Analysis of pyridyloxobutyl and pyridylhydroxybutyl DNA adducts in extra-hepatic tissues of rats treated with tobacco-specific nitrosamines.
2009-07
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Analysis of pyridyloxobutyl and pyridylhydroxybutyl DNA adducts in extra-hepatic tissues of rats treated with tobacco-specific nitrosamines.
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2009-07
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Abstract
The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK) and N’-nitrosonornicotine (NNN) are potent carcinogens in tobacco
products, and are believed to play a major role as causes of tobacco-related cancers.
NNK and NNN require metabolic activation to exert their carcinogenic effects.
Cytochrome P450-catalyzed α-hydroxylation of NNK and NNN generates a reactive
intermediate, which alkylates DNA to form pyridyloxobutyl (POB)-DNA adducts.
NNK is reduced to its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
(NNAL) in a reversible and stereoselective manner. NNAL similarly undergoes α-
hydroxylation and produces pyridylhydroxybutyl (PHB)-DNA adducts. In this thesis,
we used liquid chromatography-electrospray ionization-tandem mass spectrometry (LCESI-
MS/MS) to analyze POB- and PHB-DNA adducts in extra-hepatic tissues of F344
rats treated chronically with NNK and enantiomers of NNAL and NNN. POB- and
PHB-DNA adduct levels were remarkably similar in NNK- and (S)-NNAL-treated rats,
while distinctively different from those in (R)-NNAL-treated rats. These data indicate
extensive retention of (S)-NNAL in various tissues of NNK-treated rats, and support a
mechanism in which the preferential metabolism of NNK to (S)-NNAL, followed by
sequestration of (S)-NNAL in the target tissues and reoxidation to NNK, is important to
NNK tumorigenesis. (S)-NNN treatment produced more POB-DNA adducts in the rat
oral mucosa, whereas adduct formation from (R)-NNN treatment was more favored in
the nasal olfactory and respiratory mucosa. These results suggest that different mechanisms are involved in NNN metabolism and tumorigenesis in rat nasal and oral
tissues, and that (S)-NNN might be an oral carcinogen in rats.
In additional studies of this thesis, LC-ESI-MS/MS methods were developed for
the quantitative analysis of 1, N2-propanodeoxyguanosine adducts derived from acrolein
and crotonaldehyde (Acr-dGuo and Cro-dGuo). Acrolein and crotonaldehyde are
widely-spread environmental pollutants, are present in cigarette smoke, and are formed
endogenously through lipid peroxidation. Our methods for the analysis of Acr-dGuo
and Cro-dGuo adducts are sensitive, accurate, and precise. These adducts were detected
for the first time in the human lung. However, no differences were observed in adduct
levels between self-reported smokers and non-smokers. The potential importance of
these adducts in the human lung requires further study.
Description
University of Minnesota Ph.D. dissertation. July 2009. Major: Medicinal Chemistry. Advisor: Stephen Samuel Hecht, PhD. 1 computer file (PDF); xv, 178 pages, appendix.
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Zhang, Siyi. (2009). Analysis of pyridyloxobutyl and pyridylhydroxybutyl DNA adducts in extra-hepatic tissues of rats treated with tobacco-specific nitrosamines.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/53879.
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