Glucuronidation of 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone, a metabolically activated form of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, by phenobarbital-treated rats

Chem Res Toxicol. 1995 Jul-Aug;8(5):772-9. doi: 10.1021/tx00047a018.


In the rat, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung tumors independent of the route of administration. To exert its carcinogenic potential, NNK must be metabolically activated. Like most nitrosamines NNK is activated by alpha-hydroxylation. The striking tissue specificity of tumor induction by nitrosamines has been primarily attributed to the efficient alpha-hydroxylation of a particular nitrosamine by its target tissue. Two other factors which may contribute to this are the following: the relative capacity of different tissues to detoxify the alpha-hydroxynitrosamine and the preferential uptake of the active metabolite by the target tissue. In the present study we report the characterization of the O-glucuronide of 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone (alpha-hydroxymethylNNK-Gluc). The formation of this glucuronide could either serve as a detoxification pathway or provide a stable transport form of the alpha-hydroxylated metabolite. In addition, the metabolism of NNK to a glucuronide of the alpha-hydroxynitrosamine provides the first definitive evidence for the formation of alpha-hydroxymethylNNK. alpha-HydroxymethylNNK-Gluc was present in the urine of rats treated with phenobarbital (PB) and NNK. It was also formed by hepatocytes from PB-treated rats, accounting for 4% of the total metabolites in the media following incubation with 1 microM NNK. The data that support the identity of this metabolite as alpha-hydroxymethylNNK-Gluc are as follows. (1) Incubation of this metabolite with beta-glucuronidase resulted in the quantitative release of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), the decomposition product of alpha-hydroxymethylNNK.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • Biotransformation
  • Carcinogens / metabolism*
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 Enzyme System / metabolism*
  • Glucuronates / metabolism*
  • Glucuronidase / metabolism
  • Liver / cytology
  • Male
  • Nitrosamines / metabolism*
  • Phenobarbital / metabolism
  • Phenobarbital / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Spectrometry, Mass, Secondary Ion


  • 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone
  • Carcinogens
  • Glucuronates
  • Nitrosamines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Cytochrome P-450 Enzyme System
  • Glucuronidase
  • Phenobarbital