Molecular Therapeutic Targets in Tobacco-Induced Lung Pathology

  • Pramod K. Avti
  • Krishan L. Khanduja


Tobacco consumption globally is estimated to be around 20% and in India accounted for 12% of the world’s smokers according to the World Health Organization (WHO) statistics. It is also estimated that around six million deaths occur every year and rises to eight million by the year 2030. The socioeconomic health burden is of great concern due to the rise in cigarette smoking and related deaths. Cigarette smoking is known to cause many disorders such as chronic obstructive pulmonary diseases (COPD), oral cancers, and pulmonary tumors. More than 6000 different chemicals contain approximately 100 known pulmonary carcinogens present in the cigarette smoke (CS). Inhaled polycyclic aromatic hydrocarbons (PAHs), constituents of CS, are deposited in the airway epithelium and the majority in the alveolar epithelium which detoxifies the cigarette constituents by way of drug-metabolizing enzymes such as cytochrome p450 (CYP450) enzymes. Reactive oxygen species (ROS) present in the CS and the CS-mediated generation of mitochondrial and cellular ROS have an impact on the cellular bio-constituents such as membrane lipids, proteins, and DNA. Studies suggest that oxidative stress causes lung inflammation by remodeling of membrane lipids and pulmonary surfactants via activation of phospholipase A2 (PLA2), cyclooxygenases (COX), and lipoxygenases which directly or indirectly activates proinflammatory cytokines. Considering the complexity of lung tissue and functions, understanding the cellular and tissue mechanisms of damage and strategies overcoming the deleterious effects mediated by the CS would be prime importance. This understanding helps target specific molecules that will help in developing therapeutic strategies to circumvent the CS-mediated disease burden, mortality, morbidity, and economic burden.


Cytochrome P450 isoforms (CYP450) Phospholipase A2 isoforms (PLA2Smoking Therapy Tobacco 


  1. Agen B, Maas LM, Zwingmann IH, Schooten FJV, Kleinjans JCS (2001) B(α)P adduct formation and induction of human epithelial lung cell transformation. Environ Mol Mutagen 30:287–292CrossRefGoogle Scholar
  2. Amin S, Desai D, Hecht SS et al (1996) Synthesis of tobacco-specific N-nitrosamines and their metabolites and results of related bioassays. Crit Rev Toxicol 26:139–147PubMedCrossRefGoogle Scholar
  3. Anttila S, Hakkola J, Tuominen P et al (2003) Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res 63:8623–8628PubMedPubMedCentralGoogle Scholar
  4. Artaud-Macari E, Goven D, Brayer S, Hamimi A, Besnard V, Marchal-Somme J, Ali ZE, Crestani B, Kerdine-Romer S, Boutten A, Bonay M (2013) Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis. Antioxid Redox Signal 18:66–79PubMedCrossRefGoogle Scholar
  5. Avti PK, Kumar S, Pathak CM, Vaiphei K, Khanduja KL (2006) Smokeless tobacco impairs the antioxidant defense in liver, lung, and kidney of rats. Toxicol Sci 89(2):547–553PubMedCrossRefPubMedCentralGoogle Scholar
  6. Avti PK, Vaiphei K, Pathak CM, Khanduja KL (2010) Involvement of various molecular events in cellular injury induced by smokeless tobacco. Chem Res Toxicol 23(7):1163–1174PubMedCrossRefGoogle Scholar
  7. Aw TK (2003) Cellular redox: a modulator of intestinal epithelial cell proliferation. News Physiol Sci 18:201–204PubMedPubMedCentralGoogle Scholar
  8. Backer JM, Weinstein IB (1980) Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo(α)pyrene. Science 209:297–299CrossRefGoogle Scholar
  9. Banerjee S, Chattopadhyay R, Ghosh A, Koley H, Panda K, Roy S, Chattopadhyay D, Chatterjee IB (2008) Cellular and molecular mechanisms of cigarette smoke-induced lung damage and prevention by vitamin C. J Inflamm (Lond) 11(5):21CrossRefGoogle Scholar
  10. Bhalla DK, Hirata F, Rishi AK, Gairola CG (2009) Cigarette smoke, inflammation, and lung injury: a mechanistic perspective. J Toxicol Environ Health B Crit Rev 12:45–64PubMedCrossRefPubMedCentralGoogle Scholar
  11. Clarke J, Snelling J, Ioannides C, Flatt PR, Barnett CR (1996) Effect of vitamin C supplementation on hepatic cytochrome P450 mixed function oxidase activity in streptozotocin-diabetic rats. Toxicol Lett 89:249–256PubMedCrossRefPubMedCentralGoogle Scholar
  12. Crawford EL, Weaver DA, DeMuth JP, Jackson CM, Khuder SA, Frampton MW et al (1998) Measurement of cytochrome P450 2A6 and 2E1 gene expression in primary human bronchial epithelial cells. Carcinogenesis 19:1867–1871PubMedCrossRefPubMedCentralGoogle Scholar
  13. Cummings BS (2007) Phospholipase A2 as targets for anti-cancer drugs. Biochem Pharmacol 74:949–959PubMedCrossRefPubMedCentralGoogle Scholar
  14. de Graan AJ, Loos WJ, Friberg LE et al (2012) Influence of smoking on the pharmacokinetics and toxicity profiles of taxane therapy. Clin Cancer Res 18:4425–4432PubMedCrossRefPubMedCentralGoogle Scholar
  15. Denison MS, Rogers JM, Rushing SR, Jones CL, Tetangco SC, Heath-Pagliuso S. (2002) Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. Curr Protoc Toxicol. Chapter 4:Unit 4.8Google Scholar
  16. Diana JN (1993) Tabacco smoking and nutrition. Ann N Y Acad Sci 686:1–11CrossRefGoogle Scholar
  17. Ding X, Kaminsky LS (2003) Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 43:149–173PubMedCrossRefPubMedCentralGoogle Scholar
  18. Dong Z, Meller J, Succop P, Wang J, Wikenheiser-Brokamp K, Starnes S, Lu S (2014) Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells. Int J Oncol 45(3):978–984PubMedPubMedCentralCrossRefGoogle Scholar
  19. Douben P (2003) PAHs: an ecotoxicological perspective. Wiley, Hoboken, p 18CrossRefGoogle Scholar
  20. Drath DB, Karnovsky ML, Huber GL (1979) Tobacco smoke. Effects on pulmonary host defense. Inflammation 3:281–288PubMedCrossRefPubMedCentralGoogle Scholar
  21. Duong C et al (2010) Glutathione peroxidase-1 protects against cigarette smoke-induced lung inflammation in mice. Am J Physiol Lung Cell Mol Physiol 299(3):L425–L433PubMedCrossRefPubMedCentralGoogle Scholar
  22. Faber MS, Fuhr U (2004) Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 76:178–184PubMedCrossRefPubMedCentralGoogle Scholar
  23. Filosto S, Khan E, Tognon E, Becker C, Ashfaq M, Ravid T, Goldkorn T (2011) EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization. PLoS One 6:e23240PubMedPubMedCentralCrossRefGoogle Scholar
  24. Furusawa J, Funakoshi-Tago M, Tago K et al (2009) Licochalcone A significantly suppresses LPS signaling pathway through the inhibition of NF-jB p65 phosphorylation at serine 276. Cell Signal 21:778–785PubMedCrossRefPubMedCentralGoogle Scholar
  25. Goldkorn T, Filosto S (2010) Lung injury and cancer: mechanistic insights into ceramide and EGFR signaling under cigarette smoke. Am J Respir Cell Mol Biol 43:259–268PubMedPubMedCentralCrossRefGoogle Scholar
  26. Goldkorn T, Chung S, Filosto S (2013) Lung cancer and lung injury: the dual role of ceramide. Handb Exp Pharmacol 216:93–113CrossRefGoogle Scholar
  27. Greenhough A, Smartt HJM, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A (2009) The COX-2/ PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30:377–386PubMedCrossRefPubMedCentralGoogle Scholar
  28. Guan Y, Li FF, Hong L, Yan XF, Tan GL, He JS, Dong XW, Bao MJ, Xie QM (2012) Protective effects of liquiritin apioside on cigarette smoke-induced lung epithelial cell injury. Fundam Clin Pharmacol 26(4):473–483PubMedCrossRefPubMedCentralGoogle Scholar
  29. Guengerich FP, Shimada T (1998) Activation of procarcinogens by human cytochrome P450 enzymes. Mutat Res 400:201–213PubMedCrossRefPubMedCentralGoogle Scholar
  30. Gvinianidze K, Tsereteli D (2012) Tobacco smoking attributable mortality and years of potential life lost in Georgia. Georgian Med News 206:52–57Google Scholar
  31. Han WK, Sapirstein A, Hung CC, Alessandrini A, Bonventre JV (2003) Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release. J Biol Chem 278:24153–24163PubMedCrossRefPubMedCentralGoogle Scholar
  32. Han W, Pentecost BT, Pietropaolo RL, Fasco MJ, Spivack SD (2005) Estrogen receptor alpha increases basal and cigarette smoke extract-induced expression of CYP1A1 and CYP1B1, but not GSTP1, in normal human bronchial epithelial cells. Mol Carcinog 44:202–211PubMedPubMedCentralCrossRefGoogle Scholar
  33. Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–1210PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hecht SS (2003) Tobacco carcinogens, their biomarkers, and tobacco-induced cancer. Nat Rev Cancer 3:733–744CrossRefGoogle Scholar
  35. Hemila H (1997) Vitamin C supplementation and the common cold—was Linus Pauling right or wrong? Int J Vitam Nutr Res 67:329–335PubMedPubMedCentralGoogle Scholar
  36. Hilbert J, Mohsenin V (1996) Adaptation of lung antioxidants to cigarette smoking in humans. Chest 110:916–920PubMedCrossRefPubMedCentralGoogle Scholar
  37. Hirota T, Takane H, Higuchi S, Ieiri I (2008) Epigenetic regulation of genes encoding drug-metabolizing enzymes and transporters; DNA methylation and other mechanisms. Curr Drug Metab 9:34–38PubMedCrossRefPubMedCentralGoogle Scholar
  38. Hoffmann D, Hoffmann I (1997) The changing cigarette, 1950–1995. J Toxicol Environ Health 50(4):307–364PubMedCrossRefPubMedCentralGoogle Scholar
  39. Hoffmann D, Hoffmann I, El-Bayoumy K (2001) The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder. Chem Res Toxicol 14:767–790PubMedCrossRefPubMedCentralGoogle Scholar
  40. Hoidal JR (2001) Reactive oxygen species and cell signaling. Am J Respir Cell Mol Biol 25:661–663PubMedCrossRefPubMedCentralGoogle Scholar
  41. Huang RY, Chen GG (2011) Cigarette smoking, cyclooxygenase-2 pathway and cancer. Biochim Biophys Acta 1815:158–169PubMedPubMedCentralGoogle Scholar
  42. Hukkanen J (2012) Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Rev Clin Pharmacol 5:569–585PubMedCrossRefPubMedCentralGoogle Scholar
  43. Hukkanen J, Vaisanen T, Lassila A, Piipari R, Anttila S, Pelkonen O et al (2003) Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther 304:745–752PubMedCrossRefPubMedCentralGoogle Scholar
  44. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM (2001) Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 15:1110–1112PubMedCrossRefPubMedCentralGoogle Scholar
  45. Johnson W (1977) Pyrogenesis and physiochemical nature of tobacco smoke. In: Tobacco smoke: its formation and composition. Tennessee Eastman, Kingsport, pp 1–26Google Scholar
  46. Jozsef L, Filep JG (2003) Selenium-containing compounds attenuate peroxynitrite-mediated NF-kB and AP-1 activation and interleukin-8 gene and protein expression in human leukocytes. Free Radic Biol Med 35(9):1018–1027PubMedCrossRefPubMedCentralGoogle Scholar
  47. Kallner AB, Hartmann D, Horning DH (1981) On the requirements of ascorbic acid in man: steady-state turnover and body pool in smokers. Am J Clin Nutr 34:1347–1355PubMedCrossRefPubMedCentralGoogle Scholar
  48. Kaushik G, Kaushik T, Khanduja S, Pathak CM, Khanduja KL (2008) Cigarette smoke condensate promotes cell proliferation through disturbance in cellular redox homeostasis of transformed lung epithelial type-II cells. Cancer Lett 270(1):120–131PubMedCrossRefPubMedCentralGoogle Scholar
  49. Khan EM, Lanir R, Danielson AR, Goldkorn T (2008) EGF receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. FASEB J 22:910–917PubMedCrossRefPubMedCentralGoogle Scholar
  50. Khanduja KL, Kapur S, Koul A, Majid S, Koul IB, Sharma RR (1990) Effect of N-Nitrsodiethylamine on the carcinogen-activating and -detoxifying enzymes in Guinea pigs given excessive doses of ascorbic acid. J Clin Biochem Nutr 8(3):201–207CrossRefGoogle Scholar
  51. Koo LC, Kabat GC, Rylander R, Tominaga S, Kato I, Ho JH (1997) Dietary and lifestyle correlate of passive smoking in Hong Kong, Japan, Sweden, and the U.S.A. Soc Sci Med 45(1):159–169PubMedCrossRefGoogle Scholar
  52. Koul A, Gupta MP, Koul IB, Majid S, Sharma RR, Khanduja KL (1988) Effect of ascorbic acid on inducibility of pulmonary arylhydrocarbon hydroxylase by cigarette smoke in the Guinea pig. Med Sci Res 16:1119–1120Google Scholar
  53. Kudo I, Murakami M (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat 68–69:3–58PubMedCrossRefGoogle Scholar
  54. Kumar S, Sharma SK, Kaushik G, Avti PK, Pandey S, Sarma P, Medhi B, Khanduja KL (2019) Therapeutic potential of arachidonyl trifluromethyl ketone, a cytosolic phospholipase A2 iVA specific inhibitor, a cigarette smoke condensate induced pathological condition in alveolar type-1 and type-II epithelial cells. Toxicol In Vitro 54:215–223CrossRefGoogle Scholar
  55. Kurata T, Suzuki E, Hayashi M, Kaminao M (1998) Physiological role of L-ascorbic acid in rats exposed to cigarette smoke. Biosci Biotechnol Biochem 62:842–845PubMedCrossRefGoogle Scholar
  56. Launay JM, Del Pino M, Chironi G et al (2009) Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation. PLoS One 4:e7959PubMedPubMedCentralCrossRefGoogle Scholar
  57. Lee PN (2001) Lung cancer and type of cigarette smoked. Inhal Toxicol 13(11):951–976PubMedCrossRefGoogle Scholar
  58. Lee S, Kim D, Kang J, Kim E, Kim W, Youn H, Youn B (2017) Surfactant protein B suppresses lung cancer progression by inhibiting secretory phospholipase A2 activity and arachidonic acid production. Cell Physiol Biochem 42(4):1684–1700PubMedCrossRefGoogle Scholar
  59. Ling J, Johnson KA, Miao Z et al (2006) Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 34:420–426PubMedGoogle Scholar
  60. Lu S, Dong Z (2017) Overexpression of secretory phospholipase A2-IIa supports cancer stem cell phenotype via HER/ERBB-elicited signaling in lung and prostate cancer cells. Int J Oncol 50(6):2113–2122PubMedCrossRefGoogle Scholar
  61. Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN (2000) Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 71:530–536PubMedCrossRefGoogle Scholar
  62. Maranzana A, Mehlhorn RJ (1998) Loss of glutathione, ascorbate recycling, and free radical scavenging in human erythrocytes exposed to filtered cigarette smoke. Arch Biochem Biophys 350:169–182PubMedCrossRefGoogle Scholar
  63. Martey CA, Pollack SJ, Turner C, O’Reilly KM, Baglole CJ, Phipps RP et al (2004) Cigarette smoke induce cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol 287(5):L981–L991PubMedCrossRefGoogle Scholar
  64. Marwick JA, Kirkham PA, Stevenson CS et al (2004) Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol 31:633–642PubMedCrossRefGoogle Scholar
  65. Mays BW, Freishlag JA, Eginton MT, Cambria RA, Seabrook GR, Towne JB (1999) Ascorbic acid prevents cigarette smoke injury to endothelium-dependent arterial relaxation. J Surg Res 84:35–39PubMedCrossRefGoogle Scholar
  66. Miller JA (1998) The metabolism of xenobiotics to reactive electrophiles in chemical carcinogenesis and mutagenesis: a collaboration with Elizabeth Cavert Miller and our associates. Drug Metab Rev 30:645–674PubMedCrossRefGoogle Scholar
  67. Mori T, Itoh S, Ohgiya S, Ishizaki K, Kamataki T (1997) Regulation of CYP1A and CYP3A mRNAs by ascorbic acid in Guinea pigs. Arch Biochem Biophys 348:268–277PubMedCrossRefGoogle Scholar
  68. Moyer JD, Barbacci EG, Iwata KK et al (1997) Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848Google Scholar
  69. Murakami M, Taketomi Y, Sato H, Yamamoto K (2011) Secreted phospholipase A2 revisited. J Biochem 150:233–255PubMedCrossRefGoogle Scholar
  70. Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6:947–960PubMedCrossRefGoogle Scholar
  71. Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614PubMedCrossRefGoogle Scholar
  72. Nohl H, Gille L, Kozlov A, Staniek K (2003) Are mitochondria a spontaneous and permanent source of reactive oxygen species? Redox Rep 8:135–141PubMedCrossRefGoogle Scholar
  73. O’Malley M, King AN, Conte M, Ellingrod VL, Ramnath N (2014) Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol 9(7):917–926PubMedCrossRefGoogle Scholar
  74. Panda K, Chattopadhyay R, Ghosh MK, Chattopadhyay DJ, Chatterjee IB (1999) Vitamin C prevents cigarette smoke-induced oxidative damage of proteins and increased proteolysis. Free Radic Biol Med 27:1064–1079CrossRefGoogle Scholar
  75. Panda K, Chattopadhyay R, Chattopadhyay DJ, Chatterjee IB (2000) Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Free Radic Biol Med 29:115–124CrossRefGoogle Scholar
  76. Pascussi JM, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem MJ, Maurel P (2008) The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol 48:1–32PubMedCrossRefGoogle Scholar
  77. Pesch B, Kendzia B, Gustavsson P, Jöckel KH, Johnen G et al (2012) Cigarette smoking and lung cancer–relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 131(5):1210–1219PubMedCrossRefGoogle Scholar
  78. Petty WJ, Dragnev KH, Memoli VA et al (2004) Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers. Clin Cancer Res 10:7547–7554PubMedCrossRefGoogle Scholar
  79. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J (1998) Vitamin C exhibits pro-oxidant properties. Nature 392:559PubMedCrossRefGoogle Scholar
  80. Prokopczyk B, Hoffmann D, Bologna M, Cunningham AJ et al (2002) Identification of tobacco-derived compounds in human pancreatic juice. Chem Res Toxicol 15:677–685PubMedCrossRefPubMedCentralGoogle Scholar
  81. Ramroth H, Dietz A, Becher H (2011) Intensity and inhalation of smoking in the aetiology of laryngeal cancer. Int J Environ Res Public Health 8(4):976–984PubMedPubMedCentralCrossRefGoogle Scholar
  82. Rehman A, Collis CS, Yang M, Kelly M, Diplock AT, Halliwell B, Rice-Evans C (1998) The effect of iron and vitamin C cosupplementation on oxidative damage to DNA in healthy volunteers. Biochem Biophys Res Commun 246:293–298PubMedCrossRefPubMedCentralGoogle Scholar
  83. Remacle J, Lambert D, Pigeolet E, Michiels C, Toussaint O (1992) Importance of various antioxidant enzymes for cell stability. Biochem J 286:41–46PubMedPubMedCentralCrossRefGoogle Scholar
  84. Rodgman A (2006) The composition of cigarette smoke: a catalogue of the polycyclic aromatic hydrocarbons. Beitr Tabakforschung Int 22:13–69Google Scholar
  85. Rubin H (2001) Synergistic mechanisms in carcinogenesis by polycyclic aromatic hydrocarbons and by tobacco smoke: a bio-historical perspective with updates. Carcinogenesis 22:1903–1930PubMedCrossRefPubMedCentralGoogle Scholar
  86. Rupprecht G, Scholz K, Beck KF, Geiger H, Pfeilschifter J, Kaszkin M (1999) Cross-talk between group IIA-phospholipase A(2) and inducible NO-synthase in rat renal mesangial cells. Br J Pharmacol 127:51–56PubMedPubMedCentralCrossRefGoogle Scholar
  87. Sakai M, Kakutani S, Horikawa C, Tokuda H, Kawashima H, Shibata H, Okubo H, Sasaki S (2012) Arachidonic acid and cancer risk: a systematic review of observational studies. BMC Cancer 12:606PubMedPubMedCentralCrossRefGoogle Scholar
  88. Samara KD, Margaritopoulos G, Wells AU, Siafakas NM, Antoniou KM (2011) Smoking and pulmonary fibrosis: novel insights. Pulm Med 2011:461439PubMedPubMedCentralCrossRefGoogle Scholar
  89. Sasaki J (2013) Compounds in tobacco smoke and pathogenesis of the diseases. Nihon Rinsho 71:383–389PubMedPubMedCentralGoogle Scholar
  90. Saul RL, Gee D, Ames BN (1987) Free radicals, DNA damage, and aging. In: Warner HR, Butler RN, Sprott RL, Schneider EL (eds) Modern biological theories of aging. Raven, New York, pp 113–129Google Scholar
  91. Sen C, Packer L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10:709–720PubMedCrossRefPubMedCentralGoogle Scholar
  92. Sharma S, Yadav SK, Rana SV, Avti PK, Khanduja KL (2018) Secretory phospholipase A2 isozymes as potential targets in tobacco condensate induced colon pathologies. Life Sci (Accepted)Google Scholar
  93. Shin VY, Wu WK, Ye YN, So WH, Koo MW, Liu ES et al (2004) Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal regulated kinase and cyclooxygenase-2. Carcinogenesis 25(12):2487–2495PubMedCrossRefPubMedCentralGoogle Scholar
  94. Shin EM, Zhou HY, Guo LY et al (2008) Anti-inflammatory effects of glycyrol isolated from Glycyrrhiza uralensis in LPS-stimulated RAW264.7 macrophages. Int Immunopharmacol 8:1524–1532PubMedCrossRefPubMedCentralGoogle Scholar
  95. Shishodia S, Potdar P, Gairola CG, Aggarwal BB (2003) Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 24:1269–1279CrossRefGoogle Scholar
  96. Shou M, Martinet M, Korzekwa KR, Krausz KW, Gonzalez FJ, Gelboin HV (1998) Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics 8:391–401PubMedCrossRefPubMedCentralGoogle Scholar
  97. Slebos DJ, Ryter SW, van der Toorn M, Liu F, Guo F et al (2007) Mitochondrial localization and function of heme oxygenase-1 in cigarette smoke-induced cell death. Am J Respir Cell Mol Biol 36:409–417PubMedCrossRefGoogle Scholar
  98. Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY, Pinkerton KE (2002) Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 33(8):1106–1114PubMedCrossRefPubMedCentralGoogle Scholar
  99. Smith GBJ, Bend JR, Bedard LL, Reid KR, Petsikas D, Massey T (2003) Biotransformation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in peripheral human lung microsomes. Drug Metab Dispos 31:1134–1141PubMedCrossRefPubMedCentralGoogle Scholar
  100. Subar AF, Harlan LC, Mattson ME (1990) Food and nutrient intake differences between smokers and non-smokers in the US. Am J Public Health 80(11):1323–1329PubMedPubMedCentralCrossRefGoogle Scholar
  101. Tithof PK, Elgayyar M, Cho Y, Guan W, Fisher AB (2002) Peters-Golden M. Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism. FASEB J 16(11):1463–1464PubMedCrossRefPubMedCentralGoogle Scholar
  102. Trush MA, Mimnaugh EG, Gram TE (1982) Activation of pharmacologic agents to radical intermediates. Implications for the role of free radicals in drug action and toxicity. Biochem Pharmacol 31:3335–3346CrossRefGoogle Scholar
  103. Ueta E, Suzuki E, Nanba E, Tadokoro Y, Otsuka Y, Kurata T (2001) Regulation of cigarette smoke-induced cytochrome P4501A1 gene expression in osteogenic disorder in shionogi rat liver and in lung by high-dose ascorbic acid dose. Biosci Biotechnol Biochem 65:2548–2551PubMedCrossRefPubMedCentralGoogle Scholar
  104. Vahakangas K, Pelkonen O (1989) Host variations in carcinogen metabolism and DNA repair. In: Lynch HT, Hirayama T (eds) Genetic epidemiology of cancer. CRC Press, Boca Raton, pp 35–54Google Scholar
  105. van der Toorn M, Smit-de Vries MP, Slebos DJ, de Bruin HG, Abello N, van Oosterhout AJ, Bischoff R, Kauffman HF (2007) Cigarette smoke irreversibly modifies glutathione in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 293:L1156–L1162PubMedCrossRefPubMedCentralGoogle Scholar
  106. Villard PH, Seree E, Lacarelle B et al (1994) Effect of cigarette smoke on hepatic and pulmonary cytochromes P450 in mouse: evidence for CYP2E1 induction in lung. Biochem Biophys Res Commun 202:1731–1737PubMedCrossRefPubMedCentralGoogle Scholar
  107. Wang M, Hao FY, Wang JG, Xiao W (2014) Group IIa secretory phospholipase A2 (sPLA2IIa) and progression in patients with lung cancer. Eur Rev Med Pharmacol Sci 18:2648–2654PubMedPubMedCentralGoogle Scholar
  108. Weinstein IB, Jeffrey AM, Jennette KW et al (1976) Benzo(α)pyrene diol epoxides as intermediates in nucleic acid binding in vitro and in vivo. Science 193:592–595PubMedCrossRefPubMedCentralGoogle Scholar
  109. WHO report on the global tobacco epidemic, 2011: Warning about the dangers of tobacco. 2011Google Scholar
  110. Willey JC, Coy EL, Frampton MW et al (1997) Quantitative RT-PCR measurement of cytochromes p450 1A1, 1B1, and 2B7, microsomal epoxide hydrolase, and NADPH oxidoreductase expression in lung cells of smokers and nonsmokers. Am J Respir Cell Mol Biol 17:114–124PubMedCrossRefGoogle Scholar
  111. Yadav SK, Sharma SK, Farooque A, Kaushik G, Kaur B, Pathak CM, Dwarakanath BS, Khanduja KL (2016) Cytosolic phospholipase A2 (cPLA2) IVA as a potential signature molecule in cigarette smoke condensate induced pathologies in alveolar epithelial lineages. Lipids Health Dis 15(1):129PubMedPubMedCentralCrossRefGoogle Scholar
  112. Yamazaki H, Inui Y, Yun CH, Guengerich FP, Shimada T (1992) Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis 13:1789–1794PubMedCrossRefGoogle Scholar
  113. Zugazagoitia J, Puente J, González-Larriba JL et al (2013) Erlotinib versus pemetrexed for pretreated non-squamous non-small cell lung cancer patients in clinical practice. Oncology 84:255–264PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pramod K. Avti
    • 1
  • Krishan L. Khanduja
    • 1
  1. 1.Department of BiophysicsPostgraduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations