Increased acrolein–DNA adducts in buccal brushings of e-cigarette users

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The Multiethnic Cohort Study has demonstrated that the risk for lung cancer in cigarette smokers among three ethnic groups is highest in Native Hawaiians, intermediate in Whites, and lowest in Japanese Americans. We hypothesized that differences in levels of DNA adducts in oral cells of cigarette smokers would be related to these differing risks of lung cancer. Therefore, we used liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry to quantify the acrolein-DNA adduct (8R/S)-3-(2′-deoxyribos-1′-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) and the lipid peroxidation-related DNA adduct 1,N 6 -etheno-dAdo (εdAdo, 2) in DNA obtained by oral rinse from 101 Native Hawaiians, 101 Whites, and 79 Japanese Americans. Levels of urinary biomarkers of nicotine, acrolein, acrylonitrile, and a mixture of crotonaldehyde, methyl vinyl ketone, and methacrolein were also quantified. Whites had significantly higher levels of γ-OH-Acr-dGuo than Japanese Americans and Native Hawaiians after adjusting for age and sex. There was no significant difference in levels of this DNA adduct between Japanese Americans and Native Hawaiians, which is not consistent with the high lung cancer risk of Native Hawaiians. Levels of εdAdo were modestly higher in Whites and Native Hawaiians than in Japanese Americans. The lower level of DNA adducts in the oral cells of Japanese American cigarette smokers than Whites is consistent with their lower risk for lung cancer. The higher levels of εdAdo, but not γ-OH-Acr-dGuo, in Native Hawaiian versus Japanese American cigarette smokers suggest that lipid peroxidation and related processes may be involved in their high risk for lung cancer, but further studies are required.

Section: Methodsmentioning

confidence: 99%

Quantitation of DNA Adducts Resulting from Acrolein Exposure and Lipid Peroxidation in Oral Cells of Cigarette Smokers from Three Racial/Ethnic Groups with Differing Risks for Lung Cancer

Park

Marchand

Cheng

et al. 2022

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“…18,19 Still, elevated levels of AdG were reported in the oral cells of smokers and the buccal brushings of e-cigarette users. 19,20 Acrolein reacts with peptides and proteins much more rapidly than with DNA. Therefore, one possible reason for not observing a significant difference in AdG levels in smokers might be due to glutathione's efficient scavenging of acrolein.…”

Section: ■ Introductionmentioning

confidence: 99%

Characterization and Quantification of Acrolein-Induced Modifications in Hemoglobin by Mass Spectrometry─Effect of Cigarette Smoking

Chen

Cheng

Chen

et al. 2022

Exposure to acrolein, the smallest α, β-unsaturated aldehyde, in humans originates from cigarette smoking and other environmental sources, food cooking, and endogenous lipid peroxidation and metabolism. The protein modification caused by acrolein is associated with various diseases, including cancer, cardiovascular, and neurodegenerative diseases. In this study, acrolein-modified human hemoglobin was reduced by sodium borohydride. Thus, three types of modifications, that is, Schiff base, Michael addition, and formyl-dehydropiperidion adducts, were converted to the corresponding stable adducts, leading to mass increases of 40.0313, 58.0419, and 96.0575 Da, respectively. These stable acrolein-modified hemoglobin peptides were identified by nanoflow liquid chromatography coupled to a high-resolution nanoelectrospray ionization tandem mass spectrometry. Among the 26 different types and sites of modifications, 15 of them showed a dose-dependent increase with increasing concentrations of acrolein. To investigate the role of acrolein-induced modifications in smoking and oral cancer, the 15 dose–responsive acrolein-modified peptides, together with three ethylated peptides previously identified, were quantified in oral cancer patients, healthy smokers, and healthy nonsmokers. The results reveal that the relative extents of the Michael-type adduct at α-Lys-16, α-His-50, and β-Lys-59 are significantly higher in smokers (oral cancer and healthy) than in nonsmokers. Areas under the receiver operating characteristic curve of these peptides range from 0.7500 to 0.9375, indicating the ability to discriminate smokers from nonsmokers. Additionally, these acrolein-modified peptides correlate with three ethylated peptides at the N-termini of α- and β-globin, as well as β-His-77, and with the number of cigarettes smoked per day. Therefore, measuring the reduced Michael adducts at α-Lys-16, α-His-50, and β-Lys-59 of hemoglobin from one drop of blood by this sensitive and specific method may reflect the increase of acrolein exposure due to cigarette smoking.

“… a Cigarette smokers were from the Biorepository of the University of Minnesota Tobacco Research Programs and a study of biomarkers of cigarette smoking, e-cigarette use, or no use of any tobacco or nicotine product . Most of the subjects’ smoking statuses were verified either by exhaled CO level (Table S1) or by urinary biomarkers such as total nicotine equivalent (TNE) and total NNAL (Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Pooled smokers’ urine used as the positive control and pooled nonsmokers’ urine used as the negative control were all from the Biorepository. Urine of another 12 cigarette smokers were from an ongoing study comparing biomarkers of cigarette smoking with those of e-cigarette use or no use of any tobacco or nicotine product, approved by the University of Minnesota Institutional Review Board . Their demographics are summarized in Table S1; their smoking status was verified by the urinary biomarkers total nicotine equivalents (TNEs) and total NNAL as shown in Table S2.…”

Section: Methodsmentioning

confidence: 99%

“…Using the MS 3 quantitation method, we quantified the levels of NNN-N-oxide in the urine of 32 cigarette smokers, 14 smokeless tobacco Cigarette smokers were from the Biorepository of the University of Minnesota Tobacco Research Programs and a study of biomarkers of cigarette smoking, e-cigarette use, or no use of any tobacco or nicotine product. 23 Most of the subjects' smoking statuses were verified either by exhaled CO level (Table S1) or by urinary biomarkers such as total nicotine equivalent (TNE) and total NNAL (Table S2). b Nonsmokers were from the Biorepository of the University of Minnesota Tobacco Research Programs.…”

Section: Characterization Of Nnn-n-oxide and [Pyridined 4 ]Nnn-n-oxid...mentioning

confidence: 99%

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Mass Spectrometric Quantitation of N′-Nitrosonornicotine-1N-oxide in the Urine of Cigarette Smokers and Smokeless Tobacco Users

Hecht

2022

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N′-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which always occur together and are present exclusively in tobacco products, are classified as “carcinogenic to humans” (Group 1) by the International Agency for Research on Cancer. While 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) serves as an excellent biomarker for NNK exposure, the currently available biomarker for NNN exposure is urinary “total NNN” (free NNN plus its N-glucuronide). Quantitation of urinary NNN requires extensive precautions to prevent artifactual formation of NNN resulting from nitrosation of nornicotine during analysis. NNN itself can also be formed endogenously by the same nitrosation reaction, which may sometimes cause an overestimation of exposure to preformed NNN. It is thus important to develop an alternative biomarker to specifically reflect NNN metabolic fate and facilitate relevant cancer etiology studies. In this study, we report the first detection of N′-nitrosonornicotine-1N-oxide (NNN-N-oxide) in human urine. Using a highly specific and sensitive MS3 transition-based method, NNN-N-oxide was quantified with a mean level of 8.40 ± 6.04 fmol/mL in the urine of 10 out of 32 cigarette smokers. It occurred in a substantially higher level in the urine of 13 out of 14 smokeless tobacco users, amounting to a mean concentration of 85.2 ± 96.3 fmol/mL urine. No NNN-N-oxide was detected in any of the nonsmoker urine samples analyzed (n = 20). The possible artifactual formation of NNN-N-oxide during sample preparation steps was excluded by experiments using added ammonium sulfamate. The low levels of NNN-N-oxide in the urine of tobacco users indicate that the pyridine N-oxidation pathway represents a minor detoxification pathway of NNN, which further supports the importance of the α-hydroxylation pathway of NNN metabolic activation in humans.