Hepatoprotective Effects of Hovenia dulcis Extract on Acute and Chronic Liver Injuries induced by Alcohol and Carbon Tetrachloride

알코올 및 사염화탄소에 의해 유발된 급만성 간손상에 대한 지구자 열수추출물의 보호효과

  • Kim, Young-Sik (Korea Institute of Science and Technology for Eastern Medicine, NeuMed Co., Ltd.) ;
  • Park, Juyeon (Korea Institute of Science and Technology for Eastern Medicine, NeuMed Co., Ltd.) ;
  • Kwon, Yongbeom (Korea Institute of Science and Technology for Eastern Medicine, NeuMed Co., Ltd.) ;
  • Lim, Dong Wook (Dept. of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University) ;
  • Song, MiKyung (Dept. of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University) ;
  • Choi, Ho-Young (Dept. of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University) ;
  • Kim, Hocheol (Dept. of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University)
  • 김영식 (뉴메드 한의과학기술연구소) ;
  • 박주연 (뉴메드 한의과학기술연구소) ;
  • 권용범 (뉴메드 한의과학기술연구소) ;
  • 임동욱 (경희대학교 한의과대학 본초학교실) ;
  • 송미경 (경희대학교 한의과대학 본초학교실) ;
  • 최호영 (경희대학교 한의과대학 본초학교실) ;
  • 김호철 (경희대학교 한의과대학 본초학교실)
  • Received : 2013.06.19
  • Accepted : 2013.07.19
  • Published : 2013.07.30


Objectives : The purpose of this study was to evaluate the hepatoprotective effect of Hovenia dulcis extract on acute and chronic liver injuries induced by alcohol and $CCl_4$ in mice and rats. Methods : In acute alcohol-induced liver injury, mice were administered Hovenia dulcis extracts (60 and 200 mg/kg) orally before and after alcohol administration. In chronic alcohol-induced liver injury, mice were administered alcohol containing liquid diet for 4 weeks. The mice were administered H. dulcis extracts (60 and 200 mg/kg) mixed with the liquid diet. In acute $CCl_4$-induced liver injury, rats received a single dose of $CCl_4$ (2 mL/kg in olive oil, intraperitoneally). Rats were administered H. dulcis extracts (30, 100 and 300 mg/kg) before and after $CCl_4$ administrations. After the ends of the administrations, the serum levels of AST and ALT were measured using chemical analyzer, and ${\gamma}$-GTP levels were measured using spectrophotometer. Results : In acute alcohol-induced liver injury, H. dulcis extracts treated group showed significant reduction in ALT levels compared to those of control group. In chronic alcohol-induced liver injury, it inhibited weight-loss compared to normal group and showed significant reduction in AST, ALT and ${\gamma}$-GTP levels compared to control group. In acute $CCl_4$-induced liver injury, it also showed significant reduction in AST, ALT levels compared to control group. Conclusions : The results show that H. dulcis extract has hepatoprotective effect in acute and chronic alcohol-induced liver injury and acute $CCl_4$-induced liver injury. These findings suggest that H. dulcis could be a potent hepatoprotective agent.



  1. Statistics Korea. 2011 Korea statistical yearbook. Daejeon:Statistics Korea. 2011 : 148-52.
  2. Kim DJ, Kim HS, Choi WC, Kim YS, Park CK, Lee YS. Liver disease in society: Present and future - Emphasis on disability rating -. Korean J Hepatol. 2009 ; 15 (5) : 50-68.
  3. Kim DJ, Kim HS, Yim HJ, Suh JI, Cheong JY, Kim IH, Tark WY, Lee YS, Lee S, Lee JY. Problems faced by Korean patients with chronic liver disease and the role of the Korean Association for the Study of the Liver -Emphases on social discrimination, insufficiency of reimbursement coverage, and deficiency of the welfare system. Korean J Hepatol. 2008 ; 14(2) : 125-35.
  4. Lee HJ. Update and Perspectives on alcoholic liver disease in Korea 2010. Korean J Hepatol. 2010 ; 16(2) : 23-44.
  5. Chae HB. Alcoholic Liver Disease. Korean J Gastroenterol. 2009 ; 53(5) : 275-82.
  6. Kim HT, Kim DD, Ku SK, Kim JW, Lim MK, Oh TH, Lee KW. Therapeutic Effects of Hovenia Dulcis Thunb Extract on CCl4 Induced Liver and Kidney Damage in Rats. J Vet Clin. 2011 ; 28(1) : 20-7.
  7. Kim SM, Kang SH, Ma JY, Kim HJ. A study on the Extraction and Efficacy of Bioactive Compound from Hovenia dulcis. Korean J Biotechnol Bioeng. 2006 ; 21(1) : 11-5.
  8. Shin DH, Cho MR. The study on Zhi Ju Zi (枳椇子). Kor J Herbology. 2002 ; 17(1) : 81-91.
  9. Korea Food & Drug Administration(KFDA). The Korean Herbal Pharmacopoeia. The KFDA Notification 2013-56. 2013 : 331-2.
  10. Textbook Compilation Committee of college of Korean Medicine. Herbology. Seoul: Younglim. 1991 : 734.
  11. Yoshikawa M, Murakami T, Ueda T, Yoshizumi S, Ninomiya K, Murakami N, Matsuda H, Saito M, Fujii W, Tanaka T, Yamahara J. Bioactive constituents of Chinese natural medicines. III. Absolute stereostructures of new dihydroflavonols, hovenitins I, II, and III, isolated from hoveniae semen seufructus, the seed and fruit of Hovenia dulcis THUNB. (Rhamnaceae): inhibitory effect on alcohol-induced muscular relaxation and hepatoprotective activity. Yakugaku Zasshi. 1997 ; 117(2) : 108-18.
  12. Na CS, Chung NC, Yang KH, Kim SH, Chung HS, Dong MS. Hepatoprotective and Blood Alcohol Lowering Effects of Fruit Peduncle Extract of Hovenia dulcis var. Koreana in the In Vitro and In Vivo Animal Models. Yakhak Hoeji. 2004 ; 48(1) : 34-40.
  13. Yoshikawa M, Murakami T, Ueda T, Matsuda H, Yamahara J, Murakami N. Bioactive saponins and glycosides. IV. Four methyl-migrated 16, 17-seco-dammarane triterpene glycosides from Chinese natural medicine, hoveniae semen seu fructus, the seeds and fruit of Hovena dulcus THUNB.: Absolute stereostructures and inhibitory activity on histamine release of hovenidulciosides A1, A2, B1, and B2. Chem Pharm Bull. 1996 ; 44(9) : 1736-43.
  14. Kim OK. Protective Effects of Extracts of Hovenia dulcis Thunb on Hepatotoxicity in Carbon Tetrachloride Intoxicated Rats. J Korean Soc Food Sci Nutr. 2001 ; 30(6) : 1260-5.
  15. Ahn BS, Kim JW, Kim HT, Lee DS, Lee KW. Antioxidant Effects of Hovenia Dulcis in the Streptozotocin-Induced Diabetic Rats. J Vet Clin. 2010 ; 27(4) : 366-73.
  16. Hu W, Lee KB, Wang MH. Antioxidant Activities of Various Extracts of Hovenia dulcis Thunb Fruits. Korean J Plant Res. 2010 ; 23(3) : 207-13.
  17. Choi JK, Han HS, Lee YJ. Study on Antioxidant Effect of Hoveniae Semen cum Fructus and Hoveniae Ramulus on Liver Cells Isolated from Oxidatively Stressed Rat. Kor J Herbology. 2009 ; 24(3) : 129-38.
  18. Cho JY, Moon JH, Park KH. Isolation and Identification of 3-Methoxy-4-hydroxybenzoic Acid and 3-Methoxy-4-hydroxycinnamic Acid from Hot Water Extracts of Hovenia dulcis Thunb and Confirmation of Their Antioxidative and Antimicrobial Activity. Korean J Food Sci Technol. 2000 ; 32(6) : 1403-8.
  19. Jeong CH, Shim KH. Some Functional Properties of Extracts from Leaf and Fruit Stalk of Hovenia dulcis. Korean J Postharvest Sci Technol. 2000 ; 7(3) : 291-6.
  20. An SW, Kim YS, Kim MH, Lee BI, Lee SH, Kwon HI, Hwang B, Lee HY. Comparison of Hepatic Detoxification activity and reducing Serum Alcohol concentration of Hovenia dulsis THUNB and Alnus japonica Steud. Korean J Medicinal Crop Sci. 1999 ; 7(4) : 263-8.
  21. Lee MK, Kim YG, An SW, Kim MH, Lee JH, Lee HY. Biological activities of Hovenia dulcis THUNB. Korean J Medicinal Crop Sci. 1999 ; 7(3) : 185-92.
  22. Hong YL, Kim MH, Ahn C, Lee HY, Kim JD. Studies on the biological activities of the extracts from Hovenia dulcis Thunb. J Agr Sci 2000 ; 11 : 1-11.
  23. Ji Y, Chen S, Zhang K, Wang W. Effects of Hovenia dulcis Thunb on blood sugar and hepatic glycogen in diabetic mice. Zhong Yao Cai. 2002 ; 25(3) : 190-1.
  24. Ma JY, Kim SW. Effect of Hovenia dulcis on liver protection in SD male rats treated with $CCl_{4}$. Kor J Ori Med. 2006 ; 12(1) : 103-9.
  25. Kim JH, Seo YM, Kim JH, Hyun SH, Lee SK, Kim CH, Kang MJ, Jeon TW, Yoon SH, Jeong TC. Protective Effects of the Water Extracts of Hovenia dulcis Thunb Against Ethanol-Induced Toxicity in Primary Cultured Rat Hepatocytes. Yakhak Hoeji. 2008 ; 52(1) : 56-61.
  26. You YH, Jung KY, Lee YH, Jun WJ, Lee BY. Hepatoprotective Effects of Hovenia dulcis Fruit on Ethanol-Induced Liver Damage in vitro and in vivo. J Korean Soc Food Sci Nutr. 2009 ; 38(2) : 154-9.
  27. Du J, He D, Sun L, Han T, Zhang H, Qin L, Rahman K. Semen Hoveniae extract protects against acute alcohol-induced liver injury in mice. Pharm Biol. 2010 ; 48(8) : 953-8.
  28. Hase K, Ohsugi M, Xiong Q, Basnet P, Kadota S, Namba T. Hepatoprotective effect of Hovenia dulcis THUNB. on experimental liver injuries induced by carbon tetrachloride or D-galactosamine/lipopolysaccharide. Biol Pharm Bull. 1997 ; 20(4) : 381-5.
  29. Fang H, Lin H, Chan M, Lin W, Lin W. Treatment of chronic liver injuries in mice by oral administration of ethanolic extract of the fruit of Hovenia dulcis. Am J Chin Med. 2007 ; 35(4) : 693-703.
  30. Zhao J, Chen H, Li Y. Protective effect of bicyclol on acute alcohol-induced liver injury in mice. Eur J Pharmacol. 2008 ; 586(1-3) : 322-31.
  31. Lieber CS, DeCarli LM. The feeding of ethanol in liquid diet. Alcohol Clin Exp Res. 1986 ; 10(5) : 550-3.
  32. Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968; 12(1) : 135-61.
  33. Kim JH, Jang SW, Kweon JW, Kim WB, Choi YW. Improved Dissolution Characteristics of Silymarin and Their Bioavailability in Rats. J Kor Pharm Sci. 2003 ; 33(1) : 61-5.
  34. Lee HC, Hwang SG, Kang YK, Sohn HO, Moon JY, Lim HB, Jeon BH, Lee DW. Influence of Protaetia brevitarsis Extract on Liver Damage Induced by Carbon Tetrachloride and Ethanol in Rats. J Life Sci. 2001 ; 11(5) : 405-14.
  35. Tuma J, Casey CA. Dangerous byproducts of alcohol breakdown-focus on adducts. Alcohol Res Health. 2003 ; 27(4) : 285-90.
  36. Zimmerman HJ, Seeff LB. Enzymes in hepatic disease. In: Goodly, E.L. (Ed.), Diagnostic Enzymology. Philadelphia:Lea & Febiger. 1970 : 1-38.
  37. Molander DW, Wroblewsk F, La Due JS. Transaminase compared with cholinesterase and alkaline phosphatase an index of hepatocellular integrity. Clin Res Proc. 1955 ; 3 : 20-4.
  38. Kim YJ. Interpretation of Liver Function Tests. Korean J Gastroenterol. 2008 ; 51(4) : 219-24.
  39. Szasz G. A kinetic photometric method for serum $\gamma$-glutamyl transpeptidase. Clin Chem. 1969 ; 15(2) : 124-36.
  40. Selinger MJ, Matloff DS, Kaplan MM. $\gamma$-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity. Clin Chim Acta. 1982 ; 125(3) : 283-90.
  41. Lee HH, Yoon JS, Song SY. Protective Effect of Lithospermum erythrorhizon on Galactosamine Induced Liver Injury. Korean J Microscopy. 2010 ; 40(1) : 29-35.
  42. Barouki R, Chobert M, Finidori J, Aggerbeck M, Nalpas B, Hanoune J. Ethanol Effects in a Rat Hepatoma Cell Line: Induction of $\gamma$‐Glutamytransferase. Hepatology. 1983 ; 3(3) : 323-9.
  43. Friedman SL. Acetaldehyde and alcoholic fibrogenesis: fuel to the fire, but not the spark. Hepatology. 1990 ; 12(3) : 609-12.
  44. Yates WR, Petty F, Brown K. Risk factors for alcohol hepatotoxicity among male alcoholics. Drug Alcohol Depend. 1987 ; 20(2) : 155-62.
  45. Gjerde H, Amundsen A, SKOG O, Morland J, Aasland O. Serum Gamma‐glutamyltransferase: an epidemiological indicator of alcohol consumption? Br J Addict. 1987 ; 82(9) : 1027-31.
  46. Persson J, Magnusson PH. Comparison between different methods of detecting patients with excessive consumption of alcohol. Acta Med Scand. 1988 ; 223(2) : 101-9.
  47. Choi K, Kim BI, Cho YK, Park CY, Sohn JI, Jeon WK, Kim H, Chung ES, Keum DG, Lee HY, Lee SJ. Diagnostic usefulness of serum $\gamma$-glutamyl transferase(GGT) activity in fatty liver and relationship with other factors. Korean J Med. 1999 ; 57(6) : 1006-13.
  48. Cho MK, Choi TS. The study of the spontaneous recovery time in acute hepatitis induced by $CCl_{4}$ in three mouse strains. Korean J Lab Anim Sci. 2004 ; 20(1) : 104-8.
  49. Kim IS, Kim JW, Kim HT, Lee SD, Ku SK, Do YJ, Lee KW. Effects of Epimedium Koreanum Extract on the Carbon Tetrachloride-Induced Liver Damage and Its Related Organ Damages in Rats. J Vet Clin. 2011 ; 28(4) : 357-64.
  50. Brown R, Miller J, Miller E. The metabolism of methylated aminoazo dyes IV. Dietary factors enhancing demethylation in vitro. J Biol Chem. 1954 ; 209(1) : 211-22.
  51. Cignoli EV, Castro JA. Lipid peroxidation, necrosis and the in vivo depression of liver glucose 6-phosphatase by carbon tetrachloride. Exp Mol Pathol. 1971 ; 14(1) : 43-56.