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Hepatotoxicity and nephrotoxicity of gallotannin-enriched extract isolated from Galla Rhois in ICR mice

Abstract

To evaluate the hepatotoxicity and nephrotoxicity of Galla Rhois (GR) toward the liver and kidney of ICR mice, alterations in related markers including body weight, organ weight, urine composition, liver pathology and kidney pathology were analyzed after oral administration of 250, 500 and 1,000 mg/kg body weight/day of gallotannin-enriched extract of GR (GEGR) for 14 days. GEGR contained 68.7±2.5% of gallotannin, 25.3±0.9% of gallic acid and 4.4±0.1% of methyl gallate. Also, the level of malondialdehyde (MDA), a marker of lipid peroxidation, was decreased with 19% in the serum of high dose GEGR (HGEGR)-treated mice. The body and organ weight, clinical phenotypes, urine parameters and mice mortality did not differ among GEGR-treated groups and the vehicle-treated group. Furthermore, no significant increase was observed in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and the serum creatinine (Cr) in the GEGR-treated group relative to the vehicle- treated group. Moreover, the specific pathological features induced by most toxic compounds such as CCI4 were not observed upon liver and kidney histological analysis. Overall, the results of the present study suggest that GEGR does not induce any specific toxicity in liver and kidney organs of ICR at doses of 1,000 mg/kg body weight/day, indicating that this is no observed adverse effect level (NOAEL).

References

  1. Lee SM, Lee DW, Park ID, Kim JI. Study on formation and development of gall in Rhus javanica. Korean J Appl Entomol 1997; 36(1): 83–87.

    Google Scholar 

  2. Ren Z, Zhu B, Wang D, Ma E, Su D, Zhong Y. Comparative population structure of Chinese sumac aphid Schlechtendalia chinensis and its primary host-plant Rhus chinensis. Genetica 2008; 132(1): 103–112.

    Article  PubMed  Google Scholar 

  3. An RB, Oh H, Kim YC. Phenolic constituents of Galla Rhois with hepatoprotective effects on tacrine- and nitrofurantoin-induced cytotoxicity in Hep G2 cells. Biol Pharm Bull 2005; 28(11): 2155–2157.

    Article  CAS  PubMed  Google Scholar 

  4. Song GY, Park BJ, Kim SH. Antithrombotic effect of Galla Rhois. Korean J Pharmacogn 2002; 33(2): 120–123.

    Google Scholar 

  5. Shim YJ, Doo HK, Ahn SY, Kim YS, Seong JK, Park IS, Min BH. Inhibitory effect of aqueous extract from the gall of Rhus chinensis on alpha-glucosidase activity and postprandial blood glucose. J Ethnopharmacol 2003; 85(2-3): 283–287.

    Article  PubMed  Google Scholar 

  6. Kim SH, Park HH, Lee S, Jun CD, Choi BJ, Kim SY, Kim SH, Kim DK, Park JS, Chae BS, Shin TY. The anti-anaphylactic effect of the gall of Rhus javanica is mediated through inhibition of histamine release and inflammatory cytokine secretion. Int Immunopharmacol 2005; 5(13-14): 1820–1829.

    Article  CAS  PubMed  Google Scholar 

  7. Ahn YJ, Lee CO, Kweon JH, Ahn JW, Park JH. Growth- inhibitory effects of Galla Rhois-derived tannins on intestinal bacteria. J Appl Microbiol 1998; 84(3): 439–443.

    Article  CAS  PubMed  Google Scholar 

  8. Choi JG, Kang OH, Lee YS, Oh YC, Chae HS, Jang HJ, Kim JH, Sohn DH, Shin DW, Park H, Kwon DY. In vitro activity of methyl gallate isolated from galla rhois alone and in combination with ciprofloxacin against clinical isolates of salmonella. J Microbiol Biotechnol 2008; 18(11): 1848–1852.

    CAS  PubMed  Google Scholar 

  9. Lee JJ, Bae JH, Kim DH, Lim JJ, Kim DG, Lee HJ, Min W, Rhee MH, Chang HH, Park H, Kim S. Intracellular replication inhibitory effects of Galla Rhois ethanol extract for Brucella abortus infection. J Ethnopharmacol 2011; 138(2): 602–609.

    Article  PubMed  Google Scholar 

  10. Lee JJ, Kim DH, Lim JJ, Kim DG, Min W, Kim GS, Lee HJ, Rhee MH, Park H, Kim SC, Chang HH, Kim S. Anticoccidial effect of supplemental dietary Galla Rhois against infection with Eimeria tenella in chickens. Avian Pathol 2012; 41(4): 403–407.

    Article  CAS  PubMed  Google Scholar 

  11. Chae HS, Kang OH, Choi JG, Oh YC, Lee YS, Brice OO, Chong MS, Lee KN, Shin DW, Kwon DY. Methyl gallate inhibits the production of interleukin-6 and nitric oxide via down-regulation of extracellular-signal regulated protein kinase in RAW 264.7 cells. Am J Chin Med 2010; 38(5): 973–983.

    Article  CAS  PubMed  Google Scholar 

  12. Park PHI, Hur J, Kim YC, An RB, Sohn DH. Involvement of heme oxygenase-1 induction in inhibitory effect of ethyl gallate isolated from Galla Rhois on nitric oxide production in RAW 264.7 macrophages. Arch Pharm Res 2011; 34(9): 1545–1552.

    Article  CAS  PubMed  Google Scholar 

  13. Ata N, Oku T, Hattori M, Fujii H, Nakajima M, Saiki I. Inhibition by galloylglucose (GG6-10) of tumor invasion through extracellular matrix and gelatinase-mediated degradation of type IV collagens by metastatic tumor cells. Oncol Res 1996; 8(12): 503–511.

    CAS  PubMed  Google Scholar 

  14. Xiang Q, Fan C, Xiao S, Pan H, Wang J, Zhao N, Tian J. Effect of gallnut extract on nasopharyngeal carcinoma 5-8F cells and its mechanism. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2012; 37(9): 871–875.

    CAS  PubMed  Google Scholar 

  15. Lee K, Kim J, Lee BJ, Park JW, Leem KH, Bu Y. Protective effects of Galla Rhois, the excrescence produced by the sumac aphid, Schlechtendalia chinensis, on transient focal cerebral ischemia in the rat. J Insect Sci 2012; 12: 10.

    PubMed  PubMed Central  Google Scholar 

  16. Park EJ, Zhao YZ, An RB, Kim YC, Sohn DH. 1,2,3,4,6-penta-O-galloyl-beta-D-glucose from Galla Rhois protects primary rat hepatocytes from necrosis and apoptosis. Planta Med 2008; 74(11): 1380–1383.

    Article  CAS  PubMed  Google Scholar 

  17. Lee YH. Dyeing, fastness, and deodorizing properties of cotton, silk, and wool fabrics dyed with coffee sludge (Coffea arabica L.) extract. J Appl Polym Sci 2007; 103(1): 251–257.

    Article  CAS  Google Scholar 

  18. Newman DJ. Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 2008; 51(9): 2589–2599.

    Article  CAS  PubMed  Google Scholar 

  19. Efange SMN. Natural products: a continuing source of inspiration for the medical chemist. In: MM, Wootton JC (eds), Advances in phytomedicine, Elsevier Science, Amsterdam, 2002.

  20. Cragg GM and Newman DJ. Drug discovery and development from natural products: the way forward. 11th NAPRECA Symposium Book of Proceedings 2005; 56–69.

    Google Scholar 

  21. Yagi K. Assay for blood plasma or serum. Methods Enzymol 1984; 105: 328–331.

    Article  CAS  PubMed  Google Scholar 

  22. Cheeseman KH, Slater TF. An introduction to free radical biochemistry. Br Med Bull 1993; 49(3): 481–493.

    Article  CAS  PubMed  Google Scholar 

  23. Jacob RA, Burri BJ. Oxidative damage and defense. Am J Clin Nutr 1996; 63(6): 985–990.

    Article  Google Scholar 

  24. Mohamed EI, Elazomi A, Elabid BEH, Zwaik H. Evaluation of changes in levels of plasma MDA, and antioxidant vitamin E in Sudanese patients with type 2 diabetes. International Conference on Chemical, Environment & Biological Sciences 2014; 17–18.

    Google Scholar 

  25. Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol 2012; 2012: 137289.

    PubMed  PubMed Central  Google Scholar 

  26. Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow JD. Lipid peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol Med 2002; 33(5): 620–626.

    Article  CAS  PubMed  Google Scholar 

  27. Dahanukar SA, Kulkarni RA, Rege NN. Pharmacology of medicinal plants and natural products. Indian J Pharmacol 2000; 32: S81–S118.

    CAS  Google Scholar 

  28. Dragoev SG. Inhibition of lipid peroxidation of frozen mackerel by pre-storage antioxidant superficial treatment. Bul J Agri Sci 2008; 14(3): 283–289.

    Google Scholar 

  29. Ng TB, Liu F, Wang ZT. Antioxidative activity of natural products from plants. Life Sci 2000; 66(8): 709–723.

    Article  CAS  PubMed  Google Scholar 

  30. Chen CH, Liu TZ, Chen CH, Wong CH, Chen CH, Lu FJ, Chen SC. The efficacy of protective effects of tannic acid, gallic acid, ellagic acid, and propyl gallate against hydrogen peroxide-induced oxidative stress and DNA damages in IMR-90 cells. Mol Nutr Food Res 2007; 51(8): 962–968.

    Article  CAS  PubMed  Google Scholar 

  31. Nabavi SF, Habtemariam S, Sureda A, Hajizadeh Moghaddam A, Daglia M, Nabavi SM. In vivo protective effects of gallic acid isolated from Peltiphyllum peltatum against sodium fluoride-induced oxidative stress in rat erythrocytes. Arh Hig Rada Toksikol 2013; 64(4): 553–559.

    Article  CAS  PubMed  Google Scholar 

  32. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15(6): 412–426.

    Article  CAS  PubMed  Google Scholar 

  33. KREBS HA. The physiological role of the ketone bodies. Biochem J 1961; 80: 225–233.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Vanltallie TB, Nufert TH. Ketones: metabolism’s ugly duckling. Nutr Rev 2003; 61(10): 327–341.

    Article  Google Scholar 

  35. Ferrell KE., Thorington RW. Squirrels: the animal answer guide, Johns Hopkins University Press, 2006; pp 91.

    Google Scholar 

  36. Muller-Harvey I, McAllan AB. Tannins: Their biochemistry and nutritional properties. Adv Plant Cell Biochem Biotechnol 1992; 1: 151–217.

    Google Scholar 

  37. Dollahite JW, Pigeon RF, Camp BJ. The toxicity of gallic acid, pyrogallol, tannic acid, and Quercus havardi in the rabbit. Am J Vet Res 1962; 23(97): 1264–1267.

    CAS  PubMed  Google Scholar 

  38. Boyd EM, Bereczky K, Godi I. The acute toxicity of tannic acid administered intragastrically. Can Med Assoc J 1965; 92(25): 1292–1297.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Toxicological Evaluation of some extraction solvents and certain other substances. FAO Nutrition Meetings Series, No. 48A, 1970.

  40. Inert Reassessmen-t Tannin (CAS Reg. No. 1401-55-4), Office of prevention, pesticides and toxic substances, US Environmental Protection Agency, 2006.

    Google Scholar 

  41. Eaton GJ, Johnson FN, Custer RP, Crane AR. The Icr:Ha(ICR) mouse: a current account of breeding, mutations, diseases and mortality. Lab Animl 1980; 14(1): 17–24.

    Article  CAS  Google Scholar 

  42. Johnson M. Laboratory mice and rats. Labome 2015; doi: http://dx.doi.org/10.13070/mm.en.2.113.

    Google Scholar 

  43. Takeno S, Hirano Y, Kitamura A, Sakai T. Comparative developmental toxicity and metabolism of nitrazepam in rats and mice. Toxicol Appl Pharmacol 1993; 121(2): 233–238.

    Article  CAS  PubMed  Google Scholar 

  44. Xu X, Zhang L, Shao B, Sun X, Ho CT, Li S. Safety evaluation of meso-zeaxanthin. Food Control 2013; 32(2): 678–686.

    Article  CAS  Google Scholar 

  45. Zhang Y, Li J, Wu Z, Liu E, Shi P, Han L, Guo L, Gao X, Wang T. Acute and long-term toxicity of mango leaves extract in mice and rats. Evid Based Complement Alternat Med 2014; 2014: 691574.

    PubMed  PubMed Central  Google Scholar 

  46. Xiang F, Peng L, Yin Z, Jia R, Hu Z, Li Z, Ni X, Liang X, Li L, He C, Yin L, Su G, Lv C. Acute and subchronic toxicity as well as evaluation of safety pharmacology of Galla chinensis solution. J Ethnopharmacol 2015; 162: 181–190.

    Article  PubMed  Google Scholar 

  47. Bissell DM, Gores GJ, Laskin DL, Hoofnagle JH. Drug-induced liver injury: mechanisms and test systems. Hepatology 2001; 33(4): 1009–1013.

    Article  CAS  PubMed  Google Scholar 

  48. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis clinical research network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6): 1313–1321.

    Article  PubMed  Google Scholar 

  49. Giannini E, Botta F, Fasoli A, Ceppa P, Risso D, Lantieri PB, Celle G, Testa R. Progressive liver functional impairment is associated with an increase in AST/ALT ratio. Dig Dis Sci 1999; 44(6): 1249–1253.

    Article  CAS  PubMed  Google Scholar 

  50. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998; 93(1): 44–48.

    Article  CAS  PubMed  Google Scholar 

  51. Yoon SH, Park EJ, Oh KH, Chung YG, Kwon OJ. The effect of Lithospermi radix on benzo (a) pyrene-induced hepatotoxicity. J Korean Soc Food Sci Nutr 1993; 22(2): 144–148.

    CAS  Google Scholar 

  52. Hayes AW. Principles and methods of toxicology, Raven Press, New York, 1982; pp 447–474.

    Google Scholar 

  53. Kim DH, Deung YK, Lee YM, Yoon YS, Kwon KR, Park DB, Park YK, Lee KJ. The liver protecting effect of pomegranate (Punica granatum) seed oil in mice treated with CC14. Korean J Electron Microscopy 2006; 36(3): 173–182.

    Google Scholar 

  54. Michael B, Yano B, Sellers RS, Perry R, Morton D, Roome N, Johnson JK, Schafer K, Pitsch S. Evaluation of organ weights for rodent and non-rodent toxicity studies: a review of regulatory guidelines and a survey of current practices. Toxicol Pathol 2007; 35(5): 74–750.

    Article  Google Scholar 

  55. Singhal PC, Sharma P, Sanwal V, Prasad A, Kapasi A, Ranjan R, Franki N, Reddy K, Gibbons N. Morphine modulates proliferation of kidney fibroblasts. Kidney Int 1998; 53(2): 350–357.

    Article  CAS  PubMed  Google Scholar 

  56. Falconer IR, Hardy SJ, Humpage AR, Froscio SM, Tozer GJ, Hawkins PR. Hepatic and renal toxicity of the blue-green alga (cyanobacterium) Cylindrospermopsis raciborskii in male Swiss albino mice. Environ Toxicol 1999; 14(1): 143–150.

    Article  CAS  Google Scholar 

  57. Horiguchi H, Oguma E, Kayama F, Sato M, Fukushima M. Dexamethasone prevents acute cadmium-induced hepatic injury but exacerbates kidney dysfunction in rabbits. Toxicol Appl Pharmacol 2001; 174(3): 225–234.

    Article  CAS  PubMed  Google Scholar 

  58. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next- generation biomarkers for detecting kidney toxicity. Nat Biotechnol 2010; 28(5): 436–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Professor Young Hee Lee in Department of Organic Material Science and Engineering of Pusan National University for kindly providing Galla Rhios samples. This study was supported by grants to Dr. Dae Youn Hwang from the Korea Institute of Planning Evaluation for Technology of Food, Agriculture, Forestry and Fisheries (114034-03-1-HD030).

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Go, J., Kim, JE., Koh, EK. et al. Hepatotoxicity and nephrotoxicity of gallotannin-enriched extract isolated from Galla Rhois in ICR mice. Lab Anim Res 31, 101–110 (2015). https://doi.org/10.5625/lar.2015.31.3.101

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