Mass spectrometric analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in human lung

Hölzle, Daniel; Schlöbe, Daniela; Tricker, Anthony R.; Richter, Elmar

doi:10.1016/j.tox.2007.01.016

Cited by 37 publications

(51 citation statements)

References 35 publications

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“…Smokers had on average sevenfold higher HPB-releasing DNA adduct levels as compared to nonsmokers. Although this difference was higher than that observed for HPB-releasing hemoglobin adducts (Hölzle et al, 2007) and for other classes of DNA adducts (Phillips, 2002), it is still considerably lower than that expected from the 100-fold difference observed for total urinary NNAL excretion used as biomarker of NNK exposure in smokers and nonsmokers (Meger et al, 2000;Hecht, 2002). In addition, no correlation was found between lung DNA adducts and hemoglobin adducts releasing HPB in lung cancer patients (Hölzle et al, 2007).…”

Section: Introductionmentioning

confidence: 77%

“…The determination of HPB-releasing DNA adducts was performed as previously described (Hölzle et al, 2007). Briefly, DNA was extracted from 0.3-2 g of fresh tissue according to the protocol of Reddy and Randerath (1994).…”

Section: Analytical Proceduresmentioning

confidence: 99%

“…Using this approach, Foiles et al (1991) detected HPB-releasing DNA adducts in human peripheral lung in seven of nine smokers and one of eight nonsmokers. Using an improved analytical method, HPB-releasing DNA adducts could be determined in all lung samples of 21 smoking and in 8 of 11 nonsmoking lung cancer patients (Hölzle et al, 2007). Smokers had on average sevenfold higher HPB-releasing DNA adduct levels as compared to nonsmokers.…”

Section: Introductionmentioning

confidence: 99%

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

Schlöbe¹,

Hölzle²,

Hatz

et al. 2008

Toxicology

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Section: Introductionmentioning

confidence: 77%

Section: Analytical Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Schlöbe¹,

Hölzle²,

Hatz

et al. 2008

Toxicology

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“…Such response could be assessed in MucilAir™. CYP-dependent activation of nitrosamines leads to DNA-strand breaks and adduct formation in vivo (Holzle et al, 2007) which could also be tested in reconstituted respiratory epithelia. Interlaboratory reproducibility of simple end points such as mucus secretion, % of ciliated area, and cilia beat frequency with cells from multiple donors should also be performed with and without exposure to toxicants.…”

Section: Discussionmentioning

confidence: 99%

Targeted omics analyses, and metabolic enzyme activity assays demonstrate maintenance of key mucociliary characteristics in long term cultures of reconstituted human airway epithelia

Baxter

Thain²,

Banerjee

et al. 2015

Toxicology in Vitro

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3D reconstituted respiratory epithelia have emerged as better in vitro models for toxicological testing compared to cell lines due to the conservation of key morphological features and functions. MucilAir™ is a commercially available human airway epithelia system that can potentially maintain functional attributes for up to a year, however, detailed mucociliary characteristics and xenobiotic metabolism relevant to inhaled pro-toxicant bioactivation is lacking. Here, we assessed in MucilAir™ some key biomarkers that are characteristic of the respiratory epithelia including morphology, function and xenobiotics metabolism. The end points that were measured included targeted proteomics using a panel of 243 airway surface liquid (ASL) proteins, cilia beat frequency (CBF), a qRT-PCR screen of xenobiotic metabolizing enzymes, and CYP2A6/13, CYP1A1/1B1 activity. Comparison of ASL proteomics with human sputum identified key proteins common to both matrices, but present at different levels. Xenobiotic metabolism gene profiling demonstrated strong similarities with the normal human lung and did not reveal any consistent changes when assessed over a 6 month period. Inducibility and activity of CYP1A1/1B1 and activity of CYP2A6/2A13 were present at one month in culture and maintained in one tested MucilAir™ donor for several months. In conclusion, MucilAir™ presented important morphological and metabolic characteristics of a mucociliary epithelium in short and long term culture. MucilAir™ is therefore a potentially useful model to test repeated sub-cytotoxic doses of toxicants.

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“…Released HPB could be quantified by GC-MS, and its presence was established in the lung DNA of smokers, as well as in NNKtreated rodents (8,13,14). The structures of the adducts formed by this pathway remained elusive until the late 1990s when Peterson and co-workers characterized O 6 -(POB-1-yl)dGuo (14) (15), a highly mutagenic DNA adduct (16) (17)(18)(19).…”

Section: Tobacco-specific Nitrosamines: Metabolism Dna Adduct Formatmentioning

confidence: 99%

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Hecht

2007

Chem. Res. Toxicol.

261

242

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Tobacco use continues to be a major cause of cancer in the developed world, and despite significant progress in this country in tobacco control, which is driving a decrease in cancer mortality, there are still over 1 billion smokers in the world. This perspective discusses some selected issues in tobacco carcinogenesis focusing on progress during the 20 years of publication of Chemical Research in Toxicology. The topics covered include metabolism and DNA modification by tobacco-specific nitrosamines, tobacco carcinogen biomarkers, an unidentified DNA ethylating agent in cigarette smoke, mutations in the K-RAS and p53 gene in tobacco-induced lung cancer and their possible relationship to specific carcinogens, secondhand smoke and lung cancer, emerging issues in smokeless tobacco use, and a conceptual model for understanding tobacco carcinogenesis. It is hoped that a better understanding of mechanisms of tobaccoinduced cancer will lead to new and useful approaches for the prevention of lung cancer and other cancers caused by tobacco use.

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Mass spectrometric analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in human lung

Cited by 37 publications

References 35 publications

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

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

Targeted omics analyses, and metabolic enzyme activity assays demonstrate maintenance of key mucociliary characteristics in long term cultures of reconstituted human airway epithelia

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

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