Identification of 4-(methylnitrosamino)-1-[3-(6-hydroxypyridyl)]-1-butanone as a urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rodents.
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.
Desai
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American Health Foundation, Valhalla, New York 10595.
Kagan
S S
SS
Amin
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S
Carmella
S G
SG
Hecht
S S
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D000818:Animals; D002273:Carcinogens / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000378:metabolism / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D013056:Spectrophotometry, Ultraviolet
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone