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The proanthocyanidins inhibit dimethylnitrosamine-induced liver damage in rats

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Abstract

Proanthocyanidins are naturally occurring compounds widely available in fruits, vegetables, nuts and seeds. They are a class of phenolic compounds and have been reported to exhibit a wide range of biological effects. In this study, we investigated the protective effect of grape seed proanthocyanidins on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant increase in levels of serum alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin. Oral administration of proanthocyanidins (20 mg/kg daily for 4 weeks) remarkably prevented these elevations. Proanthocyanidins also restored serum albumin and total protein levels, and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced collagen accumulation, as estimated by histological analysis of liver tissue stained with Sirius red, was reduced in the proanthocyanidinstreated rats. A reduction in hepatic stellate cell activation, as assessed by α-smooth muscle actin staining, was associated with proanthocyanidins treatment. In conclusion, these results demonstrate that proanthocyanidins exhibited in vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury. It suggests that grape seed proanthocyanidins may be useful in preventing the development of hepatic fibrosis.

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References

  • Albanis, E. and Friedman, S. L., Antifibrotic agents for liver disease. Am. J. Transplant., 6, 12–19 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Bagchi, D., Bagchi, M., Stohs, S. J., Das, D. K., Ray, S. D., Kuszynski, C. A., Joshi, S. S., and Pruess, H. G., Free radicals and grape seed proanthocyanidins extract: importance in human health and disease prevention, Toxicology, 148, 187–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Bagchi, D., Bagchi, M., Stohs, S., Ray, S. D., Sen, C. K., and Preuss, H. G., Cellular protection with proanthocyanidins derived from grape seeds. Ann. N. Y. Acad. Sci., 957, 260–270 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Broadhust, R. B. and Jones, W. T., Analysis of condensed tannin using acidified vanillin. J. Sci. Food Agri., 29, 788–794 (1978).

    Article  Google Scholar 

  • Bruck, R., Ashkenazi, M., Weiss, S., Goldiner, I., Shapiro, H., Aeed, H., Genina, O., Helpern, Z., and Pines, M., Prevention of liver cirrhosis in rats by curcumin. Liver Int., 27, 373–383 (2007).

    Article  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 

  • Chen, W. H., Liu, P., Xu, G. F., Lu, W., Xiong, W. G., Li, F. H., and Liu, C. H., Role of lipid peroxidation liver fibrogenesis induced by dimethylnitrosamine in rats. Shijie Huaren Xiaohua ZaZhi, 9, 645–648 (2001).

    CAS  Google Scholar 

  • Dryden, G. W. Jr., Deaciuc, I., Arteel, G., and McClain, C. J., Clinical implications of oxidative stress and antioxidant therapy. Curr. Gastroenterol. Rep., 7, 308–316 (2005).

    Article  PubMed  Google Scholar 

  • Dulundu, E., Ozel, Y., Topaloglu, U., Ercan, F., Gedik, N., and Sener, G., Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J. Gastroenterol. Hepatol., 22, 885–892 (2007).

    Article  PubMed  Google Scholar 

  • Friedman, S. L., Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem., 275, 2247–2250 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Friedman, S. L., Mechanism of hepatic fibrogenesis. Gastroenterol., 134, 1655–1669 (2008)

    Article  CAS  Google Scholar 

  • Gabetta, B., Fuzzati, N., Griffini, A., Lolla, E., Pace, R., Ruffilli, T., and Peterlongo, F., Characterization of proanthocyanidins from grape seeds. Fitoterapia, 71, 162–175 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Haggerty H. G. and Holsapple M. P., Role of metabolism in dimethylnitrosamine-induced immunosupression: 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. J. Histochem., 11, 447–455 (1979).

    Article  CAS  Google Scholar 

  • Karaa, A., Thompson, K. J., McKillop, I. H., Clemens, M. G., and Schrum, L. W., S-adenosyl-L-methionine attenuates oxidative stress and hepatic stellate cell activation in an ethanol-LPS-induced fibrotic rat model. Shock, 30, 197–205 (2008).

    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. Pharmacol., 55, 1169–1174 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Maher, J. J. and Bissell D. M., Cell-matrix interations in liver. Semin. Cell Biol., 4, 189–201 (1993).

    Article  CAS  PubMed  Google Scholar 

  • McMullen, M. R, Pritchard, M. T., and Nagy L. E., Isolation of Kupffer cells from rats fed chronic ethanol. Methods Mol. Biol., 447, 199–212 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Medina, J. and Moreno-Otero, R., Pathophysiological basis for antioxidant therapy. Drugs, 65, 2445–2461 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Moon, J. O., Park, S. K., and Nagano, T., Hepatoprotective effect of Fe-TPEN on carbon tetrachloride induced liver injury in rats. Biol. Pharm. Bull., 21, 284–288 (1998).

    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 

  • Nakamura, T., Ueno, T., Sakamoto, M., Sakata, R., Torimura, T., Hashimoto, O., Ueno, H., and Sata, M., Suppression of transforming growth factor-beta results in upregulation of transcription of regeneration factors after chronic liver injury. J. Hepatol., 41, 974–982 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Nieto, N. and Cederbaum, A. I., S-adenosylmethionine blocks collagen I production by preventing transforming growth factor-beta induction of the COL1A2 promoter. J. Biol. Chem., 280, 30963–30974 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Parola, M., Pinzani, M., Casini, A., Albano, E., Poli, G., Gentilini, A., Gentilini, M., and Dianzani, U., Stimulation of lipid peroxidation or 4-hydrononenal treatment increase procollagen alpha 1 (1) gene expression in human liver fat-storing cells. Biochem. Biophys. Res. Commun., 194, 1004–1050 (1993).

    Article  Google Scholar 

  • Pinzani, M., Marra, F., and Carloni, V., Signal transduction in hepatic stellate cells. Liver, 18, 2–13 (1998).

    CAS  PubMed  Google Scholar 

  • Terracini, B., Magee, P. N., and Barnes, J. M., Hepatic pathology in rats on dietary levels of dimethylnitrosamine. Br. J. Cancer, 61, 559–565 (1967).

    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-acethylcysteine and interferon-α, Toxicol. Appl. Pharmacol., 175, 130–139 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Weng, H., L., Cai, W. M., and Liu, R. H., Animal experiment and clinical study of effect of gamma-interferon on hepatic fibrosis. World J. Gastroenterol., 7, 42–48 (2001).

    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 CCl4-induced acute liver injury of mice. Free Radic. Biol. Med., 29, 870–880 (2000).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Jeon-Ok Moon.

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Shin, MO., Yoon, S. & Moon, JO. The proanthocyanidins inhibit dimethylnitrosamine-induced liver damage in rats. Arch. Pharm. Res. 33, 167–173 (2010). https://doi.org/10.1007/s12272-010-2239-1

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  • DOI: https://doi.org/10.1007/s12272-010-2239-1

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