biliary Excretion Covalent Binding Intestinal Microflora Enterohepatic Recycling Microsomal Metabolism 
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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Douglas E. Rickert
    • 1
  • John P. Chism
    • 1
  • Gregory L. Kedderis
    • 2
  1. 1.Department of Biochemical Toxicology and PathobiologyChemical Industry Institute of ToxicologyResearch Triangle ParkUSA
  2. 2.Department of Animal Drug MetabolismMerck Sharp & Dohme Research LaboratoriesRahwayUSA

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