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Methyl DNA Phosphate Adduct Formation in Rats Treated Chronically with 4‑(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4‑(Methylnitrosamino)-1-(3-pyridyl)-1-butanol
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posted on 2017-12-14, 20:18 authored by Bin Ma, Adam T. Zarth, Erik S. Carlson, Peter W. Villalta, Pramod Upadhyaya, Irina Stepanov, Stephen S. HechtThe
tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) is a powerful lung carcinogen in animal models and is considered
a causative factor for lung cancer in tobacco users. NNK is stereoselectively
and reversibly metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
(NNAL), which is also a lung carcinogen. Both NNK and NNAL undergo
metabolic activation by α-hydroxylation on their methyl groups
to form pyridyloxobutyl and pyridylhydroxybutyl DNA base and phosphate
adducts, respectively. α-Hydroxylation also occurs on the α-methylene
carbons of NNK and NNAL to produce methane diazohydroxide, which reacts
with DNA to form methyl DNA base adducts. DNA adducts of NNK and NNAL
are important in their mechanisms of carcinogenesis. In this study,
we characterized and quantified methyl DNA phosphate adducts in the
lung of rats treated with 5 ppm of NNK, (S)-NNAL,
or (R)-NNAL in drinking water for 10, 30, 50, and
70 weeks, by using a novel liquid chromatography-nanoelectrospray
ionization-high resolution tandem mass spectrometry method. A total
of 23, 21, and 22 out of 32 possible methyl DNA phosphate adducts
were detected in the lung tissues of rats treated with NNK, (S)-NNAL, and (R)-NNAL, respectively. Levels
of the methyl DNA phosphate adducts were 2290–4510, 872–1120,
and 763–1430 fmol/mg DNA, accounting for 15–38%, 8%,
and 5–9% of the total measured DNA adducts in rats treated
with NNK, (S)-NNAL, and (R)-NNAL,
respectively. The methyl DNA phosphate adducts characterized in this
study further enriched the diversity of DNA adducts formed by NNK
and NNAL. These results provide important new data regarding NNK-
and NNAL-derived DNA damage and new insights pertinent to future mechanistic
and biomonitoring studies of NNK, NNAL, and other chemical methylating
agents.
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Keywords
NNKpyridylhydroxybutyl DNA basechromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry methodlung carcinogenchemical methylating agentsMethyl DNA Phosphate Adduct FormationNNAL-derived DNA damageDNA adductsα- methylene carbonsform methyl DNA base adductsRats Treated Chronicallymethyl DNA phosphate adducts
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