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N-Nitrosonornicotine
Names
Preferred IUPAC name
3-[(2S)-1-Nitrosopyrrolidin-2-yl]pyridine
Identifiers
3D model (JSmol)
Abbreviations NNN
ChemSpider
KEGG
UNII
  • InChI=1S/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1 checkY
    Key: XKABJYQDMJTNGQ-VIFPVBQESA-N checkY
  • InChI=1/C9H11N3O/c13-11-12-6-2-4-9(12)8-3-1-5-10-7-8/h1,3,5,7,9H,2,4,6H2/t9-/m0/s1
    Key: XKABJYQDMJTNGQ-VIFPVBQEBO
  • O=NN2CCC[C@H]2c1cnccc1
Properties
C9H11N3O
Molar mass 177.207 g·mol−1
Appearance Oily yellow liquid
Melting point 47 °C (117 °F; 320 K)
Boiling point 154 °C (309 °F; 427 K)
Soluble
Hazards
Flash point 177 °C (351 °F; 450 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

N-Nitrosonornicotine (NNN) is a tobacco-specific nitrosamine (TSNAs) produced during the curing, aging, processing, and smoking of tobacco. NNN is a derivative of nicotine. Nicotine is demethylated to nornicotine which proceeds through nitrosation to yield NNN. Identified as a Group 1 carcinogen,[1] NNN is known to cause DNA adducts and mutations as well as promote tumor growth to induce carcinogenesis.[2] NNN induces specific carcinogenesis through genotoxicity and constructing tumor promotion environments. The mechanism of action to achieve genotoxicity (i.e. DNA adducts and mutations) is primarily through the 2'- and 5'-α-hydroxylation pathways, and the mechanism of action to achieve a tumor promoting environment is NNN working in conjunction with NNK to selectively desensitize or upregulate various nicotinic acetylcholine receptors (nAChRs). Among the greater than 70 confirmed carcinogens found in cigarette smoke,[3] NNN is found in the greatest concentration of any esophageal carcinogen and induces predominately esophageal and oral cavity cancer and not lung cancer.[4] Because of this, NNN has the potential for use as a risk biomarker for esophageal cancer in tobacco users; however, there is yet to be a conclusive relationship between NNN exposure and human cancer reported. In cases of NNN poisoning, primary symptoms include irritation at the point of absorption, nausea/vomiting, sleep disturbances, headache, and chest pain.[5]

Sources

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NNN is found in a variety of tobacco products including smokeless tobacco like chewing tobacco and snuff,[6] cigarettes, and cigars. It is present in smoke from cigars and cigarettes, in the saliva of people who chew betel quid with tobacco, and in the saliva of oral-snuff and e-cigarette[7] users. NNN is produced by the nitrosation of nornicotine during the curing, aging, processing, and smoking of tobacco.[8] Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning.

NNN can be produced in the acidic environment of the stomach in users of oral nicotine replacement therapies, due to the combination of dietary/endogenous nitrates, and nornicotine (either present as a minor metabolite of nicotine, or as an impurity in the product).[9] NNN can also be produced within the oral cavity when incubated in saliva with the precursor nornicotine.[10]

Toxicity

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NNN has been classified as a Group 1 carcinogen.[1] There is no known "safe" levels of NNN ingestion in humans due to its carcinogenic activity.[11] However, in mice, the median lethal dose (LD50) is 1g/kg.[12]

In cigarette smoke, NNN has been found in levels between 2.2-6.6 parts per million (ppm). The FDA has put limits of nitrosamines in other consumable products (such as cured meats) at levels below 10 parts per billion (ppb).[13]

Symptoms

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Symptoms of NNN are similar to those of nicotine poisoning and include irritation at the point of absorption (for example, the gums when dipping tobacco is used), nausea and vomiting, sleep disturbances, headache, and chest pain.[5] The substance is also a known carcinogen, meaning that any exposure to the substance can lead to cancer and is proven to cause esophageal and nasal cancer in animals.[14] In rats, exposure to NNN through drinking water caused cancer within the naval cavity, as well as benign and malignant esophageal tumors. In hamsters, exposure through subcutaneous injection caused benign tracheal tumors; and in mice, exposure through intraperitoneal injection resulted in benign lung tumors.[15] Although no adequate studies of the relationship between exposure to NNN and human cancer have been reported, it has been proposed that NNN in toombak-using patients (toombak contains high levels of the TSNAs N-Nitrosonornicotine and N-Nitrosonornicotine ketone (NNK)) may be associated with induction of mutations in the p53 tumor suppressor gene in a similar manner observed in nitrosamine-induced lung tumors in mice.[16]

Mechanism of action

[edit]

NNN plays a role in promotion of two conditions for tobacco-specific nitrosamines-induced cancer: genotoxicity and tumor promotion environment.

NNN has been observed to metabolize in three ways: pyridine N-oxidation, hydroxylation of the pyrrolidine ring (including α-hydroxylation at the 2'- and 5'-positions and β-hydroxylation at the 3'- and 4'-positions), and norcotinine formation.[2] The enzymology of pyridine N-oxidation is not yet determined, β-hydroxylation is a minor pathway which was reported in one study, and studies of norcotinine formation in vivo are yet to be reported.[17] Catalyzed predominately by cytochrome P450 (CYPs), the primary mechanism of action to form DNA adducts is the 2'- and 5'-α-hydroxylation pathways. 2'-hydroxylation appears more prevalent in humans, while 5'-hydroxylation is more prevalent in non-primate animals.[18] The α-Hydroxylation of NNN at the 2‘-position results in 2'-Hydroxy NNN. Via a spontaneous ring opening of this unstable intermediate, this will produce 4-(3-pyridyl)-4-oxobutane 1-diazohydroxide. The conclusion of this pathway is the metabolite formation of a keto alcohol, diol, and keto acid. 5'-hydroxylation of NNN yields 5'-hydroxyNNN which leads to spontaneous ring-opening to produce diazohydroxide. Diazohydroxide reacts with H2O and produces a hydroxy aldehyde to cyclize to lactol that is further oxidized to hydroxy acid. These products are expected to react with DNA to form adducts and cause genotoxicity overtime by causing mutations in oncogenes and tumor suppressor genes from unresolved adducts.

NNN promotes tumor growth environments through activating nicotinic acetylcholine receptors (nAChRs) and β-Adrenergic receptors (β-AdrRs) leading to enhancement and dysregulation of cell proliferation, survival, migration and invasion.[2] Nicotine has a higher affinity for α4β2 heteromeric nicotinic acetylcholine receptors (α4β2nAChRs) than to α7 homomeric nicotinic acetylcholine receptors (α7nAChRs). On the other hand, functions of α7nAChR (stimulant of cancer cells) in smokers are increased and functions of α4β2nAChRs are impaired (inhibitor of cancer cells). NNN and NNK work in conjunction as NNN binds to heteromeric αβnAChRs and NNK to α7nAchR to create a tumor promoting environment. An upregulation of nAChRs (i.e. α7nAChR signaling) and desensitization of α4β2nAChR results in the stimulation of cancer cell growth, while the concurrent reduction of GABA release, which acts to counteract these conditions, also occurs.

The general schematic of NNK- and NNN-specific carcinogenesis is to induce DNA adducts. These adducts can be repaired, but those which are unresolved cause mutations in oncogenes and tumor suppressor genes. NNN and NNK also desensitize or upregulate nAChRs selectively, promoting a tumor growth environment. The combination of these two conditions results in NNK- and NNN-induced cancer.

Synthesis

[edit]

NNN is a derivative of nicotine that is produced in the curing of tobacco, in the burning of tobacco (such as with cigarettes), and in the acidic conditions of the stomach. NNN is synthesized by either nicotine or nornicotine by nitrosation of nicotine, but most will be derived from nicotine. This process is slow and the rate-limited step is the formation of the iminium intermediate; however, addition of thiocyanate can double the rate of nitrosation by acting as a catalyst. Nicotine will largely be metabolized to cotinine in a two step process. Catalysis by cytochrome P450 with the enzymes CYP2A6 and CYP2B6 responsible for this first reaction.[19] This catalysis will produce the nicotine-Δ1′(5′)-iminium ion, which is in equilibrium with 5'-hydroxynicotine.[2] To complete cotinine production, cytoplasmic aldehyde oxidase catalyzes the iminium ion. Cotinine can now be further metabolized to norcotinine in small amounts. The remaining nicotine is converted into other metabolites, including norcotinin. Nicotine can be converted into nornicotine via nicotine N-demethylase (NND), an enzyme found in the tobacco plant that works by removing the methyl group from the nitrogen on the 5-membered ring of nicotine.[20] From there, Nornicotine undergoes nitrosation (the conversion of organic compounds into nitroso derivatives by gaining a nitrosonium (N=O) group) on that same nitrogen, converting it to NNN.[9] The nitrosonium group forms from nitrous acid (HNO2) under acidic conditions present in the tobacco curing process. It can also be formed in the stomach when stomach acid reacts with nitrite ions that are typically used as a salt to preserve red meats and inhibit bacterial growth.[21] Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water.[22]

References

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  1. ^ a b "Agents Classified by the IARC Monographs, Volumes 1–105" (PDF). IARC.
  2. ^ a b c d Xue, Jiaping; Yang, Suping; Seng, Seyha (2014-05-14). "Mechanisms of Cancer Induction by Tobacco-Specific NNK and NNN". Cancers. 6 (2): 1138–1156. doi:10.3390/cancers6021138. ISSN 2072-6694. PMC 4074821. PMID 24830349.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Tobacco Smoke and Involuntary Smoking (83 ed.). Lyon, FR: International Agency for Research on Cancer. 2004. ISBN 978-92-832-1583-7.
  4. ^ Hecht, Stephen S. (2014-07). "It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco". Cancer Prevention Research (Philadelphia, Pa.). 7 (7): 639–647. doi:10.1158/1940-6207.CAPR-14-0095. ISSN 1940-6215. PMC 4135519. PMID 24806664. {{cite journal}}: Check date values in: |date= (help)
  5. ^ a b "N-NITROSONORNICOTINE - National Library of Medicine HSDB Database". toxnet.nlm.nih.gov. Retrieved 2017-04-23.
  6. ^ Balbo, S. (April 2, 2012). "Strong Oral Carcinogen Identified in Smokeless Tobacco". American Association for Cancer Research. Archived from the original on June 11, 2012.
  7. ^ Bustamante, Gabriela; Ma, Bin; Yakovlev, Galina; Yershova, Katrina; Le, Chap; Jensen, Joni; Hatsukami, Dorothy K.; Stepanov, Irina (July 2018). "Presence of the Carcinogen N'-Nitrosonornicotine in Saliva of E-cigarette Users". Chem. Res. Toxicol. 31 (8): 731–738. doi:10.1021/acs.chemrestox.8b00089. PMC 8556657. PMID 30019582.
  8. ^ Siminszky, B.; Gavilano, L.; Bowen, S. W.; Dewey, R. E. (2005). "Conversion of nicotine to nornicotine in Nicotiana tabacum is mediated by CYP82E4, a cytochrome P450 monooxygenase". Proceedings of the National Academy of Sciences. 102 (41): 14919–14924. Bibcode:2005PNAS..10214919S. doi:10.1073/pnas.0506581102. PMC 1253577. PMID 16192354.
  9. ^ a b Stepanov, Irina; Carmella, Steven; Briggs, Anna; Hertsgaard, Louise; Lindgren, Bruce; Hatsukami, Dorothy; Hecht, Stephen. "Presence of the carcinogen N′-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products". PubMed Central. Masonic Cancer Center and Transdisciplinary Tobacco Use Research Center.
  10. ^ Knezevich, Aleksandar; Muzic, John; Hatsukami, Dorothy; Hecht, Stephen S.; Stepanov, Irina. [10.1093/ntr/nts172 "Nornicotine Nitrosation in Saliva and Its Relation to Endogenous Synthesis of N′-Nitrosonornicotine in Humans"]. PubMed Central. Oxford Journals. {{cite web}}: Check |url= value (help)
  11. ^ "New Jersey Department of Health and Senior Services Hazardous Substance Fact Sheet: N-Nitrosonornicotine" (PDF). nj.gov/health.
  12. ^ Pubchem. "N'-Nitrosonornicotine | C9H11N3O - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2017-04-26.
  13. ^ Hecht, Stephen S. (2017-05-05). "It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco". Cancer Prevention Research (Philadelphia, Pa.). 7 (7): 639–647. doi:10.1158/1940-6207.CAPR-14-0095. ISSN 1940-6207. PMC 4135519. PMID 24806664.
  14. ^ Balbo, Silvia; James-Yi, Sandra; Johnson, Charles S.; O’Sullivan, Michael G.; Stepanov, Irina; Wang, Mingyao; Bandyopadhyay, Dipankar; Kassie, Fekadu; Carmella, Steven; Upadhyaya, Pramod; Hecht, Stephen S. (2013). "(S)-N′-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats". Carcinogenesis. 34 (9): 2178–2183. doi:10.1093/carcin/bgt162. PMC 3765046. PMID 23671129.
  15. ^ "N-Nitrosonornicotine". U.S. Department of Health & Human Services/National Toxicology Program; Twelfth Report on Carcinogens (12): 19, 20. 2011.
  16. ^ Lazarus, P.; Idris, A. M.; Kim, J.; Calcagnotto, A.; Hoffmann, D. (1996). "p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users". Cancer Detection and Prevention. 20 (4): 270–278. ISSN 0361-090X. PMID 8818386.
  17. ^ Hecht, Stephen S. (1998-06-01). "Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N -Nitrosamines". Chemical Research in Toxicology. 11 (6): 559–603. doi:10.1021/tx980005y. ISSN 0893-228X.
  18. ^ Zarth, Adam T.; Upadhyaya, Pramod; Yang, Jing; Hecht, Stephen S. (2016-03-21). "DNA Adduct Formation from Metabolic 5′-Hydroxylation of the Tobacco-Specific Carcinogen N′-Nitrosonornicotine in Human Enzyme Systems and in Rats". Chemical Research in Toxicology. 29 (3): 380–389. doi:10.1021/acs.chemrestox.5b00520. ISSN 0893-228X. PMC 4805523. PMID 26808005.
  19. ^ Tutka, Piotr (2005). "Pharmacokinetics and metabolism of nicotine" (PDF). Pharmacological Reports. 57. Institute of Pharmacology Polish Academy of Sciences: 143–153. ISSN 1734-1140.
  20. ^ Dong-yun, Hao (1996). "Nicotine N-demethylase in cell-free preparations from tobacco cell cultures". Phytochemistry. 42 (2): 325–329. doi:10.1016/0031-9422(95)00868-3.
  21. ^ "oxyacid - Nitrous acid and nitrite salts | chemical compound". Encyclopedia Britannica. Retrieved 2017-05-06.
  22. ^ Vogel, Arthur Israel (1962). Practical Organic Chemistry (3rd ed.). London: Longman Group Limited.



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