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Alteration of benzo(a)pyrene biotransformation by resveratrol in ApcMin/+ mouse model of colon carcinogenesis

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Summary

Epidemiological surveys have revealed that environmental and dietary factors contribute to most of the human cancers. Our earlier studies have shown that resveratrol (RVT), a phytochemical reduced the tumor number, size and incidence of dysplasias induced by benzo(a)pyrene (BaP), an environmental toxicant in the ApcMin/+ mouse model of colon cancer. In this study we investigated to ascertain whether the preventive effects of RVT on BaP-induced colon carcinogenesis is a result of altered BaP biotransformation by RVT. For the first group of mice, 100 μg BaP/kg bw was administered in peanut oil via oral gavage over a 60 day period. For the second group, 45 μg RVT/kg bw was co-administered with BaP. For the third group, RVT was administered for 1 week prior to BaP exposure. Blood, colon and liver were collected from control and BaP/RVT-treated mice at 60 days post-BaP & RVT exposure. We have assayed activities and expression (protein & mRNA) of drug metabolizing enzymes such as cytochrome P4501A1 (CYP1A1), CYP1B1, and glutathione-S-transferase (GST) in colon and liver samples from the treatment groups mentioned above. An increased expression of CYP1A1 in liver and colon and of CYP1B1 in liver of BaP-treated mice was seen, while RVT inhibited the extent of biotransformation mediated by these enzymes in the respective tissue samples. In the case of GST, an increased expression in colon of BaP alone-treated mice was noted when RVT was administered prior to BaP or simultaneously with BaP. However, there is no change in liver GST expression between BaP and RVT treatment groups. The concentrations of BaP aqueous (phase II) metabolites were found to be greater than the organic (phase I) metabolites, suggesting that RVT slows down the phase I metabolism (metabolic activation) of BaP, while enhancing phase II metabolism (detoxification). Additionally, the BaP-DNA adduct concentrations measured in colon and liver of BaP + RVT-treated mice were low relative to their BaP counterparts. Taken together, our findings strongly suggest that RVT alleviates BaP-induced colon carcinogenesis by impairing biotransformation pathways and DNA adduct formation, and therefore holds promise as a chemopreventive agent.

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References

  1. Harris DL, Washington MK, Hood DB, Roberts LJ II, Ramesh A (2009) Dietary fat-influenced development of colon neoplasia in ApcMin/+ mouse exposed to benzo(a)pyrene. Toxicol Pathol 37:938–946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Diggs DL, Huderson AC, Harris KL, Myers JN, Banks LD, Rekhadevi PV, Niaz MS, Ramesh A (2011) Polycyclic aromatic hydrocarbons and digestive tract cancers: a perspective. Environ Sci Health C Environ Carcinog Ecotoxicol Rev 29:1–34

    Article  CAS  Google Scholar 

  3. Sonoda J, Seki Y, Hakura A, Hosokawa S (2015) Time course of the incidence/multiplicity and histopathological features of murine colonic dysplasia, adenoma and adenocarcinoma induced by benzo[a]pyrene and dextran sulfate sodium. J Toxicol Pathol 28:109–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res 2:409–418

    Article  CAS  Google Scholar 

  5. Banks LD, Amoah P, Niaz MS, Washington MK, Adunyah SE, Ramesh A (2016) Olive oil prevents benzo(a)pyrene [BaP]-induced colon carcinogenesis through altered BaP metabolism and decreased oxidative damage in Apc(min) mouse model. J Nutr Biochem 28:37–50

    Article  CAS  PubMed  Google Scholar 

  6. Li W, Guo Y, Zhang C, Wu R, Yang AY, Gaspar J, Kong AN (2016) Dietary phytochemicals and cancer chemoprevention: a perspective on oxidative stress, inflammation, and epigenetics. Chem Res Toxicol 29:2071–2095

    Article  CAS  PubMed  Google Scholar 

  7. Morris J, Fang Y, De Mukhopdhyay K, Wargovich MJ (2016) Natural agents used in chemoprevention of aerodigestive and GI cancers. Curr Pharmacol Rep 2:11–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Reddivari L, Charepalli V, Radhakrishnan S, Vadde R, Elias RJ, Lambert JD, Vanamala JK (2016) Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. BMC Complement Altern Med 16:278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Omidian K, Rafiei H, Bandy B (2017) Polyphenol inhibition of benzo[a]pyrene-induced oxidative stress and neoplastic transformation in an in vitro model of carcinogenesis. Food Chem Toxicol 106(Pt A) 106:165–174

    Article  CAS  Google Scholar 

  10. Pezzuto J (2008) Resveratrol as an inhibitor of carcinogenesis. Pharm Biol 46:443–573

    Article  CAS  Google Scholar 

  11. Chung MY, Lim TG, Lee KW (2013) Molecular mechanisms of chemopreventive phytochemicals against gastroenterological cancer development. World J Gastroenterol 19:984–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Carter LG, D'Orazio JA, Pearson KJ (2014) Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer 21:R209–R225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mazué F, Delmas D, Murillo G, Saleiro D, Limagne E, Latruffe N (2014) Differential protective effects of red wine polyphenol extracts (RWEs) on colon carcinogenesis. Food Funct 5:663–670

    Article  CAS  PubMed  Google Scholar 

  14. Huderson AC, Myers JN, Niaz MS, Washington MK, Ramesh A (2013) Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin/+ mice by resveratrol. J Nutr Biochem 24:713–724

    Article  CAS  PubMed  Google Scholar 

  15. Yates MS, Kensler TW (2011) Detoxication of chemical carcinogens and chemoprevention. In: Penning TM (ed) Chemical carcinogenesis. Springer, New York, pp 159–180

    Chapter  Google Scholar 

  16. Wu TY, Khor TO, Lee JH, Cheung KL, Shu L, Chen C, Kong AN (2013) Pharmacogenetics, pharmacogenomics and epigenetics of Nrf2-regulated xenobiotic-metabolizing enzymes and transporters by dietary phytochemical and cancer chemoprevention. Curr Drug Metab 14:688–694

    Article  CAS  PubMed  Google Scholar 

  17. Abel EL, DiGiovanni J (2015) Environmental carcinogenesis. In: Mendelsohn J, Gray JW, Howley PM, Israel MA, Thompson CB (eds) The Molecular Basis of Cancer. Elsevier Publishers, Philadelphia, pp 103–128

    Google Scholar 

  18. NIH guidelines for the laboratory use of chemical carcinogens. U.S. Government Printing Office; Washington, DC: 1981. NIH publication no. 81–2385

  19. Ramesh A, Inyang F, Hood DB, Archibong AE, Knuckles ME, Nyanda AM (2001) Metabolism, bioavailability, and toxicokinetics of benzo(alpha)pyrene in F-344 rats following oral administration. Exp Toxic Pathol 53:275–290

    Article  CAS  Google Scholar 

  20. Ramesh A, Inyang F, Knuckles ME (2004) Modulation of adult rat benzo(a)pyrene (BaP) metabolism and DNA adduct formation by neonatal diethylstilbestrol (DES) exposure. Exp Toxic Pathol 56:129–138

    Article  CAS  Google Scholar 

  21. Katsagonis A, Atta-Politou J, Koupparis MA (2005) HPLC method with UV detection for the determination of trans-resveratrol in plasma. J Liq Chromatogr Relat Technol 28:1393–1405

    Article  CAS  Google Scholar 

  22. Wenzel E, Soldo T, Erbersdobler H, Somoza V (2005) Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res 49:482–494

    Article  CAS  PubMed  Google Scholar 

  23. Baggot JD (2001) Pharmacokinetic terms: symbols and units. J Vet Pharmacol Ther 24:81–82

    Article  CAS  PubMed  Google Scholar 

  24. Gupta RC, Randerath K (1988) Analysis of DNA adducts by 32P labeling and thin layer chromatography. In: Friedberg EC, Hanawalt PC (eds) DNA repair. Vol. 3. Marcel Dekker, Inc, New York, pp 399–418

    Google Scholar 

  25. Ramesh A, Knuckles ME (2006) Dose-dependent benzo(a)pyrene [BaP]-DNA adduct levels and persistence in F-344 rats following subchronic dietary exposure to BaP. Cancer Lett 240:268–278

    Article  CAS  PubMed  Google Scholar 

  26. Kundu JK, Surh Y-J (2008) Cancer chemo-preventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett 269:243–261

    Article  CAS  PubMed  Google Scholar 

  27. Halberg RB, Larsen MC, Elmergreen TL, Ko AY, Irving AA, Clipson L, Jefcoate CR (2008) Cyp1b1 exerts opposing effects on intestinal tumorigenesis via exogenous and endogenous substrates. Cancer Res 68:7394–7402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baur J, Sinclair D (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506

    Article  CAS  PubMed  Google Scholar 

  29. Andrieux L, Langouet S, Fautrel A, Ezan F, Krauser J, Savouret J, Guengerich F, Baffet G, Guillouzo A (2004) Aryl hydrocarbon receptor activation and cytochrome P450 1A induction by the mitogen-activated protein kinase inhibitor U0126 in hepatocytes. Mol Pharmacol 65:934–943

    Article  CAS  PubMed  Google Scholar 

  30. Kang J, Park Y, Choi S, Yang E, Lee W (2003) Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells. Exp Mol Med 35:467–474

    Article  CAS  PubMed  Google Scholar 

  31. Ciolino H, Daschner P, Yeh G (1998) Resveratrol inhibits transcription of CYP1A1 in Vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res 58:5707–5712

    CAS  PubMed  Google Scholar 

  32. Ciolino H, Yeh G (1999) Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. Mol Pharmacol 56:760–767

    CAS  PubMed  Google Scholar 

  33. Berge G, Øvrebø S, Eilertsen E, Haugen A, Mollerup S (2004b) Analysis of resveratrol as a lung cancer chemopreventive agent in a/J mice exposed to benzo[a]pyrene. Br J Cancer 91:1380–1383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Coumoul X, Diry M, Robillot C, Barouki R (2001) Differential regulation of cytochrome P450 1A1 and 1B1 by a combination of dioxin and pesticides in the breast tumor cell line MCF-7. Cancer Res 61:3942–3948

    CAS  PubMed  Google Scholar 

  35. Tsuji PA, Walle T (2006) Inhibition of benzo[a]pyrene-activating enzymes and DNA binding in human bronchial epithelial BEAS-2B cells by methoxylated flavonoids. Carcinogenesis 27:1579–1585

    Article  CAS  PubMed  Google Scholar 

  36. Berge G, Øvrebø S, Botnen IV, Hewer A, Phillips DH, Haugen A, Mollerup S (2004) Resveratrol inhibits benzo[a]pyrene-DNA adduct formation in human bronchial epithelial cells. Br J Cancer 91:333–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Beedanagari S, Bebenek I, Bui P, Hankinson O (2009) Resveratrol inhibits dioxin-induced expression of human CYP1A1 and CYP1B1 by inhibitng recruitment of the aryl hydrocarbon receptor and complex and RNA polymerase II to the regulatory regions of the corresponding genes. Toxicol Sci 110:61–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hack CJ (2004) Integrated transcriptome and proteome data: the challenges ahead. Brief Funct Genomic Proteomic 3:212–219

    Article  CAS  PubMed  Google Scholar 

  39. Cox B, Kislinger T, Emili A (2005) Integrating gene and protein expression data: pattern analysis and profile mining. Methods 35:303–314

    Article  CAS  PubMed  Google Scholar 

  40. Guo Y, Xiao P, Lei S, Deng F, Xiao GG, Liu Y, Chen X, Li L, Wu S, Chen Y, Jiang H, Tan L, Xie J, Zhu X, Liang S, Deng H (2008) How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin Shanghai 40:426–436

    Article  CAS  PubMed  Google Scholar 

  41. Hoensch H, Morgenstern I, Petereit G, Siepmann M, Peters WH, Roelofs HM, Kirch W (2002) Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system. Gut 50(2):235–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR (1998) Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc Natl Acad Sci US A 95(9):5275–5280

    Article  CAS  Google Scholar 

  43. Talalay P, Fahey W, Holtzclaw D, Prestera T, Zhang Y (1995) Chemoprevention against cancer by phase 2 enzyme induction. Toxic Lett 82(83):173–179

    Article  Google Scholar 

  44. Hebbar V, Shen G, Hu R, Kim B, Chen C, Korytko P, Crowell J, Levine B, Kong A (2005) Toxicogenomics of resveratrol in rat liver. Life Sci 76:2299–2314

    Article  CAS  PubMed  Google Scholar 

  45. Vitrac X, Desmoulière A, Brouillaud B, Krisa S, Deffieux G, Barthe N, Rosenbaum J, Mérillon JM (2003) Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci 72:2219–2233

    Article  CAS  PubMed  Google Scholar 

  46. Sale S, Tunstall R, Ruparelia K, Potter G, Steward W, Gescher A (2005) Comparison of the effects of the chemo-preventive agent resveratrol and its synthetic analog trans 3,4,5,4-tetramethoxystilbene (DMU-212) on adenoma development in the ApcMin/++ mouse and cyclooxygenase-2 in human derived colon cancer cells. Int J Cancer 115:194–201

    Article  CAS  PubMed  Google Scholar 

  47. Andlauer W, Kolb J, Siebert K, Fürst P (2000) Assessment of resveratrol bioavailability in the perfused small intestine of the rat. Drugs Exp Clin Res 26:47–55

    CAS  PubMed  Google Scholar 

  48. Soleas GJ, Angelini M, Grass L, Diamandis EP, Goldberg DM (2001) Absorption of trans-resveratrol in rats. Methods Enzymol 335:145–154

    Article  CAS  PubMed  Google Scholar 

  49. Azorín-Ortuño M, Yáñez-Gascón MJ, Vallejo F, Pallarés FJ, Larrosa M, Lucas R, Morales JC, Tomás-Barberán FA, García-Conesa MT, Espín JC (2011) Metabolites and tissue distribution of resveratrol in the pig. Mol Nutr Food Res 55:1154–1168

    Article  CAS  PubMed  Google Scholar 

  50. Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD, Vasilinin G, Sen A, Schinas AM, Piccirilli G, Brown K, Steward WP, Gescher AJ, Brenner DE (2010) Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res 70:9003–9011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. la Porte C, Voduc N, Zhang G, Seguin I, Tardiff D, Singhal N, Cameron DW (2010) Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet 49:449–454

    Article  PubMed  Google Scholar 

  52. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214

    Article  CAS  PubMed  Google Scholar 

  53. Delmas D, Lançon A, Colin D, Jannin B, Latruffe N (2006) Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 7:423–442

    Article  CAS  PubMed  Google Scholar 

  54. Gatz SA, Wiesmüller L (2008) Take a break--resveratrol in action on DNA. Carcinogenesis 29:321–332

    Article  CAS  PubMed  Google Scholar 

  55. Revel A, Raanani H, Younglai E, Xu J, Rogers I, Han R, Savouret JF, Casper RF (2003) Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. J Appl Toxicol 23:255–261

    Article  CAS  PubMed  Google Scholar 

  56. Diggs DL, Myers JN, Banks LD, Niaz MS, Hood DB, Roberts LJ 2nd, Ramesh A (2013) Influence of dietary fat type on benzo(a)pyrene [BaP] biotransformation in a BaP-induced mouse model of colon cancer. J Nutr Biochem 24(12):2051–2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ramesh A, Archibong AE, Niaz MS (2010) Ovarian susceptibility to benzo[a]pyrene: tissue burden of metabolites and DNA adducts in F-344 rats. J Toxicol Environ Health A 73(23):1611–1625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ross J, Nelson G, Kligerman A, Erexson G, Bryant M, Earley K, Gupta RC, Nesnow S (1990) Formation and persistence of novel benzo(a)pyrene adducts in rat lung, liver, and peripheral blood lymphocyte DNA. Cancer Res 50:5088–5094

    CAS  PubMed  Google Scholar 

  59. Arif JM, Shappell N, Sikka HC, Kumar S, Gupta RC (1999) 32P-postlabeling analysis of lipophilic DNA adducts resulting from interaction with (+/−)-3-hydroxy-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Chem Biol Interact 118:87–97

    Article  CAS  PubMed  Google Scholar 

  60. Stoner GD, Morse MA, Kelloff GJ (1997) Perspectives in cancer chemoprevention. Environ Health Perspect 105(Suppl 4):945–954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ndiaye M, Kumar R, Ahmad N (2011) Resveratrol in cancer management: where are we and where we go from here? Ann N Y Acad Sci 1215:144–149

    Article  CAS  PubMed  Google Scholar 

  62. Hecht SS, Kenney PM, Wang M, Trushin N, Agarwal S, Rao AV, Upadhyaya P (1999) Evaluation of besylated hydroxyanisole myoinositol, cerceumin, esculation, resveratrol and lycopene as inhibitors of benzo(a)pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-bentanone- induced lung tumorigenesis in a/J mice. Cancer Lett 137:123–130

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Financial support of this study by the National Institutes of Health (NIH) is gratefully appreciated. The authors would like to thank Drs. LaMonica Stewart, Anthony Archibong, and Deacqunita Diggs for helpful suggestions.

Funding

Research reported in this publication was supported by NIH grants 1F31ES019432-01A1 (ACH), 5R01CA142845–04 (AR), 5T32HL007735–12 (ACH, SEA), 5 U54CA163069–04 (SEA, AR), 5U54MD007593–07 (SEA, AR), and 5R25GM059994–13 (ACH), and G12RR003022 (AR, SEA). The content is solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. The American Society of Mechanical Engineers, 1828 L St. N.W, Washington, DC, 20036, USA

    Ashley C. Huderson

  2. Toxicology and Pharmacology Unit, Biology Division, Indian Institute of Chemical Technology, Hyderabad, Telangana, 500007, India

    P. V. Rekha Devi

  3. Department of Biochemistry, Cancer Biology, Neuroscience & Pharmacology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN, 37208, USA

    Mohammad S. Niaz, Samuel E. Adunyah & Aramandla Ramesh

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  1. Ashley C. Huderson
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Contributions

ACH and AR designed the study and applied for Institutional Animal Care & Use Committee approval. ACH, PVR, MSN and AR performed the experiments and collected the data. ACH, PVR and AR analyzed the data and prepared draft figures and tables. ACH, PVR and AR prepared the manuscript draft with intellectual input from SEA. All authors approved the final manuscript.

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Correspondence to Aramandla Ramesh.

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Ashley Huderson declares that she has no conflict of interest. P.V. Rekhadevi declares that she has no conflict of interest. Mohammad Niaz declares that he has no conflict of interest. Samuel Adunyah declares that he has no conflict of interest. Aramandla Ramesh declares that he has no conflict of interest.

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This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Huderson, A.C., Rekha Devi, P.V., Niaz, M.S. et al. Alteration of benzo(a)pyrene biotransformation by resveratrol in ApcMin/+ mouse model of colon carcinogenesis. Invest New Drugs 37, 238–251 (2019). https://doi.org/10.1007/s10637-018-0622-9

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