4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

Schlöbe, Daniela; Hölzle, Daniel; Hatz, Dorothea; Meyer, Ludwig von; Tricker, Anthony R.; Richter, Elmar

doi:10.1016/j.tox.2007.12.021

Cited by 33 publications

(27 citation statements)

References 60 publications

(71 reference statements)

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“…GC-MS in the NICI mode was also employed for the measurement of 4-hydroxy-1-(3-pyridyl)-1-butanone (4-HPB)-releasing DNA adducts formed from metabolites of the tobacco-specific nitrosamines 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N ′-nitrosonornicotine (NNN). 8,87,203 Samples of human urinary bladder and lung DNA, hydrolyzed and subjected to GC-NICI-MS analysis, were shown to contain 4-ABP-DNA adducts at levels that are in keeping with 32 P-postlabeling analysis of the same samples using appropriate standards. 204,205 Additionally, the levels of MDA-induced M 1 dG were determined to be as low as 52 and 6.2 adducts per 10 8 nucleosides in rat liver 83 and human leukocyte DNA, 192 respectively, by the GC/EC-NICI-MS method.…”

Section: Quantitative Analysis Of Dna Adductsmentioning

confidence: 79%

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

2015

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Exogenous and endogenous sources of chemical species can react, directly or after metabolic activation, with DNA to yield DNA adducts. If not repaired, DNA adducts may compromise cellular functions by blocking DNA replication and/or inducing mutations. Unambiguous identification of the structures and accurate measurements of the levels of DNA adducts in cellular and tissue DNA constitute the first and important step towards understanding the biological consequences of these adducts. The advances in mass spectrometry (MS) instrumentation in the past 2–3 decades have rendered MS an important tool for structure elucidation, quantification, and revelation of the biological consequences of DNA adducts. In this review, we summarized the development of MS techniques on these fronts for DNA adduct analysis. We placed our emphasis of discussion on sample preparation, the combination of MS with gas chromatography-or liquid chromatography (LC)-based separation techniques for the quantitative measurement of DNA adducts, and the use of LC-MS along with molecular biology tools for understanding the human health consequences of DNA adducts. The applications of mass spectrometry-based DNA adduct analysis for predicting the therapeutic outcome of anti-cancer agents, for monitoring the human exposure to endogenous and environmental genotoxic agents, and for DNA repair studies were also discussed.

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Section: Quantitative Analysis Of Dna Adductsmentioning

confidence: 79%

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

2015

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“…Therefore, these researchers hypothesized that in vivo nitrosation of dietary myosmine could lead to the formation of HPB-releasing Hb or DNA adducts in non-tobacco users not exposed to secondhand tobacco smoke (22). This could then explain some of the reported observations of HPB-releasing DNA and Hb adducts in nontobacco exposed humans (13), and would call into question the tobacco specificity of this biomarker. In this paper, we further test this hypothesis by studying the reaction of myosmine with nitrite and quantifying HPB-releasing DNA and Hb adducts in rats treated with myosmine and nitrite.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Reaction of Myosmine with Sodium Nitrite in Vitro and in Rats

Hecht¹,

Han

Kenney

et al. 2007

Chem. Res. Toxicol.

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Previous studies have shown that the minor tobacco alkaloid myosmine (5) reacts with NaNO 2 in the presence of acid to yield 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, 8) via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7). Intermediate 7 is also formed in the metabolism of the tobacco-specific nitrosamines N′-nitrosonornicotine (NNN, 1) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 2), resulting in pyridyloxobutylation of DNA and Hb. These pyridyloxobutyl adducts can be quantified by analyzing HPB released upon acid treatment of DNA or base treatment of Hb. Quantitation of HPB-releasing DNA and Hb adducts has been used to assess the metabolic activation of NNN and NNK in smokers and smokeless tobacco users. Since myosmine is found in the diet as well as in tobacco products, it has been suggested that nitrosation of myosmine could lead to the formation of HPB-releasing adducts in people not exposed to tobacco products. We investigated the nitrosation of myosmine in vitro and in vivo in rats. Reaction of myosmine with NaNO 2 under acidic conditions produced HPB, as previously reported. A new product was identified as 3′-oximinomyosmine (11) based on its spectral properties. NNN was not detected. Groups of rats were treated with NNN, NNK, myosmine, NaNO 2 , or combinations of myosmine and NaNO 2 . HPBreleasing Hb and DNA adducts were clearly detected in the rats treated with NNN or NNK, but we found no evidence for production of these adducts from the combination of myosmine plus NaNO 2 . The results of this study do not support the hypothesis that exposure to dietary myosmine could lead to HPB-releasing DNA or Hb adducts in humans.

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“…Similar phrasing was used in 1998 by Tricker and Richter to explain to PM the significance of their TSNA research proposal to PM: “The Foiles study, although frequently cited, is characterised by poor analytical methodology […], while the technically superior Blömeke study […] is seldomly [sic] cited in the scientific literature.”52 In 2004–2005, Richter received a grant36 from the ‘Philip Morris External Research Program’69 to determine a common DNA adduct from dietary myosmine and TSNAs in different stages of oesophageal carcinoma. Two papers were published by Richter's working group in 2007 and 200866 70 which were consistent with the study design recommended in PM's ‘TSNA strategy’ 27. As proposed, the published results questioned the suitability of TSNA–DNA adducts as biomarkers of carcinogens related to the exposure to tobacco smoke 66 70…”

Section: Resultsmentioning

confidence: 66%

“…Two papers were published by Richter's working group in 2007 and 200866 70 which were consistent with the study design recommended in PM's ‘TSNA strategy’ 27. As proposed, the published results questioned the suitability of TSNA–DNA adducts as biomarkers of carcinogens related to the exposure to tobacco smoke 66 70…”

Section: Resultsmentioning

confidence: 66%

The development of scientific consultants: how the tobacco industry creates controversy on the carcinogenicity of tobacco-specific nitrosamines

Kyriss

Schneider

2012

Tob Control

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Economic interests of the tobacco industry have strongly influenced the research activity of Richter and his group. The publications of his working group about carcinogenic effects of TSNAs published between 1992 and 2009 should therefore not be regarded as independent. Scientists and policy makers should consider the long-standing and intensive inter-relation between certain toxicologists and the tobacco industry when assessing the research results and consider ignoring them.

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4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

Cited by 33 publications

References 60 publications

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

Investigation of the Reaction of Myosmine with Sodium Nitrite in Vitro and in Rats

The development of scientific consultants: how the tobacco industry creates controversy on the carcinogenicity of tobacco-specific nitrosamines

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