Tobacco nitrosamines as culprits in disease: mechanisms reviewed

Journal of Physiology and Biochemistry

Volumn 72, Issue 1, 2016, Pages 107-120

  Yalcin, Emine ^a   de la Monte, Suzanne ^a  

^a BROWN UNIVERSITY   (United States)

Author keywords

Adduct; Carcinogenesis; Diabetes; Neurodegeneration; Nicotine; NNK; Smoking; Tobacco; Tobacco specific nitrosamine

Indexed keywords

ADENOSINE DIPHOSPHATE; CYTOCHROME P450; DNA; DOPAMINE RECEPTOR; HEMOGLOBIN; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROTRANSMITTER; NICOTINE; NITROSAMINE; PYRIDINE; SINGLE STRANDED DNA;

ANTIOXIDANT ACTIVITY; APOPTOSIS; BRAIN DISEASE; CANCER RISK; CARCINOGENESIS; CARDIOVASCULAR DISEASE; DNA ADDUCT; DNA DAMAGE; DNA STRAND BREAKAGE; ENZYME METABOLISM; GENITAL SYSTEM DISEASE; GENOTOXICITY; HUMAN; INSULIN RESISTANCE; METABOLIC DISORDER; MOLECULAR MECHANICS; MUTAGENESIS; NERVE DEGENERATION; NEUROPROTECTION; NEUROTOXICITY; NEUROTRANSMITTER RELEASE; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; SMOKING; TOBACCO DEPENDENCE; CHEMISTRY; TOBACCO;

HUMANS; NITROSAMINES; TOBACCO;

EID: 84959138448     PISSN: 11387548     EISSN: 18778755     Source Type: Journal    
DOI: 10.1007/s13105-016-0465-9     Document Type: Review

References (106)

1. Akaike A, Tamura Y, Yokota T, Shimohama S, Kimura J (1994) Nicotine-induced protection of cultured cortical neurons against N-methyl-d-aspartate receptor-mediated glutamate cytotoxicity. Brain Res 644:181–187
2. Anderson KE, Hammons GJ, Kadlubar FF, Potter JD, Kaderlik KR, Ilett KF, Minchin RF, Teitel CH, Chou HC, Martin MV et al (1997) Metabolic activation of aromatic amines by human pancreas. Carcinogenesis 18:1085–1092
3. Asami S, Hirano T, Yamaguchi R, Tomioka Y, Itoh H, Kasai H (1996) Increase of a type of oxidative DNA damage, 8-hydroxyguanine, and its repair activity in human leukocytes by cigarette smoking. Cancer Res 56:2546–2549
4. Azzalini L, Ferrer E, Ramalho LN, Moreno M, Dominguez M, Colmenero J, Peinado VI, Barbera JA, Arroyo V, Gines P et al (2010) Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology (Baltimore, Md) 51:1567–1576
5. Baserga R, Peruzzi F, Reiss K (2003) The IGF-1 receptor in cancer biology. Int J Cancer 107:873–877
6. Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–541
7. Carlson J, Noguchi K, Ellison G (2001) Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus. Brain Res 906:127–134
8. Carmella SG, Hecht SS (1987) Formation of hemoglobin adducts upon treatment of F344 rats with the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and n′-nitrosonornicotine. Cancer Res 47:2626–2630
9. Castonguay A, Pepin P, Briere N (1991) Modulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone demethylation and denitrosation by rat liver microsomes. Cancer Lett 59:67–74
10. Dahlstrom A, Lundell B, Curvall M, Thapper L (1990) Nicotine and cotinine concentrations in the nursing mother and her infant. Acta Paediatr Scand 79:142–147
11. Dalgic A, Okay O, Helvacioglu F, Daglioglu E, Akdag R, Take G, Belen D (2013) Tobacco-induced neuronal degeneration via cotinine in rats subjected to experimental spinal cord injury. J Neurol Surg A Cent Eur Neurosurg 74:136–145
12. Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729
13. Das D, Cherbuin N, Anstey KJ, Sachdev PS, Easteal S (2012) Lifetime cigarette smoking is associated with striatal volume measures. Addict Biol 17:817–825
14. de la Monte SM, Neusner A, Chu J, Lawton M (2009) Epidemiological trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer’s disease, diabetes mellitus, and non-alcoholic steatohepatitis. J Alzheimers Dis 17:519–529
15. Devereux TR, Anderson MW, Belinsky SA (1988) Factors regulating activation and DNA alkylation by 4-(n-methyl-n-nitrosamino)-1-(3-pyridyl)-1-butanone and nitrosodimethylamine in rat lung and isolated lung cells, and the relationship to carcinogenicity. Cancer Res 48:4215–4221
16. Devereux TR, Anderson MW, Belinsky SA (1991) Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. Carcinogenesis 12:299–303
17. Durazzo TC, Gazdzinski S, Meyerhoff DJ (2007) The neurobiological and neurocognitive consequences of chronic cigarette smoking in alcohol use disorders. Alcohol Alcohol 42:174–185
18. Durazzo TC, Mattsson N, Weiner MW (2014) Alzheimer’s disease neuroimaging, I. Smoking and increased Alzheimer’s disease risk: a review of potential mechanisms. Alzheimers Dement 10:S122–S145
19. Fritz HC, Wittfeld K, Schmidt CO, Domin M, Grabe HJ, Hegenscheid K, Hosten N, Lotze M (2014) Current smoking and reduced gray matter volume—a voxel-based morphometry study. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39:2594–2600
20. Fuxe K, Rosen L, Lippoldt A, Andbjer B, Hasselrot U, Finnman UB, Agnati LF (1994) Chronic continuous infusion of nicotine increases the disappearance of choline acetyltransferase immunoreactivity in the cholinergic cell bodies of the medial septal nucleus following a partial unilateral transection of the fimbria fornix. Clin Investig 72:262–268
21. Garcia-Montes JR, Boronat-Garcia A, Lopez-Colome AM, Bargas J, Guerra-Crespo M, Drucker-Colin R (2012) Is nicotine protective against Parkinson’s disease? An experimental analysis. CNS Neurol Disord Drug Targets 11:897–906
22. Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA (1996) Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716
23. Guo Z, Smith TJ, Ishizaki H, Yang CS (1991) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytochrome P450IIB1 in a reconstituted system. Carcinogenesis 12:2277–2282
24. Guo Z, Smith TJ, Thomas PE, Yang CS (1991) Metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone as measured by DNA alkylation in vitro and its inhibition by isothiocyanates. Cancer Res 51:4798–4803
25. Guo Z, Smith TJ, Thomas PE, Yang CS (1992) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by inducible and constitutive cytochrome P450 enzymes in rats. Arch Biochem Biophys 298:279–286
26. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11:559–603
27. Hecht SS, Adams JD, Numoto S, Hoffmann D (1983) Induction of respiratory tract tumors in Syrian golden hamsters by a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the effect of smoke inhalation. Carcinogenesis 4:1287–1290
28. Hecht SS, Chen CB, Ornaf RM, Jacobs E, Adams JD, Hoffmann D (1978) Reaction of nicotine and sodium nitrite: formation of nitrosamines and fragmentation of the pyrrolidine ring. J Org Chem 43:72–76
29. Hecht SS, Hochalter JB, Villalta PW, Murphy SE (2000) 2′-hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor. Proc Natl Acad Sci U S A 97:12493–12497
30. Hecht SS, Hoffmann D (1988) Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9:875–884
31. Hecht SS, Spratt TE, Trushin N (1997) Absolute configuration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formed metabolically from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 18:1851–1854
32. Hecht SS, Trushin N, Castonguay A, Rivenson A (1986) Comparative tumorigenicity and DNA methylation in F344 rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosodimethylamine. Cancer Res 46:498–502
33. Hecht SS, Trushin N, Rigotty J, Carmella SG, Borukhova A, Akerkar S, Desai D, Amin S, Rivenson A (1996) Inhibitory effects of 6-phenylhexyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation and lung tumorigenesis in rats. Carcinogenesis 17:2061–2067
34. Hecht SS, Young R, Chen CB (1980) Metabolism in the F344 rat of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen. Cancer Res 40:4144–4150
35. Heusch WL, Maneckjee R (1998) Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. Carcinogenesis 19:551–556
36. Howard LA, Miksys S, Hoffmann E, Mash D, Tyndale RF (2003) Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br J Pharmacol 138:1376–1386
37. International Agency for Research on Cancer (IARC), I.A.f.o.C. (1986) IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, tobacco smoking
38. International Agency for Research on Cancer (IARC), I.A.f.o.C. (2007) IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, smokeless tobacco and some tobacco-specific N-nitrosamines
39. Improgo MR, Tapper AR, Gardner PD (2011) Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem Pharmacol 82:1015–1021
40. Janson AM, Meana JJ, Goiny M, Herrera-Marschitz M (1991) Chronic nicotine treatment counteracts the decrease in extracellular neostriatal dopamine induced by a unilateral transection at the mesodiencephalic junction in rats: a microdialysis study. Neurosci Lett 134:88–92
41. Kannel WB, Higgins M (1990) Smoking and hypertension as predictors of cardiovascular risk in population studies. J Hypertens Suppl 8:S3–S8
42. Kato S, Bowman ED, Harrington AM, Blomeke B, Shields PG (1995) Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo. J Natl Cancer Inst 87:902–907
43. Kemp PM, Sneed GS, George CE, Distefano RF (1997) Postmortem distribution of nicotine and cotinine from a case involving the simultaneous administration of multiple nicotine transdermal systems. J Anal Toxicol 21:310–313
44. Leanderson P (1993) Cigarette smoke-induced DNA damage in cultured human lung cells. Ann N Y Acad Sci 686:249–259, discussion 259–261
45. Lee VM, Keefer LK, Archer MC (1996) An evaluation of the roles of metabolic denitrosation and alpha-hydroxylation in the hepatotoxicity of n-nitrosodimethylamine. Chem Res Toxicol 9:1319–1324
46. Liao Y, Tang J, Liu T, Chen X, Hao W (2012) Differences between smokers and non-smokers in regional gray matter volumes: a voxel-based morphometry study. Addict Biol 17:977–980
47. Liu L, Castonguay A, Gerson SL (1992) Lack of correlation between DNA methylation and hepatocarcinogenesis in rats and hamsters treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 13:2137–2140
48. Liu Y, Zeng X, Hui Y, Zhu C, Wu J, Taylor DH, Ji J, Fan W, Huang Z, Hu J (2015) Activation of alpha7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson’s disease. Neuropharmacology 91:87–96
49. Madsbad S, McNair P, Christensen MS, Christiansen C, Faber OK, Binder C, Transbol I (1980) Influence of smoking on insulin requirement and metabolic status in diabetes mellitus. Diabetes Care 3:41–43
50. Marin P, Maus M, Desagher S, Glowinski J, Premont J (1994) Nicotine protects cultured striatal neurones against N-methyl-d-aspartate receptor-mediated neurotoxicity. Neuroreport 5:1977–1980
51. Maser E (1997) Stress, hormonal changes, alcohol, food constituents and drugs: factors that advance the incidence of tobacco smoke-related cancer? Trends Pharmacol Sci 18:270–275
52. Maser E, Richter E, Friebertshauser J (1996) The identification of 11 beta-hydroxysteroid dehydrogenase as carbonyl reductase of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Eur J Biochem 238:484–489
53. Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF (2003) Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology 45:122–132
54. Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C (2013) Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease. Nat Commun 4:1495
55. Murphy SE, Palomino A, Hecht SS, Hoffmann D (1990) Dose–response study of DNA and hemoglobin adduct formation by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats. Cancer Res 50:5446–5452
56. Murphy SE, Spina DA, Nunes MG, Pullo DA (1995) Glucuronidation of 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone, a metabolically activated form of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, by phenobarbital-treated rats. Chem Res Toxicol 8:772–779
57. Nesnow S, Ross JA, Stoner GD, Mass MJ (1995) Mechanistic linkage between DNA adducts, mutations in oncogenes and tumorigenesis of carcinogenic environmental polycyclic aromatic hydrocarbons in strain A/J mice. Toxicology 105:403–413
58. Oliveira-da-Silva A, Vieira FB, Cristina-Rodrigues F, Filgueiras CC, Manhaes AC, Abreu-Villaca Y (2009) Increased apoptosis and reduced neuronal and glial densities in the hippocampus due to nicotine and ethanol exposure in adolescent mice. Int J Dev Neurosci 27:539–548
59. Pan P, Shi H, Zhong J, Xiao P, Shen Y, Wu L, Song Y, He G (2013) Chronic smoking and brain gray matter changes: evidence from meta-analysis of voxel-based morphometry studies. Neurol Sci 34:813–817
60. Parain K, Hapdey C, Rousselet E, Marchand V, Dumery B, Hirsch EC (2003) Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonian toxin. Brain Res 984:224–232
61. Parain K, Marchand V, Dumery B, Hirsch E (2001) Nicotine, but not cotinine, partially protects dopaminergic neurons against MPTP-induced degeneration in mice. Brain Res 890:347–350
62. Patten CJ, Smith TJ, Murphy SE, Wang MH, Lee J, Tynes RE, Koch P, Yang CS (1996) Kinetic analysis of the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by heterologously expressed human P450 enzymes and the effect of P450-specific chemical inhibitors on this activation in human liver microsomes. Arch Biochem Biophys 333:127–138
63. Peterson LA, Carmella SG, Hecht SS (1990) Investigations of metabolic precursors to hemoglobin and DNA adducts of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 11:1329–1333
64. Peterson LA, Hecht SS (1991) O6-methylguanine is a critical determinant of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone tumorigenesis in a/j mouse lung. Cancer Res 51:5557–5564
65. Peterson LA, Liu XK, Hecht SS (1993) Pyridyloxobutyl DNA adducts inhibit the repair of o6-methylguanine. Cancer Res 53:2780–2785
66. Peterson LA, Mathew R, Hecht SS (1991) Quantitation of microsomal alpha-hydroxylation of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res 51:5495–5500
67. Peterson LA, Ng DK, Stearns RA, Hecht SS (1994) Formation of NADP(H) analogs of tobacco-specific nitrosamines in rat liver and pancreatic microsomes. Chem Res Toxicol 7:599–608
68. Petruzzelli S, Tavanti LM, Celi A, Giuntini C (1996) Detection of N7-methyldeoxyguanosine adducts in human pulmonary alveolar cells. Am J Respir Cell Mol Biol 15:216–223
69. Picciotto MR, Zoli M (2002) Nicotinic receptors in aging and dementia. J Neurobiol 53:641–655
70. Pidoplichko VI, Noguchi J, Areola OO, Liang Y, Peterson J, Zhang T, Dani JA (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60–69
71. Placzek AN, Zhang TA, Dani JA (2009) Age dependent nicotinic influences over dopamine neuron synaptic plasticity. Biochem Pharmacol 78:686–692
72. Prendergast MA, Harris BR, Mayer S, Holley RC, Hauser KF, Littleton JM (2001) Chronic nicotine exposure reduces N-methyl-d-aspartate receptor-mediated damage in the hippocampus without altering calcium accumulation or extrusion: evidence of calbindin-D28K overexpression. Neuroscience 102:75–85
73. Preusmann R, Stewart B (1984) N-nitroso carcinogens. Searle. C. E, Washington, DC
74. Quik M, Kulak JM (2002) Nicotine and nicotinic receptors; relevance to Parkinson’s disease. Neurotoxicology 23:581–594
75. Quik M, McIntosh JM (2006) Striatal alpha6* nicotinic acetylcholine receptors: potential targets for Parkinson’s disease therapy. J Pharmacol Exp Ther 316:481–489
76. Quik M, Parameswaran N, McCallum SE, Bordia T, Bao S, McCormack A, Kim A, Tyndale RF, Langston JW, Di Monte DA (2006) Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98:1866–1875
77. Riljak V, Milotova M, Jandova K, Pokorny J, Langmeier M (2007) Morphological changes in the hippocampus following nicotine and kainic acid administration. Physiol Res 56:641–649
78. Rotsch M, Maasberg M, Erbil C, Jaques G, Worsch U, Havemann K (1992) Characterization of insulin-like growth factor I receptors and growth effects in human lung cancer cell lines. J Cancer Res Clin Oncol 118:502–508
79. Schuller HM (2009) Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Reviews Cancer 9:195–205
80. Sheppard BJ, Williams M, Plummer HK, Schuller HM (2000) Activation of voltage-operated Ca2+-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Int J Oncol 16:513–518
81. Sipowicz MA, Amin S, Desai D, Kasprzak KS, Anderson LM (1997) Oxidative DNA damage in tissues of pregnant female mice and fetuses caused by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk). Cancer Lett 117:87–91
82. Siwicky MD, Petrik JJ, Moorehead RA (2011) The function of IGF-IR in NNK-mediated lung tumorigenesis. Lung Cancer 71:11–18
83. Smith TJ, Guo Z, Gonzalez FJ, Guengerich FP, Stoner GD, Yang CS (1992) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human lung and liver microsomes and cytochromes P-450 expressed in hepatoma cells. Cancer Res 52:1757–1763
84. Smith TJ, Guo Z, Hong JY, Ning SM, Thomas PE, Yang CS (1992) Kinetics and enzyme involvement in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in microsomes of rat lung and nasal mucosa. Carcinogenesis 13:1409–1414
85. Smith TJ, Guo ZY, Thomas PE, Chung FL, Morse MA, Elkind K, Yang CS (1990) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes and its inhibition by isothiocyanates. Cancer Res 50:6817–6822
86. Staretz ME, Foiles PG, Miglietta LM, Hecht SS (1997) Evidence for an important role of DNA pyridyloxobutylation in rat lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: effects of dose and phenethyl isothiocyanate. Cancer Res 57:259–266
87. Staretz ME, Koenig LA, Hecht SS (1997) Effects of long term dietary phenethyl isothiocyanate on the microsomal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F344 rats. Carcinogenesis 18:1715–1722
88. Staretz ME, Murphy SE, Patten CJ, Nunes MG, Koehl W, Amin S, Koenig LA, Guengerich FP, Hecht SS (1997) Comparative metabolism of the tobacco-related carcinogens benzo[a]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and n′- nitrosonornicotine in human hepatic microsomes. Drug Metab Dispos 25:154–162
89. Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T et al (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 87:576–585
90. Trushin N, Rivenson A, Hecht SS (1994) Evidence supporting the role of DNA pyridyloxobutylation in rat nasal carcinogenesis by tobacco-specific nitrosamines. Cancer Res 54:1205–1211
91. U.S. Department of Health and Human Services, P.H.S., Office of the Surgeon General (2014) The health consequences of smoking—50 years of progress: a report of the surgeon general. Atlanta, GA
92. Urbanavicius J, Ferreira M, Costa G, Abin-Carriquiry JA, Wonnacott S, Dajas F (2007) Nicotine induces tyrosine hydroxylase plasticity in the neurodegenerating striatum. J Neurochem 102:723–730
93. Vahakangas K, Pelkonen O (1993) Extrahepatic metabolism of nicotine and related compounds by P-450, in nicotine and related alkaloids: absorption-distribution-metabolism-excretion. Chapman & Hall, London
94. Wang JJ, Durazzo TC, Gazdzinski S, Yeh PH, Mon A, Meyerhoff DJ (2009) MRSI and DTI: a multimodal approach for improved detection of white matter abnormalities in alcohol and nicotine dependence. NMR Biomed 22:516–522
95. Wang L, Spratt TE, Liu XK, Hecht SS, Pegg AE, Peterson LA (1997) Pyridyloxobutyl adduct o6-[4-oxo-4-(3-pyridyl)butyl]guanine is present in 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone-treated DNA and is a substrate for o6-alkylguanine-DNA alkyltransferase. Chem Res Toxicol 10:562–567
96. Weitberg AB, Corvese D (1993) Oxygen radicals potentiate the genetic toxicity of tobacco-specific nitrosamines. Clin Genet 43:88–91
97. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA (2003) Rapid akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest 111:81–90
98. Whitehouse PJ, Kalaria RN (1995) Nicotinic receptors and neurodegenerative dementing diseases: basic research and clinical implications. Alzheimer Dis Assoc Disord 9(Suppl 2):3–5
99. WHO (2013) World Health Organization report on the global tobacco epidemic
100. Xie XT, Liu Q, Wu J, Wakui M (2009) Impact of cigarette smoking in type 2 diabetes development. Acta Pharmacol Sin 30:784–787
101. Xu Y, Ho CT, Amin SG, Han C, Chung FL (1992) Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 52:3875–3879
102. Xu Z, Seidler FJ, Ali SF, Slikker W Jr, Slotkin TA (2001) Fetal and adolescent nicotine administration: effects on CNS serotonergic systems. Brain Res 914:166–178
103. Xue J, Yang S, Seng S (2014) Mechanisms of cancer induction by tobacco-specific NNK and NNN. Cancers 6:1138–1156
104. Yamazaki Y, Hamaue N, Sumikawa K (2002) Nicotine compensates for the loss of cholinergic function to enhance long-term potentiation induction. Brain Res 946:148–152
105. Yuan JM, Knezevich AD, Wang R, Gao YT, Hecht SS, Stepanov I (2011) Urinary levels of the tobacco-specific carcinogen n′-nitrosonornicotine and its glucuronide are strongly associated with esophageal cancer risk in smokers. Carcinogenesis 32:1366–1371
106. Zabala V, Tong M, Yu R, Ramirez T, Yalcin EB, Balbo S, Silbermann E, Deochand C, Nunez K, Hecht S et al (2015) Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease. Alcohol and alcoholism (Oxford, Oxfordshire) 50:118–131