Skip to main content
Log in

Resveratrol inhibits dimethylnitrosamine-induced hepatic fibrosis in rats

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Resveratrol, a phytoalexin found in grapes and red wines, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of resveratrol on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Oral administration of resveratrol (20 mg/kg daily for 4 weeks) remarkably prevented the DMN-induced loss in body and liver weight, and inhibited the elevation of serum alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin levels. Resveratrol also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde due to its antioxidant effect. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the resveratrol treated rats, the result of which was consistent with the reduction in type I collagen mRNA expression and the histological analysis of liver tissue stained with Sirius red. The reduction in hepatic stellate cell activation, as assessed by α-smooth muscle actin staining, and the reduction in transforming growth factor-β1 mRNA expression were associated with resveratrol treatment. In conclusion, resveratrol exhibited in vivo hepatoprotective and antifibrogenic effects against DMN-induced liver injury, suggesting that resveratrol may be useful in the prevention of the development of hepatic fibrosis.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Ara, C., Kirimlioglu, H., Karabulut, A. B., Coban, S., Ay, S., Harputluoglu, M., and Yilmaz, S., Protective effect of resveratrol against oxidative stress in cholestasis. J. Surg. Res., 127, 112–117 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Athar, M., Back, J. H., Tang, X., Kim, H. K., Kopelovich, L., Bickers, D. R., and Kim, A. L., Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol. Appl. Pharmacol., 224, 274–283 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Bataller, R. and Brenner, D. A., Liver fibrosis. J. Clin. Invest., 115, 209–218 (2005).

    CAS  PubMed  Google Scholar 

  • Buege, J. A. and Aust, S. D., Microsomal lipid peroxidation. Methods Enzymol., 52, 302–310 (1978).

    Article  CAS  PubMed  Google Scholar 

  • Chávez, E., Reyes-Gordillo, K., Segovia, J., Shibayama, M., Tsutsumi, V., Vergara, P., Moreno, M. G., and Muriel, P., Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats. J. Appl. Toxicol., 28, 35–43 (2008).

    Article  PubMed  Google Scholar 

  • Friedman, S. L., Mechanisms of hepatic fibrogenesis. Gastroenterology, 134, 1655–1669 (2008a).

    Article  CAS  PubMed  Google Scholar 

  • Friedman, S. L., Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev., 88, 125–172 (2008b)

    Article  CAS  PubMed  Google Scholar 

  • Gasso, M., Rubio, M., Varela, G., Cabre, M., Caballeria, J., Alonso, E., Deulofem, R., Camps, J., Gimene, Z, A., Piares, M., Pares, A., Mato, J. M., and Rodes, J., Effects of S-adenosylmethionine on lipid peroxidation and liver fibrogenesis in carbon tetrachloride-induced cirrhosis. J. Hepatol., 25, 200–205 (1996).

    Article  CAS  PubMed  Google Scholar 

  • George, J., Roulot, D., Koteliansky, V. E., and Bissell, D. M., In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis. Proc. Natl. Acad. Sci. U.S.A., 96, 12719–12724 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Godichaud, S., Krisa, S., Couronne, B., Dubuisson, L., Merillon, J.-M., Desmouliere, A., and Rosenbaum, J., Deactivation of cultured human liver myofibroblasts by trans-resveratrol, a grapevine-derived polyphenol. Hepatology, 31, 922–931 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Godichaud, S., Si-Tayeb, K., Auge, N,. Desmouliere, A., Balabaud, C., Payrastre, B., Negre-Salvayre, A., and Rosenbaum, J., The grape-derived polyphenol resveratrol differentially affects epidermal and platelet-derived growth factor signaling in human liver myofibroblasts. Int. J. Biochem. Cell Biol., 38, 629–637 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Haggerty, H. G. and Holsapple, M. P., Role of metabolism in dimethylnitrosamine-induced immunosuppression: A review. Toxicology, 63, 1–23 (1990).

    Article  CAS  PubMed  Google Scholar 

  • Jezequel, A. M., Mancini, R., Ranaldesi, M. L., Balllardini, G., Fallani, M., Bianchi, F., and Orlandi, F., Dimethylnitrosamine-induced cirrhosis. Evidence for an immunological mechanism, J. Hepatol., 8, 42–52 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Junqueira, L. C., Bignolas, G., and Brentani, R. R., Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem. J., 11, 447–455 (1979).

    Article  CAS  PubMed  Google Scholar 

  • Kawada, N., Seki, S., Inoue, M., and Kuroki, T., Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology, 27, 1265–1274 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Kolios, G., Valatas. V., and Kouroumalis E., Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroenterol., 14, 7413–7420 (2006).

    Google Scholar 

  • Lee, E. S., Lee, H. E., Shin, J. Y., Yoon, S., and Moon, J. O., The flavonoid quercetin inhibits dimethylnitrosamineinduced liver damage in rats. J. Pharm. Pharmcol., 55, 1169–1174 (2003).

    Article  CAS  Google Scholar 

  • Li, D. and Friedman, S. L., Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J. Gastroenterol. Hepatol., 14, 618–633 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randal, R. J., Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193, 265–275 (1951).

    CAS  PubMed  Google Scholar 

  • Moreira, R. K., Hepatic stellate cells and liver fibrosis. Arch. Pathol. Lab. Med., 131, 1728–1734 (2007).

    CAS  PubMed  Google Scholar 

  • Parola, M., Pinzani, M., Casini, A., Albano, E., Poli, G., Gentilini, A., Gentilini, P., and Dianzani, M. U., Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fatstoring cells. Biochem. Biophys. Res. Commun., 194, 1044–1050 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Rubiolo, J. A., Mithieux, G., and Vega, F. V., Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur. J. Pharmacol., 591, 66–72 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Shankar, S., Singh, G., and Srivastava, R. K., Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front. Biosci., 12, 4839–4854 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Terracini, B., Magee, P. N., and Barnes, J. M., Hepatic pathology in rats on low dietary levels of dimethylnitrosamine. Br. J. Cancer, 21, 559–565 (1967).

    CAS  PubMed  Google Scholar 

  • Tsukamoto, H., Rippe, R., Niemela, O., and Lin, M., Role of oxidative stress in activation of Kupffer cell and Ito cells in liver fibrogenesis. J. Gastroenterol. Hepatol., 10, S50–S53 (1995).

    Article  PubMed  Google Scholar 

  • Vendemiale, G., Grattagliano, I., Caruso, M. L., Serviddio, G., Valentini, A. M., Pirrelli, M., and Altomare, E., Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat: effect of N-acetylcysteine and interferon-alpha. Toxicol. Appl. Pharmacol., 175, 130–139 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Wallace, K., Burt, A. D., and Wright, M. C., Liver fibrosis. Biochem. J., 411, 1–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Woessner, J. F. Jr., The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch. Biochem. Biophys., 93, 440–447 (1961).

    Article  CAS  PubMed  Google Scholar 

  • Zhu, W. and Fung, P. C., The roles played by crucial free radicals like lipid free radicals, nitric oxide, and enzymes NOS and NADPH in CCl(4)-induced acute liver injury of mice. Free Radic. Biolic. Med., 29, 870–880 (2000).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeon-Ok Moon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, ES., Shin, MO., Yoon, S. et al. Resveratrol inhibits dimethylnitrosamine-induced hepatic fibrosis in rats. Arch. Pharm. Res. 33, 925–932 (2010). https://doi.org/10.1007/s12272-010-0616-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-0616-4

Key words

Navigation