From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications

Stephen B. Stanfill; Stephen S. Hecht; Andreas C. Joerger; Pablo J. González; Luisa B. Maia; Maria G. Rivas; José J.G. Moura; Alpana K. Gupta; Nick E. Le Brun; Jason C. Crack; Pierre Hainaut; Courtney Sparacino-Watkins; Robert E. Tyx; Suresh D. Pillai; Ghazi S. Zaatari; S. Jane Henley; Benjamin C. Blount; Clifford H. Watson; Bernd Kaina; Ravi Mehrotra

doi:10.1080/10408444.2023.2264327

From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications

Stephen B. Stanfill, Stephen S. Hecht, Andreas C. Joerger, Pablo J. González, Luisa B. Maia, Maria G. Rivas, José J.G. Moura, Alpana K. Gupta, Nick E. Le Brun, Jason C. Crack, Pierre Hainaut, Courtney Sparacino-Watkins, Robert E. Tyx, Suresh D. Pillai, Ghazi S. Zaatari, S. Jane Henley, Benjamin C. Blount, Clifford H. Watson, Bernd Kaina, Ravi Mehrotra

Laboratory Medicine and Pathology

Research output: Contribution to journal › Review article › peer-review

3 Scopus citations

Abstract

Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.

Original language	English (US)
Pages (from-to)	658-701
Number of pages	44
Journal	Critical Reviews in Toxicology
Volume	53
Issue number	10
DOIs	https://doi.org/10.1080/10408444.2023.2264327
State	Published - 2023

Bibliographical note

Publisher Copyright:
©, This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.

Keywords

DNA repair
NNK
NNN
Ras
TSNA
Tobacco-specific N-nitrosamines
adduct
cancer
dissimilatory nitrate reductase
mutagenicity
mutation
nitrate-reducing bacteria
oncogene
p53
smokeless tobacco

PubMed: MeSH publication types

Journal Article
Review

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Stanfill, S. B., Hecht, S. S., Joerger, A. C., González, P. J., Maia, L. B., Rivas, M. G., Moura, J. J. G., Gupta, A. K., Le Brun, N. E., Crack, J. C., Hainaut, P., Sparacino-Watkins, C., Tyx, R. E., Pillai, S. D., Zaatari, G. S., Henley, S. J., Blount, B. C., Watson, C. H., Kaina, B., & Mehrotra, R. (2023). From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications. Critical Reviews in Toxicology, 53(10), 658-701. https://doi.org/10.1080/10408444.2023.2264327

Stanfill, SB, Hecht, SS, Joerger, AC, González, PJ, Maia, LB, Rivas, MG, Moura, JJG, Gupta, AK, Le Brun, NE, Crack, JC, Hainaut, P, Sparacino-Watkins, C, Tyx, RE, Pillai, SD, Zaatari, GS, Henley, SJ, Blount, BC, Watson, CH, Kaina, B & Mehrotra, R 2023, 'From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications', Critical Reviews in Toxicology, vol. 53, no. 10, pp. 658-701. https://doi.org/10.1080/10408444.2023.2264327

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abstract = "Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.",

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T2 - formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications

AU - Stanfill, Stephen B.

AU - Hecht, Stephen S.

AU - Joerger, Andreas C.

AU - González, Pablo J.

AU - Maia, Luisa B.

AU - Rivas, Maria G.

AU - Moura, José J.G.

AU - Gupta, Alpana K.

AU - Le Brun, Nick E.

AU - Crack, Jason C.

AU - Hainaut, Pierre

AU - Sparacino-Watkins, Courtney

AU - Tyx, Robert E.

AU - Pillai, Suresh D.

AU - Zaatari, Ghazi S.

AU - Henley, S. Jane

AU - Blount, Benjamin C.

AU - Watson, Clifford H.

AU - Kaina, Bernd

AU - Mehrotra, Ravi

N1 - Publisher Copyright: ©, This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.

PY - 2023

Y1 - 2023

N2 - Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.

AB - Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.

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KW - NNK

KW - NNN

KW - Ras

KW - TSNA

KW - Tobacco-specific N-nitrosamines

KW - adduct

KW - cancer

KW - dissimilatory nitrate reductase

KW - mutagenicity

KW - mutation

KW - nitrate-reducing bacteria

KW - oncogene

KW - p53

KW - smokeless tobacco

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SN - 1040-8444

VL - 53

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EP - 701

JO - Critical Reviews in Toxicology

JF - Critical Reviews in Toxicology

IS - 10

ER -

From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Access

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