Tobacco products present a deadly combination of nicotine addiction and carcinogen exposure resulting in millions of cancer deaths per year worldwide. A plethora of smokeless tobacco products lead to unacceptable exposure to multiple carcinogens, including the tobacco-specific nitrosamine N′-nitrosonornicotine, a likely cause of the commonly occurring oral cavity cancers observed particularly in South-East Asian countries. Cigarettes continue to deliver a large number of carcinogens, including tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons and volatile organic compounds. The multiple carcinogens in cigarette smoke are responsible for the complex mutations observed in critical cancer genes. The exposure of smokeless tobacco users and smokers to carcinogens and toxicants can now be monitored by urinary and DNA adduct biomarkers that may be able to identify those individuals at highest risk of cancer so that effective cancer prevention interventions can be initiated. Regulation of the levels of carcinogens, toxicants and nicotine in tobacco products and evidence-based tobacco control efforts are now recognized as established pathways to preventing tobacco related cancer. This Review discusses carcinogens in smokeless tobacco products and cigarette smoke and biomarkers that may be able to identify those individuals at highest risk of tobacco-related cancers. It also discusses regulation of the levels of carcinogens and nicotine in these products as approaches to cancer prevention. 

Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention

The planning and development of new chiral stationary phases (CSPs) for liquid chromatography (LC) are considered as continuous and evolutionary issues since the introduction of the first CSP in 1938. The main objectives of the development strategies were to attempt the improvement of the chromatographic enantioresolution performance of the CSPs as well as enlarge their versatility and range of applications. Additionally, the transition to ultra-high-performance LC were underscored. The most recent strategies have comprised the introduction of new chiral selectors, the use of new materials as chromatographic supports or the reduction of its particle size, and the application of different synthetic approaches for preparation of CSPs. This review gathered the most recent developments associated to the different types of CSPs providing an overview of the relevant advances that are arising on LC.

https://www.mdpi.com/1420-3049/24/5/865/pdf

Chiral Stationary Phases for Liquid Chromatography: Recent Developments.

DNA adducts are believed to play a central role in the induction of cancer in cigarette smokers and are proposed as being potential biomarkers of cancer risk. We have summarized research conducted since 2012 on DNA adduct formation in smokers. A variety of DNA adducts derived from various classes of carcinogens, including aromatic amines, polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, alkylating agents, aldehydes, volatile carcinogens, as well as oxidative damage have been reported. The results are discussed with particular attention to the analytical methods used in those studies. Mass spectrometry-based methods that have higher selectivity and specificity compared to 32P-postlabeling or immunochemical approaches are preferred. Multiple DNA adducts specific to tobacco constituents have also been characterized for the first time in vitro or detected in vivo since 2012, and descriptions of those adducts are included. We also discuss common issues related to measuring DNA adducts in humans, including the development and validation of analytical methods and prevention of artifact formation.

https://www.mdpi.com/2305-6304/7/1/16/pdf

Recent Studies on DNA Adducts Resulting from Human Exposure to Tobacco Smoke

/pdf/chemical-analysis-of-dna-damage-4l4z83oftg.pdf

Chemical Analysis of DNA Damage

Benzo[a]pyrene (BaP), an archetypical polycyclic aromatic hydrocarbon, is classified as “carcinogenic to humans” and is ubiquitous in the environment, as evident by the measurable levels of BaP metabolites in virtually all human urine samples examined. BaP carcinogenicity is believed to occur mainly through its covalent modification of DNA, resulting in the formation of BPDE–N2-dG, an adduct formed between deoxyguanosine and a diol epoxide metabolite of BaP, with subsequent mutation of critical growth control genes. In spite of the liquid chromatography–mass spectrometry (LC–MS)-based detection of BPDE–N2-dG in BaP-treated rodents, and indirectly through high-performance liquid chromatography (HPLC)-fluorescence detection of BaP-7,8,9,10-tetraols released from human DNA upon acid hydrolysis, BPDE–N2-dG adducts have rarely if ever been observed directly in human samples using LC–MS techniques, even though sophisticated methodologies have been employed which should have had sufficient sensitivity. With this...

Ultrasensitive High-Resolution Mass Spectrometric Analysis of a DNA Adduct of the Carcinogen Benzo[a]pyrene in Human Lung.

N′-Nitrosonornicotine (NNN) is carcinogenic in multiple animal models and has been evaluated as a human carcinogen. NNN can be metabolized by cytochrome P450s through two activation pathways: 2′-hydroxylation and 5′-hydroxylation. While most previous studies have focused on 2′-hydroxylation in target tissues of rats, available evidence suggests that 5′-hydroxylation is a major activation pathway in human enzyme systems, in nonhuman primates, and in target tissues of some other rodent carcinogenicity models. In the study reported here, we investigated DNA damage resulting from NNN 5′-hydroxylation by quantifying the adduct 2-(2-(3-pyridyl)-N-pyrrolidinyl)-2′-deoxyinosine (py-py-dI). In rats treated with NNN in the drinking water (7–500 ppm), py-py-dI was the major DNA adduct resulting from 5′-hydroxylation of NNN in vivo. Levels of py-py-dI in the lung and nasal cavity were the highest, consistent with the tissue distribution of CYP2A3. In rats treated with (S)-NNN or (R)-NNN, the ratios of formation of (R...

DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

(S)-N'-Nitrosonornicotine [(S)-NNN] and racemic NNN are powerful oral and esophageal carcinogens in the F344 rat, whereas (R)-NNN has only weak activity. Tumor formation in these tissues of rats treated with racemic NNN was far greater than the sum of the activities of the individual enantiomers. We hypothesized that metabolites of (R)-NNN enhanced levels of DNA adducts produced by (S)-NNN. A test of that hypothesis necessitated the development of a novel liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the analysis of O(6)-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O(6)-POB-dGuo), a highly mutagenic DNA adduct not previously quantified in rats treated with NNN. The new method, with a limit of detection of 6.5 amol for diluted standard and 100 amol for DNA samples, was applied in this study. Groups of nine F344 rats were treated with doses as follows: 7 ppm (R)-NNN, 7 ppm (S)-NNN, and 14 ppm racemic NNN; 14 ppm (R)-NNN, 14 ppm (S)-NNN, and 28 ppm racemic NNN; or 28 ppm (R)-NNN, 28 ppm (S)-NNN, and 56 ppm racemic NNN for 5 weeks, and tissues were analyzed for DNA adducts. We found statistically significant, but modest, synergistic enhancement of levels of O(6)-POB-dGuo in the esophagus but not the oral cavity of rats treated with racemic NNN (low and median doses only) compared to the sum of the amounts formed in these tissues of rats treated with (S)-NNN or (R)-NNN. There was no synergy in the formation of other POB-DNA adducts of NNN in oral cavity and esophagus, nor was there any evidence for synergy in nasal respiratory and olfactory epithelium, lung, or liver. Our results provide the first quantitation of O(6)-POB-dGuo in DNA from tissues of rats treated with NNN and evidence for synergy in DNA adduct formation as one possible mechanism by which (R)-NNN enhances the carcinogenicity of (S)-NNN in rats.

Analysis of O(6)-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine and Other DNA Adducts in Rats Treated with Enantiomeric or Racemic N'-Nitrosonornicotine.

Analysis of N'-nitrosonornicotine enantiomers in human urine by chiral stationary phase liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry.

INTRODUCTION This 8-week multisite, randomized controlled trial of snus examined the differential effects of instructions on (1) snus use, (2) smoking and smoking-related measures, and (3) exposure to tobacco-related constituents. METHOD US adult daily cigarette smokers (n = 150; 43.3% female; Medianage = 43.5) were recruited from Minneapolis, Minnesota; Columbus and Coshocton, Ohio; and Buffalo, New York. Following a 1-week sampling phase of snus, participants who used at least 7 pouches were randomized to either (1) partial substitution (PS; "use snus as you like with your cigarettes"), (2) complete substitution (CS; "avoid cigarettes"), or (3) usual brand cigarettes (UB). Analyses included between-group analyses (eg, PS vs. CS) using Wilcoxon rank sum test of cigarettes per day and snus pouches per day, and a linear mixed model (biomarkers). RESULTS Compared to the PS and UB groups, smokers assigned to CS reported greater reductions in cigarettes per day (ps < .001), using more snus pouches per day (p = .02), and more smoke-free days (CS median = 14.5, PS and UB medians = 0, p < .001). In addition, results demonstrated reductions in carbon monoxide (p < .001), total nicotine equivalents (p = .02), and four out of five measured volatile organic compounds (ps < .01) over time among the CS group. Exposure to N'-nitrosonornicotine increased by trial end only among the PS group (p < .04). Phenanthrene tetraol increased among all groups by trial end (p = .02) with no difference between groups. CONCLUSIONS Instructions to completely switch from cigarettes to snus resulted in the greatest reduction in cigarettes and exposure to harmful constituents. IMPLICATIONS Directly instructing smokers to switch completely to snus, rather than using ad libitum (with no instructions to avoid cigarettes), is necessary for reductions in smoking and subsequent exposure to harmful constituents.

/pdf/a-randomized-clinical-trial-of-snus-examining-the-effect-of-33y7bdcdqn.pdf

A Randomized Clinical Trial of Snus Examining the Effect of Complete Versus Partial Cigarette Substitution on Smoking-Related Behaviors, and Biomarkers of Exposure.

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DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats

Analysis of O(6)-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine and Other DNA Adducts in Rats Treated with Enantiomeric or Racemic N'-Nitrosonornicotine.

Analysis of N'-nitrosonornicotine enantiomers in human urine by chiral stationary phase liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry.

A Randomized Clinical Trial of Snus Examining the Effect of Complete Versus Partial Cigarette Substitution on Smoking-Related Behaviors, and Biomarkers of Exposure.