Skip to main content
SpringerLink
Log in

Carvacrol modulates instability of xenobiotic metabolizing enzymes and downregulates the expressions of PCNA, MMP-2, and MMP-9 during diethylnitrosamine-induced hepatocarcinogenesis in rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma is the fifth most common malignant tumor in the world, both in terms of incidence and mortality in Asian and Western countries. There are currently limited therapeutic regimens available for effective treatment of this cancer. Carvacrol is a predominant monoterpenoic phenol believed to impede cancer promotion and progression. The present study was conducted to decipher the role of carvacrol during diethylnitrosamine (DEN)-induced hepatocarcinogenesis in male wistar albino rats. Carvacrol (15 mg/kg body weight) suppressed the elevation of serum tumor marker enzymes, carcinoembryonic antigen, and α-feto protein induced by DEN. The activities of phase I enzymes increased markedly during DEN induction, but was found to be significantly lowered upon carvacrol treatment. On the contrary, the phase II enzymes decreased in DEN-administered animals, which was improved normalcy upon carvacrol-treated animals. DEN-administered animals showed increased mast cell counts, argyrophilic nucleolar organizing regions, proliferating cell nuclear antigen, and matrix metalloproteinases (MMPs-2/9), whereas carvacrol supplementation considerably suppressed all the above abnormalities. The results suggest that the carvacrol exhibited the potential anticancer activity by inhibiting cell proliferation and preventing metastasis in DEN-induced hepatocellular carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576

    Article  CAS  PubMed  Google Scholar 

  2. Michael J, John Oliver DeLancey, Melissa M, Jemal Ahmedin, Elizabeth M (2010) The global burden of cancer: priorities for prevention. Carcinogenesis 31:100–110

    Article  Google Scholar 

  3. Loeppky RN (1994) Nitrosamine and Nitroso compound chemistry and biochemistry. ACS Symposium series 553. American Chemical Society, Washington, pp 1–12

  4. Reh BD, Fajen JM (1996) Worker exposures to nitrosamines in a rubber vehicle sealing plant. Am Ind Hyg Assoc J 57:918–923

    Article  CAS  PubMed  Google Scholar 

  5. Verna L, Whysner J, Williams GM (1996) N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharm Ther 71:57–81

    Article  CAS  Google Scholar 

  6. Daisy Glory M, Devaki T (2011) Chrysin attenuates the instability of xenobiotic metabolizing and mitochondrial enzymes during diethyl nitrosamine induced liver carcinoma. J Pharm Res 4(6):1839–1842

    Google Scholar 

  7. Rafter JJ (2002) Scientific basis of biomarkers and benefits of functional foods for reduction of disease risk: cancer. Br J Nutr 88(2):S219–S224

    Article  CAS  PubMed  Google Scholar 

  8. Loo G (2003) Redox-sensitive mechanisms of phytochemical mediated inhibition of cancer cell proliferation. J Nutr Biochem 14:64–73

    Article  CAS  PubMed  Google Scholar 

  9. Arcila-Lozano CC, Loarca-Pina G, Lecona-Uribe S, Gonzalez de Mejia E (2004) Oregano: properties, composition and biological activity. Arch Latinoam Nutr 54:100–111

    CAS  PubMed  Google Scholar 

  10. De Vincenzi M, Stammati A, De Vincenzi A, Silano M (2004) Constituents of aromatic plants: carvacrol. Fitoterapia 75:801–804

    Article  PubMed  Google Scholar 

  11. Ultee A, Slump RA, Steging G, Smid EJ (2000) Antimicrobial activity of carvacrol toward Bacillus cereus on rice. J Food Prot 63:620–624

    CAS  PubMed  Google Scholar 

  12. Dadalioglu I, Evrendilek GA (2004) Chemical compositions and antibacterial effects of essential oils of Turkish oregano (Origanum minutiflorum), bay laurel (Laurus nobilis), Spanish lavender (Lavandula stoechas L.), and fennel (Foeniculum vulgare) on common foodborne pathogens. J Agric Food Chem 52:8255–8260

    Article  CAS  PubMed  Google Scholar 

  13. Alma MH, Mavi A, Yildirim A (2003) Screening chemical composition and in vitro antioxidant and antimicrobial activities of the essential oils from Origanum syriacum L. growing in Turkey. Biol Pharm Bul 26:1725–1729

    Article  CAS  Google Scholar 

  14. Ruberto G, Baratta MT, Deans SG, Dorman HJ (2000) Antioxidant and antimicrobial activity of Foeniculum vulgare and Crithmum maritimum essential oils. Planta Med 66:687–693

    Article  CAS  PubMed  Google Scholar 

  15. Karkabounas S, Sofis G, Evangelou A (1996) Implication of free radicals in platelet aggregation: antiplatelet effects of free radical scavengers ex vivo. Epith Klin Farmacol Farmakokin 10:84–91

    CAS  Google Scholar 

  16. Evangelou A, Kalpouzos G, Karkabounas S (1997) Dose-related preventive and therapeutic effects of antioxidants and anticarcinogens on experimentally induced malignant tumors in wistar rats. Cancer Lett 115:105–111

    Article  CAS  PubMed  Google Scholar 

  17. Arunasree KM (2010) Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine 17:581–588. doi:10.1016/j.phymed.2009.12.008

    Article  CAS  PubMed  Google Scholar 

  18. Koparal AT, Zeytinoglu M (2003) Effects of carvacrol on a human non-small cell lung cancer (NSCLC) cell line, A549. Cytotechnology 43:149–154. doi:10.1023/B:CYTO.0000039917.60348.45

    Article  PubMed Central  PubMed  Google Scholar 

  19. Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, Naveenkumar C, Asokkumar S, Devaki T (2009) Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis. Mol Cell Biochem 331:135–143. doi:10.1007/s11010-009-0151-0

    Article  CAS  PubMed  Google Scholar 

  20. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  21. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification, and properties. J Biol Chem 239:2379–2380

    CAS  PubMed  Google Scholar 

  22. Phillips AH, Langdon RG (1962) Hepatic triphosphopyridine nucleotide-cytochrome c reductase: isolation, characterization, and kinetic studies. J Biol Chem 237:2652–2660

    CAS  PubMed  Google Scholar 

  23. Strittmatter P, Velick SF (1956) A microsomal cytochrome reductase specific for diphosphopyridine nucleotide. J Biol Chem 221:277–286

    CAS  PubMed  Google Scholar 

  24. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  PubMed  Google Scholar 

  25. Bock KW, Burchell B, Dutton GJ (1983) UDP-glucuronosyltransferase activities. Guidelines for consistent interim terminology and assay conditions. Biochem Pharmacol 32:953–955

    Article  CAS  PubMed  Google Scholar 

  26. Macnab GM, Urbanowicz JM, Kew MC (1978) Carcinoembryonic antigen in hepatocellular cancer. Br J Cancer 38:51–54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Sell S, Becker FF (1978) Alpha-Fetoprotein. J Natl Cancer Inst 60:19–26

    CAS  PubMed  Google Scholar 

  28. Aubele M, Biesterfeld S, Derenzini M (1994) Guidelines of AgNOR quantitation. Committee on AgNOR quantitation within the European Society of Pathology. Zentralbl Pathol 140:107–108

    CAS  PubMed  Google Scholar 

  29. Voorzanger-Rousselot N, Garnero P (2007) Biochemical markers in oncology. Part I: molecular basis. Part II: clinical uses. Cancer Treat Rev 33:230–283

    Article  CAS  PubMed  Google Scholar 

  30. Bray F, Sankila R, Ferlay J, Parkin DM (2002) Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer 38:99–166

    Article  CAS  PubMed  Google Scholar 

  31. Shibayama T, Ueoka H, Nishii K (2001) Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small-cell lung cancer (SCLC). Lung Cancer 32:61–69

    Article  CAS  PubMed  Google Scholar 

  32. Zheng H, He BF, Luo RC (2003) Diagnostic value of combined detection of TPS, NSE and CEA in lung cancer. Di Yi Jun Yi Da Xue Xue Bao 23:165–166

    PubMed  Google Scholar 

  33. Esscher T, Steinholtz L, Bergh J (1985) Neurone specific enolase: a useful diagnostic serum marker for small cell carcinoma of the lung. Thorax 40:85–90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Banker DD (2003) Viral hepatitis (Part-IV). Indian J Med Sci 57:511–517

    CAS  PubMed  Google Scholar 

  35. Srinivasan P, Suchalatha S, Babu PV, Devi RS, Narayan S, Sabitha KE, Shyamala Devi CS (2008) Chemopreventive and therapeutic modulation of green tea polyphenols on drug metabolizing enzymes in 4-Nitroquinoline 1-oxide induced oral cancer. Chem Biol Interact 172:224–234. doi:10.1016/j.cbi.2008.01.010

    Article  CAS  PubMed  Google Scholar 

  36. Subapriya R, Velmurugan B, Nagini S (2005) Modulation of xenobiotic-metabolizing enzymes by ethanolic neem leaf extract during hamster buccal pouch carcinogenesis. J Exp Clin Cancer Res 24:223–230

    CAS  PubMed  Google Scholar 

  37. McLellan LI, Wolf CR (1999) Glutathione and glutathione-dependent enzymes in cancer drug resistance. Drug Resist Updat 2:153–164

    Article  CAS  PubMed  Google Scholar 

  38. Hiraku Y, Yamashita N, Nishiguchi M, Kawanishi S (2001) Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation. Int J Cancer 92:333–337

    CAS  PubMed  Google Scholar 

  39. Qin LX, Tang ZY (2002) The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 8:385–392

    CAS  PubMed  Google Scholar 

  40. Lamberti JW, Chapel JL (1977) Development and evaluation of a sex education program for medical students. J Med Educ 52:582–586

    CAS  PubMed  Google Scholar 

  41. Ng IO, Lai EC, Fan ST (1994) Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma. Cancer 73:2268–2274

    Article  CAS  PubMed  Google Scholar 

  42. Chakraborty T, Chatterjee A, Saralaya MG (2006) Vanadium inhibits the development of 2-acetylaminofluorene-induced premalignant phenotype in a two-stage chemical rat hepatocarcinogenesis model. Life Sci 78:2839–2851

    Article  CAS  PubMed  Google Scholar 

  43. Miller OJ, Miller DA, Dev VG (1976) Expression of human and suppression of mouse nucleolus organizer activity in mouse-human somatic cell hybrids. Proc Natl Acad Sci USA 73:4531–4535

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Moreno FJ, Rodrigo RM, Garcia-Herdugo G (1990) AgNOR proteins and rDNA transcriptional activity in plant cells. J Histochem Cytochem 38:1879–1887

    Article  CAS  PubMed  Google Scholar 

  45. Jagan S, Ramakrishnan G, Anandakumar P, Kamaraj S, Devaki T (2008) Antiproliferative potential of gallic acid against diethylnitrosamine-induced rat hepatocellular carcinoma. Mol Cell Biochem 319:51–59. doi:10.1007/s11010-008-9876-4

    Article  CAS  PubMed  Google Scholar 

  46. Ishizaka T, Mitsui H, Yanagida M (1993) Development of human mast cells from their progenitors. Curr Opin Immunol 5:937–943

    Article  CAS  PubMed  Google Scholar 

  47. Francis H, Meininger CJ (2010) A review of mast cells and liver disease: what have we learned? Dig Liver Dis 42:529–536. doi:10.1016/j.dld.2010.02.016

    CAS  PubMed  Google Scholar 

  48. Takanami I, Takeuchi K, Naruke M (2000) Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer 88:2686–2692

    Article  CAS  PubMed  Google Scholar 

  49. Tchougounova E, Lundequist A, Fajardo I (2005) A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 280:9291–9296

    Article  CAS  PubMed  Google Scholar 

  50. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174

    Article  CAS  PubMed  Google Scholar 

  51. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387–2392

    Article  CAS  PubMed  Google Scholar 

  52. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  CAS  PubMed  Google Scholar 

  53. Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270

    Article  CAS  PubMed  Google Scholar 

  54. Rundhaug JE (2003) Matrix metalloproteinases, angiogenesis, and cancer: commentary re: A. C. Lockhart et al., Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin Cancer Res 9:551–554

    PubMed  Google Scholar 

Download references

Acknowledgments

Author Jayakumar. S wishes to thank Indian Council of Medical Research (ICMR), New Delhi, India, for the financial assistance in the form of Senior Research Fellowship (SRF), File No. 45/55/2011/PHA-BMS.

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, Tamilnadu, India

    Jayakumar Subramaniyan, Gokuladhas Krishnan, Rajan Balan, Divya MGJ, Elamaran Ramasamy, Premkumar Thandavamoorthy, Gopi Krishnan Mani & Devaki Thiruvengadam

  2. Centre for Nanoscience and Technology, Anna University, Chennai, 600 025, Tamilnadu, India

    Shenbhagaraman Ramalingam

  3. Department of Medical Biotechnology, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, 603103, Tamilnadu, India

    Ramakrishnan Veerabathiran

Authors
  1. Jayakumar Subramaniyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gokuladhas Krishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajan Balan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Divya MGJ
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elamaran Ramasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shenbhagaraman Ramalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ramakrishnan Veerabathiran
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Premkumar Thandavamoorthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gopi Krishnan Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Devaki Thiruvengadam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Devaki Thiruvengadam.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Subramaniyan, J., Krishnan, G., Balan, R. et al. Carvacrol modulates instability of xenobiotic metabolizing enzymes and downregulates the expressions of PCNA, MMP-2, and MMP-9 during diethylnitrosamine-induced hepatocarcinogenesis in rats. Mol Cell Biochem 395, 65–76 (2014). https://doi.org/10.1007/s11010-014-2112-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2112-5

Keywords

Search

Navigation