Identification of 4-(Methylnitrosamino)-1-[3-(6-hydroxypyridyl)]-1-butanone as a Urinary Metabolite of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Rodents

Dhimant Desai, Shashi S. Kagan, Shantu Amin, Steven G. Carmella, Stephen S. Hecht

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)794-799
Number of pages6
JournalChemical research in toxicology
Volume6
Issue number6
DOIs
StatePublished - Nov 1 1993

All Science Journal Classification (ASJC) codes

  • Toxicology

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