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Journal of Complementary and Integrative Medicine

Editor-in-Chief: Lui, Edmund

Ed. by Ko, Robert / Leung, Kelvin Sze-Yin / Saunders, Paul / Suntres, PH. D., Zacharias

CiteScore 2017: 1.41

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Attenuation of genotoxicity, oxidative stress, apoptosis and inflammation by rutin in benzo(a)pyrene exposed lungs of mice: plausible role of NF-κB, TNF-α and Bcl-2

Ayaz Shahid
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
  • Other articles by this author:
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/ Rashid Ali
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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/ Nemat Ali
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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/ Syed Kazim Hasan
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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/ Summya Rashid
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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/ Ferial Majed
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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/ Sarwat Sultana
  • Corresponding author
  • Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India
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Published Online: 2016-02-02 | DOI: https://doi.org/10.1515/jcim-2015-0078


Background: Benzo(a)pyrene [B(a)P] is an environmental contaminant and potential carcinogenic agent that causes lung injuries which leads to lung cancer. Rutin, a well-known flavonoid present in various natural sources, possesses biological activities such as anti-oxidative and anti-inflammatory properties. The aim of this study was to evaluate the protective effects of rutin against B(a)P-induced genotoxicity, oxidative stress, apoptosis and inflammation in Swiss albino mice.

Methods: Pretreatment of rutin was given by oral gavage at doses of 40 and 80 mg/kg body weight (b.wt.) for 7 days before the administration of a single oral dose of B(a)P (125 mg/kg b.wt.). The ameliorative effect of rutin on oxidative stress, apoptotic and inflammatory markers in lung tissues and genotoxicity was studied using an alkaline unwinding assay and DNA fragmentation.

Results: B(a)P enhanced lipid peroxidation, xanthine oxidase, H2O2 generation and lactate dehydrogenase (LDH) activity; depleted activities of anti-oxidant enzymes and glutathione content; induced DNA strand breaks and fragmentation; disrupted normal histopathological architecture and also showed abnormal expression of NF-κB, COX-2, IL-6, TNF-α and Bcl-2. Rutin pretreatment caused a significant reduction in lipid peroxidation and LDH activity; increased glutathione content; restored antioxidant enzyme activity; reduced DNA strand breaks and fragmentation; modulated the expression of inflammatory, and apoptotic markers and restored the histopathological structure.

Conclusions: The findings of the present study supported the protective effect of rutin against B(a)P-induced lung toxicity and genotoxicity.

Keywords: benzo(a)pyrene; genotoxicity; histopathology; inflammation; rutin


  • 1. Piccardo MT, Stella A, Valerio F. Is the smokers exposure to environmental tobacco smoke negligible? Environ Health 2010;29:5.Google Scholar

  • 2. Yeo CD, Kim JW, Ha JH, Kim SJ, Lee SH, Kim IK, et al. Chemopreventive effect of phosphodieasterase-4 inhibition in benzo(a)pyrene-induced murine lung cancer model. Exp Lung Res 2014;40:500–6.Google Scholar

  • 3. Jahangir T, Sultana S. Benzo(a)pyrene induced genotoxicity: attenuation by farnesol in a mouse model. J Enzyme Inhib Med Chem 2008;23:888–94.Google Scholar

  • 4. Miller KP, Ramos KS. Impact of cellular metabolism on the biological effects of benzo[a]pyrene and related hydrocarbons. Drug Metab Rev 2001;33:1–35.Google Scholar

  • 5. Denissenko MF, Pao A, Tang MS, Pfeifer GP. Preferential formation of benzo(a)pyrene adducts at lung cancer mutational hotspots in p53. Science 1996;274:430–32.Google Scholar

  • 6. Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD. COPD prevalence increases in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009;34:380–6.Google Scholar

  • 7. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997;155:242–48.Google Scholar

  • 8. Qamar W, Khan AQ, Khan R, Lateef A, Tahir M, Rehman MU, et al. Benzo(a)pyrene-induced pulmonary inflammation, edema, surfactant dysfunction, and injuries in rats: alleviation by farnesol. Exp Lung Res 2012;38:19–27.Google Scholar

  • 9. Tanaka T, Kohno H, Mori H. Chemoprevention of colon carcinogenesis by dietary non-nutritive compounds. Asian Pac J Cancer Prev 2001;2:165–77.Google Scholar

  • 10. Yang K, Lamprecht SA, Liu Y, Fan K, Leung D, Newmark H, et al. Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon. Carcinogenesis 2000;21:1655–60.Google Scholar

  • 11. Nafees S, Rashid S, Ali N, Hasan SK, Sultana S. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact 2015;25:98–107.Google Scholar

  • 12. Ghiasi M, Heravi MM. Quantum mechanical study of antioxidative ability and antioxidative mechanism of rutin (vitamin P) in solution. Carbohydr Res 2011;346:739–44.Google Scholar

  • 13. Lin CF, Leu YL, Al-Suwayeh SA, Ku MC, Hwang TL, Fang JY. Anti-inflammatory activity and percutaneous absorption of quercetin and its polymethoxylated compound and glycosides: the relationships of chemical structures. Eur J Pharm Sci 2012;47:47.Google Scholar

  • 14. Wang SW, Wang YJ, Su YJ, Zhou WW, Yang SG, Zhang R, et al. Rutin inhibits beta-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. Neurotoxicology 2012;33:482–90.Google Scholar

  • 15. Lapa FR, Soares KC, Rattmann YD, Crestani S, Missau FC, Pizzolatti MG, et al. Vasorelaxant and hypotensive effects of the extract and the isolated flavonoid rutin obtained from Polygala paniculata L. J Pharm Pharm 2011;63:875–81.Google Scholar

  • 16. Tsurunaga Y, Takahashi T, Katsube T, Kudo A, Kuramitsu O, Ishiwata M, et al. Effects of UV-B irradiation on the levels of anthocyanin, rutin and radical scavenging activity of buckwheat sprouts. Food Chem 2013;141:552–6.Google Scholar

  • 17. Mahmoud AM. Influence of rutin on biochemical alterations in hyperammonemia in rats. Exp Toxicol Pathol 2012;64:783–9.Google Scholar

  • 18. Tongjaroenbuangam W, Ruksee N, Chantiratikul P, Pakdeenarong N, Kongbuntad W, Govitrapong P. Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice. NeuroChem Int 2011;59:677–85.Google Scholar

  • 19. Arjumand W, Seth A, Sultana S. Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NF-κB, TNF-α and caspase-3 expression in Wistar rats. Food Chem Toxicol 2011;49:2013–21.Google Scholar

  • 20. Janbaz KH, Saeed SA, Gilani AH. Protective effect of rutin on paracetamol and CCl4-induced hepatotoxicity in rodents. Fitoterapia 2002;73:557–63.Google Scholar

  • 21. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation and cancer: how are they linked? Free Radic Biol Med 2010;49:1603–16.Google Scholar

  • 22. Luedde T, Schwabe RF. NF-kB in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011;8:108–18.Google Scholar

  • 23. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: downregulation of COX-2 and iNOS through suppression of NF-kB activation. Mutat Res 2001;480–1:243–68.Google Scholar

  • 24. Posadas I, Santos P, Ceña V. Acetaminophen induces human neuroblastoma cell death through NF-kB activation. PLoS One 2012;7:e50160.Google Scholar

  • 25. Carthy CM, Yanagawa B, Luo H, Granville DJ, Yang D, Cheung P, et al. Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection. Virology 2003;313:147–57.Google Scholar

  • 26. Hacker G, Weber A. BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys 2007;462:150–5.Google Scholar

  • 27. Ashraf J, Nagma JS, Nagma M, Mirani N, Rub A. Protective effect of rutin against carbon tetrachloride-induced hepatotoxicity in mice. Int J Drug Dev Res 2012;4(2):352–357.Google Scholar

  • 28. Sehgal A, Kumar M, Jain M, Dhawan DK. Combined effects of curcumin and piperine in ameliorating benzo(a)pyrene induced DNA damage. Food Chem Toxicol 2011;49:3002–6.Google Scholar

  • 29. Ahmad ST, Sultana SH. Tannic acid mitigates cisplatin-induced nephrotoxicity in mice. J Hum Exp Toxicol 2011;31(2):145–56.Google Scholar

  • 30. Shugart LR. Quantitation of chemically induced damage to DNA of aquatic organisms by alkaline unwinding assay. Aquat Toxicol 1988;13:43–52.Google Scholar

  • 31. Sarkar A, Gaitonde DC, Sarkar A, Vashistha D, D’Silva C, Dalal SG. DNA alkaline unwinding assay for monitoring the impact of environmental genotoxins. Environ Toxicol Water Qual 1996;11:351–4.Google Scholar

  • 32. Tahir M, Sultana S. Chrysin modulates ethanol metabolism in Wistar rats: a promising role against organ toxicities. Alcohol 2011;46:383–92.Google Scholar

  • 33. Wright JR. Cytosolic factors which affect microsomal lipid peroxidation in lung and lung. Arch Biochem Biophys 1981;206:296–304.Google Scholar

  • 34. Kornberg A. Methods in enzymology, New York: Academic Press, 1955.Google Scholar

  • 35. Carlberg I, Mannervik B. Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 1975;250:5475–80.Google Scholar

  • 36. Stirpe F, Della CE. The regulation of rat liver xanthine oxidase. Conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O). J Biol Chem 1969;244:3855–63.Google Scholar

  • 37. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974;47:469–74.Google Scholar

  • 38. Benson AM, Hunkeler MJ, Talalay P. Increase of NAD(P)H quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci 1980;77:5216–20.Google Scholar

  • 39. Habig WH, Pabst MJ, Jakoby WB. Glutathione-S- transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974;249:7130–9.Google Scholar

  • 40. Athar M, Sharma SD, Iqbal M, Sultana S, Pandeya KB, Tripathi IP. Coordination of copperpolyamine complex with imidazoles potentates, its superoxide dismutase mimicking activity and abolishes its interaction with albumin. Biochem Mol Biol Int 1996;39:813–21.Google Scholar

  • 41. Zaheer N, Tewari KK, Krishnan PS. Exposure and solubilization of hepatic mitochondrial shunt dehydrogenases. Arch Biochem Biophys 1965;109:646–8.Google Scholar

  • 42. Claiborne, A. Catalase activity: CRC handbook of methods in oxygen radical research, Boca Raton: CRC Press, 1975:283–4.Google Scholar

  • 43. Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ. Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer. Cancer Res 1984;44:5086–91.Google Scholar

  • 44. Athar M, Iqbal M. Ferric nitrilotriacetate promotes N-diethylnitrosamine-induced renal tumorigenesis in the rat: implications for the involvement of oxidative stress. Carcinogenesis 1998;19:1133–9.Google Scholar

  • 45. Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene-induced lung necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 1974;11:151–69.Google Scholar

  • 46. Pick A, Keisari Y. Superoxide anion and H2O2 production by chemically elicited peritoneal macrophages – induction of multiple non-phagocytic stimuli. Cell Immunol 1981;59:301–8.Google Scholar

  • 47. Lowry OH, Nira JR, Lewis F, Rose JR. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–75.Google Scholar

  • 48. Steward WP, Brown K. Cancer chemoprevention: a rapidly evolving field. Br J Cancer 2013;109:1–7.Google Scholar

  • 49. Bilecová-R M, Birková A, Urban P, Gregová K, Durovcová E, Mareková M. Naturally occurring substances and their role in chemo-protective effects. Cent Eur J Public Health 2013;21:213–19.Google Scholar

  • 50. Ching SL, Min HP. Mechanism for possible chemopreventive effects of natural dietary compounds on smoking-induced tumorigenesis. J Exp Clin Med 2011;3:262–71.Google Scholar

  • 51. MacLeod MC, Daylong A, Adair G, Humphrey RM. Differences in the rate of DNA adduct removal and the efficiency of mutagenesis for two benzo(a)pyrene diol epoxides in CHO cells. Mutat Res 1991;261:267–79.Google Scholar

  • 52. Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis 2008;29:1022–32.Google Scholar

  • 53. Alvarez-Gonzalez I, Mojica R, Madrigal-Bujaidar E, Camacho-Carranza R, Escobar-García D, Espinosa-Aguirre JJ. The antigenotoxic effects of grapefruit juice on the damage induced by benzo(a)pyrene and evaluation of its interaction with hepatic and intestinal cytochrome P450 (Cyp) 1a1. Food Chem Toxicol 2011;49:807–11.Google Scholar

  • 54. Khan TH, Prasad L, Anuradha SS. Soy isoflavones inhibits the genotoxicity of benzo(a)pyrene in Swiss albino mice. Hum Exp Toxicol 2005;24:149, 155.Google Scholar

  • 55. Zhang YB, Zhong ZM, Hou G, Jiang H, Chen JT. Involvement of oxidative stress in age-related bone loss. J Surg Res 2011;169:e37–e42.Google Scholar

  • 56. Rath E, Haller D. Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies. Eur J Nutr 2011;50:219–33.Google Scholar

  • 57. Drummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 2011;10:453–71.Google Scholar

  • 58. Beal MF. Oxidatively modified proteins in aging and disease. Free Radic Biol Med 2002;32:797–803.Google Scholar

  • 59. Ravi T, Mahima B, Deepti P, Kanchan K, Reena N, Khanna HD. Oxidative stress induced lipid peroxidation and DNA adduct formation in the pathogenesis of multiple myeloma and lymphoma. J Stress Physiol Biochem 2013;9:106–12.Google Scholar

  • 60. Seven A, Civelek S, Inci E, Inci F, Korkut N, Burçak G. Evaluation of oxidative stress parameters in blood of patients with laryngeal carcinoma. Clin Biochem 1999;32:369–73.Google Scholar

  • 61. Mukai FH, Goldstein BD. Mutagenicity of malonaldehyde, a decomposition product of peroxidized polyunsaturated fatty acids. Science 1976;191:868–9.Google Scholar

  • 62. Heunks LM, Dekhuijzen PN. Respiratory muscle functions and free radicals, from cell to COPD. Thorax 2000;55:704–16.Google Scholar

  • 63. Kawanishi S, Yamamoto K. Mechanism of site-specific DNA damage induced by methylhydrazines in the presence of copper (II) or manganese (III). Biochemistry 1991;30:3069–75.Google Scholar

  • 64. Wang W, Ballatori N. Endogenous glutathione conjugates, occurrence and biological functions. Pharmacol Rev 1998;50:335–56.Google Scholar

  • 65. Alhouayek M, Muccioli GG. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 2014;35:6.Google Scholar

  • 66. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480–481:243–68.Google Scholar

  • 67. Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Asokkumar S, Naveenkumar C, et al. Capsaicin inhibits benzo(a)pyrene induced lung carcinogenesis in an in vivo mouse model. Inflamm Res 2012;61:1169–75.Google Scholar

  • 68. Kwon KH, Murakami A, Tanaka T, Ohigashi H. Dietary rutin, but not its aglyconequercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: attenuation of pro-inflammatory gene expression. Biochem Pharmacol 2005; 169:395–406.Google Scholar

  • 69. Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990;348:334–36.Google Scholar

  • 70. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322–26.Google Scholar

  • 71. Ashkenazi A, Dixit VM. Death receptors: signalling and modulation. Science 1998;281:1305–8.Google Scholar

  • 72. Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 1998;8:324–30.Google Scholar

About the article

Received: 2015-09-18

Accepted: 2015-10-29

Published Online: 2016-02-02

Published in Print: 2016-03-01

Citation Information: Journal of Complementary and Integrative Medicine, Volume 13, Issue 1, Pages 17–29, ISSN (Online) 1553-3840, ISSN (Print) 2194-6329, DOI: https://doi.org/10.1515/jcim-2015-0078.

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