Identification of 4-(methylnitrosamino)-1-[3-(6-hydroxypyridyl)]-1-butanone as a urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rodents

Chem Res Toxicol. Nov-Dec 1993;6(6):794-9. doi: 10.1021/tx00036a007.


A previously unknown urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was identified as 4-(methylnitrosamino)-1-[3-(6-hydroxypyridyl)]-1-butanone (6-hydroxyNNK). The metabolite was initially isolated from rat urine. On the basis of its MS and NMR, it was either a 4- or 6-hydroxypyridyl derivative of NNK. Model compounds were synthesized to distinguish between these possibilities; the results indicated that the metabolite was 6-hydroxyNNK. This was confirmed by independent synthesis; the spectral and chromatographic properties of 6-hydroxyNNK were the same as those of the metabolite. F-344 rats and A/J mice treated with 100 mg/kg NNK excreted approximately 1% of urinary metabolites as 6-hydroxyNNK; it was not detected as a sulfate or glucuronide conjugate. This is the first example of a pyridyl-hydroxylated metabolite of a tobacco-specific nitrosamine. On the basis of comparison to published data on other pyridine derivatives, 6-hydroxyNNK may be formed by bacterial metabolism. The potential utility of 6-hydroxyNNK as a dosimeter of human uptake of NNK is discussed.

Publication types

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

MeSH terms

  • Animals
  • Carcinogens / chemistry*
  • Carcinogens / metabolism
  • Chromatography, High Pressure Liquid
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Inbred A
  • Nitrosamines / metabolism
  • Nitrosamines / urine*
  • Rats
  • Rats, Inbred F344
  • Spectrophotometry, Ultraviolet


  • Carcinogens
  • Nitrosamines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone