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

Stanfill, Stephen B., Hecht, Stephen S., Joerger, Andreas C., González, Pablo J., Maia, Luisa B., Rivas, Maria G., Moura, José J. G., Gupta, Alpana K., Le Brun, Nick E. ORCID:, Crack, Jason C., Hainaut, Pierre, Sparacino-Watkins, Courtney, Tyx, Robert E., Pillai, Suresh D., Zaatari, Ghazi S., Henley, S. Jane, Blount, Benjamin C., Watson, Clifford H., Kaina, Bernd and Mehrotra, Ravi (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). pp. 658-701. ISSN 1040-8444

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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.

Item Type: Article
Additional Information: Copyright information: 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. Funding information: The research of Bernd Kaina was funded by Deutsche Forschungsgemeinschaft, DFG KA724/31-1. Luisa Maia wishes to thank Fundação para a Ciência e a Tecnologia, MCTES (FCT/MCTES), for the CEEC-Individual 2017 Program Contract. Jose Moura and Luisa Maia also received financial support from PT National Funds (FCT/MCTES) through projects UIDB/50006/2020 and UIDP/50006/2020. Maria Rivas and Pablo Gonzalez are members of CONICET in Argentina. Andreas C. Joerger is supported by the German Research Foundation Grant JO 1473/1-3 and is also grateful for support by the Structural Genomics Consortium, a registered charity (No. 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN Grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer, and Takeda. Dr. Jason C. Crack and Dr. Nick E. Le Brun are supported by the UK’s Biotechnology and Biological Sciences Research Council, Grant BB/V006851/1. Stephen B. Stanfill, Robert E. Tyx, S. Jane Henley, Benjamin C. Blount, and Clifford H. Watson were internally funding by US Centers for Disease Control and Prevention (CDC). This work is also supported by American Lung Association; National Center for Chronic Disease Prevention and Health Promotion; Department of Science and Technology, Ministry of Science and Technology; Universidade do Algarve Faculdade de Ciências e Tecnologia.
Uncontrolled Keywords: adduct,cancer,dissimilatory nitrate reductase,dna repair,mutagenicity,mutation,nitrate-reducing bacteria,nnk,nnn,oncogene,p53,ras,smokeless tobacco,tobacco-specific n-nitrosamines,tsna,toxicology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/3000/3005
Faculty \ School: Faculty of Science > School of Chemistry
UEA Research Groups: Faculty of Science > Research Groups > Chemistry of Life Processes
Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry
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Depositing User: LivePure Connector
Date Deposited: 07 Oct 2023 01:22
Last Modified: 03 Jan 2024 03:16
DOI: 10.1080/10408444.2023.2264327


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