(S)-N'-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats

Balbo, Silvia; James-Yi, Sandra; Johnson, Carey K.; O’Sullivan, M. Gerard; Stepanov, Irina; Wang, Mingyao; Bandyopadhyay, Dipankar; Kassie, Fekadu; Carmella, Steven G.; Upadhyaya, Pramod; Hecht, Stephen S.

doi:10.1093/carcin/bgt162

Cited by 63 publications

(102 citation statements)

References 35 publications

(47 reference statements)

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“…5 Balbo et al reported a significant association between NNN in drinking water and the development of oesophageal and oral cancers in rats. 27 In addition, NNK has been found to increase the risk of lung cancer. 28 The NNN and NNK compounds are also known to form haemoglobin adducts in humans as well as in experimental animals.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Tobacco-Specific Nitrosamines in the Common Smokeless Tobacco Afzal in Oman

Al-Mukhaini

Ba-Omar

Eltayeb

et al. 2016

SQUMJ

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abstract:Objectives: There is a lack of awareness regarding the carcinogenicity of Afzal, an illegal smokeless tobacco product (STP) widely used among the Omani youth. Previous research has shown that certain types of tobacco-specific nitrosamines (TSNAs) are associated with oral and lung cancers. This study therefore aimed to assess levels of four common TSNAs in a randomly selected sample of Afzal. Methods: This study was carried out at Sultan Qaboos University in Muscat, Oman, between April and September 2013. A random sample of Afzal was analysed for four types of TSNAs using high-performance liquid chromatography-tandem mass spectrometry. The four types of TSNAs analysed were 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosonornicotine (NNN), N-nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB). As a reference product, a sample of laboratory-manufactured American moist snuff (Centers for Disease Control and Prevention, Atlanta, Georgia, USA) was also used to confirm the accuracy and precision of the analysis. Results: The analysis revealed total TSNA levels of 3.573 μg/g in the Afzal sample. Mean levels of NNN, NNK, NAT and NAB were 1.205, 1.015, 0.809 and 0.545 μg/g, respectively. Conclusion: Levels of the two most abundant TSNAs (NNN and NNK) found in the Afzal sample exceeded international regulatory limits. Afzal users therefore need to be educated regarding the potential health risks associated with their STP use. Stricter implementation of current legislation is recommended to reduce the availability and usage of Afzal in Oman.

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Section: Discussionmentioning

confidence: 99%

Analysis of Tobacco-Specific Nitrosamines in the Common Smokeless Tobacco Afzal in Oman

Al-Mukhaini

Ba-Omar

Eltayeb

et al. 2016

SQUMJ

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“…This is likely, although not definitively demonstrated, due to direct contact with esophageal mucosa during swallowing. Interestingly, Balbo et al investigated the carcinogenic effects of NNN enantiomers, (S)-NNN and (R)-NNN, in rats [33]. Rats were administered either (S)-NNN, (R)-NNN, racemic NNN, or tap water (control group) in their drinking water.…”

Section: Tobacco Carcinogensmentioning

confidence: 99%

“…Interestingly, tumor development in rats receiving racemic NNN in the oral cavity and esophagus was significantly greater than that in the (S)-NNN only group and greater than the added effects of (S)-NNN and (R)-NNN. This suggests that (R)-NNN acts as a co-carcinogen, synergistically enhancing the effects of (S)-NNN while itself being relatively inactive in terms of tumorgenecity [33]. This data is clinically relevant because (S)-NNN is the predominant form of NNN present in smokeless tobacco and is found at higher levels than combustible tobacco.…”

Section: Tobacco Carcinogensmentioning

confidence: 99%

Tobacco-related carcinogenesis in head and neck cancer

Jethwa

Khariwala

2017

Cancer Metastasis Rev

207

166

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Head and neck cancer (HNSCC) is a devastating disease. Patients require intensive treatment that is often disfiguring and debilitating. Those who survive are often left with poor speech articulation, difficulties in chewing and swallowing, cosmetic disfigurement, as well as loss of taste. Furthermore, given that HNSCC survivors are frequently disabled and unable to return to work, the economic and societal costs associated with HNSCC are massive. HNSCC is one of many cancers that are strongly associated with tobacco use. The risk for HNSCC in smokers is approximately 10 times higher than that of never-smokers and 70–80% of new HNSCC diagnoses are associated with tobacco and alcohol use. Tobacco products have been used for centuries, however it is just within the last 60–70 years that we have developed an understanding of their damaging effects. This relatively recent understanding has created a pathway towards educational and regulatory efforts aimed at reducing tobacco use. Understanding the carcinogenic components of tobacco products and how they lead to HNSCC is critical to regulatory and harm reduction measures. To date, nitrosamines and other carcinogenic agents present in tobacco products have been associated with cancer development. The disruption of DNA structure through DNA adduct formation is felt to be a common mutagenic pathway of many carcinogens. Intense work pertaining to tobacco product constituents, tobacco use and tobacco regulation has resulted in decreased use in some parts of the world. Still, much work remains as tobacco continues to impart significant harm and contribute to HNSCC development worldwide.

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“…Alternatively, the proliferating cell layer could be dissected out for adduct analysis (e.g., by laser capture microdissection), but the amount of DNA would be insuffi cient for analysis by mass spectrometry given the sensitivity of the technique currently. Conceivably, cell types of interest could be separated in bulk using cell-sorting techniques (e.g., [ 43 ]). However, this would require amounts of tissue that could not be obtained from humans.…”

Section: Anatomical Considerationsmentioning

confidence: 99%

Implications of Acetaldehyde-Derived DNA Adducts for Understanding Alcohol-Related Carcinogenesis

Balbo

Brooks

2014

Biological Basis of Alcohol-Induced Cancer

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Among various potential mechanisms that could explain alcohol carcinogenicity, the metabolism of ethanol to acetaldehyde represents an obvious possible mechanism, at least in some tissues. The fundamental principle of genotoxic carcinogenesis is the formation of mutagenic DNA adducts in proliferating cells. If not repaired, these adducts can result in mutations during DNA replication, which are passed on to cells during mitosis. Consistent with a genotoxic mechanism, acetaldehyde does react with DNA to form a variety of different types of DNA adducts. In this chapter we will focus more specifically on N2-ethylidene-deoxyguanosine (N2-ethylidene-dG), the major DNA adduct formed from the reaction of acetaldehyde with DNA and specifically highlight recent data on the measurement of this DNA adduct in the human body after alcohol exposure. Because results are of particular biological relevance for alcohol-related cancer of the upper aerodigestive tract (UADT), we will also discuss the histology and cytology of the UADT, with the goal of placing the adduct data in the relevant cellular context for mechanistic interpretation. Furthermore, we will discuss the sources and concentrations of acetaldehyde and ethanol in different cell types during alcohol consumption in humans. Finally, in the last part of the chapter, we will critically evaluate the concept of carcinogenic levels of acetaldehyde, which has been raised in the literature, and discuss how data from acetaldehyde genotoxicity are and can be utilized in physiologically based models to evaluate exposure risk.

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(S)-N'-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats

Cited by 63 publications

References 35 publications

Analysis of Tobacco-Specific Nitrosamines in the Common Smokeless Tobacco Afzal in Oman

Analysis of Tobacco-Specific Nitrosamines in the Common Smokeless Tobacco Afzal in Oman

Tobacco-related carcinogenesis in head and neck cancer

Implications of Acetaldehyde-Derived DNA Adducts for Understanding Alcohol-Related Carcinogenesis

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