Carcinogenesis, Vol 18, 587-592, Copyright © 1997 by Oxford University Press
SG Carmella, A Borukhova, D Desai and SS Hecht
Carcinogenic tobacco-specific nitrosamines are present in tobacco products
and are believed to play a significant role in human cancers associated
with tobacco use. Additional amounts of tobacco-specific nitrosamines could
be formed endogenously. We tested this hypothesis by treating rats with
nicotine and sodium nitrite and analyzing their urine. Initially, we
treated groups of rats with (S)-nicotine (60 micromol/kg) and NaNO2 (180
micromol/kg), (S)-nicotine alone, NaNO2 alone or
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 12 nmol/kg) by gavage
twice daily for 4 days. We collected urine and analyzed for two metabolites
of NNK; 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanol and its glucuronide.
We did not detect these metabolites in the urine of rats treated with
nicotine alone or nicotine plus NaNO2, indicating that endogenous
conversion of nicotine to NNK did not occur. However, the urine did contain
N'- nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB) and N'-
nitrosoanatabine (NAT). Analysis of the (S)-nicotine used in this
experiment demonstrated that it contained trace amounts of nornicotine,
anabasine and anatabine. In a second experiment, we used an identical
protocol to compare the endogenous nitrosation of this (S)-nicotine with
that of synthetic (R,S)-nicotine, which did not contain detectable amounts
of nornicotine, anabasine or anatabine. NNN (0.53 x 10(-3)% of nicotine
dose), NAB (0.68%) and NAT (2.1%) were detected in the urine of the rats
treated with the (S)-nicotine and NaNO2. NNN (0.47 x 10(- 3)% of dose), but
not NAB or NAT, was present in the urine of the rats treated with synthetic
(R,S)-nicotine and NaNO2. NNN probably formed via nitrosation of
metabolically formed nornicotine. These results demonstrate for the first
time that endogenous formation of tobacco- specific nitrosamines occurs in
rats treated with tobacco alkaloids and NaNO2. The potential significance
of the results with respect to nitrosamine formation in people who use
tobacco products or nicotine replacement therapy is discussed.
ARTICLES
Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite
American Health Foundation, Valhalla, NY 10595, USA.
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