Hepatoprotective Activity of Crataegii Fructus Water Extract against Cadmium-induced Toxicity in Rats

카드뮴유발 흰쥐의 간손상에 대한 산사(山査)추출물의 보호효과

  • 신정훈 (대구한의대학교 한의과대학) ;
  • 조미정 (대구한의대학교 한의과대학) ;
  • 박상미 (대구한의대학교 한의과대학) ;
  • 박숙자 (대구한의대학교 한의과대학) ;
  • 김상찬 (대구한의대학교 한의과대학)
  • Received : 2010.02.08
  • Accepted : 2010.02.24
  • Published : 2010.04.25

Abstract

Crataegii Fructus is commonly used as a improving digestion, removing retention of food, promoting blood circulation and resolving blood stasis agent in East Asia. Cadmium (Cd) is widely distributed in the environment due to its use in industry. An exposure to Cd causes dysuria, polyuria, chest pain, hepatic and renal tubular diseases. The liver is the most important target organ when considering Cd-induced toxicity because Cd primarily accumulates in the liver. This study investigated the protective effect of Crataegii Fructus water extract against cadmium ($CdCl_2$, Cd)-induced liver toxicity in H4IIE cells, a rat hepatocyte-derived cell line and in rats. Cell viability was significantly reduced in Cd-treated H4IIE cells in a time and concentration-dependent manner. However, Crataegii Fructus water extract (CFE) protected the cells from Cd-induced cytotoxicity via inhibition of PARP cleavage. To induce acute toxicity in rats, Cd (4 mg/kg body weight) was dissolved in normal saline and intravenously injected into rats. The rats then received either a vehicle or silymarin (as a positive control) or CFE (50, 100 mg/kg/day) for 3 days, and were subsequently exposed to a single injection of Cd. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were significantly increased by Cd treatment. In contrast, pretreatment with CFE reduced ALT, AST and LDH. In histopathological analysis, CFE reduced the hepatic degenerative regions and the number of degenerative hepatocytes. These are considered as direct evidences that Crataegii Fructus has favorable inhibitory effects on the Cd-intoxicated liver damages. The efficacy of Crataegii Fructus shows slight lower than that of silymarin in the present study.

Keywords

References

  1. 전국한의과대학 본초학교수. 본초학. 서울, 영림사, pp 369-370, 1992.
  2. 배명효, 김호현. 산사의 내피세포 의존성 혈관이완효과 기전에 대한 연구. 대한본초학회지 18: 269-180, 2003.
  3. 송정춘, 박남규, 허한순, 방면호, 백남인. 국내산 약용식물의 항산화물질 탐색 및 분리. 한국약용작물학회지 8: 94-101, 2000.
  4. 최수임, 이윤미, 허태련. 생약재 추출물의 hyalurinidase 저해 및 라디칼 소거 활성 탐색. 대한생물공학회지 18: 282-288, 2003.
  5. 박찬성, 양경미, 김미림. 한방식재료 추출물의 기능성. 한국조리과학회지 22: 720-727, 2006.
  6. 김정숙, 이기동, 권동호, 윤형식. 산사 항산화성 물질의 분리 및 동정. 한국농화학회지 36: 154-157, 1993.
  7. 김정숙, 이기동, 권동호, 윤형식. 산사 및 가자 에테르 추출물의 항산화 효과. 한국농화학회지 36: 203-207, 1993.
  8. 오덕환, 함승시, 박부길, 안철, 유진영. 식품부패 및 병원미생 물에 대한 천연약용식물 추출물의 항균효과. 한국식품과학회지 30: 957-963, 1998.
  9. 박춘근, 방경환, 이승은, 차문석, 성정숙, 박희운, 성낙술. 수종 한약재 추출물의 Staphylococcus aureus에 대한 항균활성. 한국약용작물학회지 9: 251-258, 2001.
  10. 최원균, 김용성, 조규성, 성창근. 국내산 식물의 항균활성 검색. 한국식품영양학회지 15: 300-306, 2002.
  11. 정영표, 윤여충, 윤대환. 위유의 산사 약침이 고지방 식이로 유발된 비만백서에 미치는 영향. 대한침구학회지 24: 55-68, 2007.
  12. 반상석. 고지방 식이로 유도된 비만 흰쥐에 인진, 지실, 산사가 미치는 영향. 대구한의대학교 대학원, 박사학위논문, 2006.
  13. 김정환, 김명욱, 조영제. 산사(Crataegi Fructus) 추출물로부터 $\alpha$-amylase와 $\alpha$-glucosidase 저해 물질 분리 및 동정. 한국응용생명화학회지 50: 204-209, 2007.
  14. 채종걸, 정인철, 이상용. 산사육이 CT105로 유도된 Alzheimer's Disease 병태모델에 미치는 영향. 신경정신과학회지 13: 79-115, 2002.
  15. 정인철, 이상용. 산사육이 Alzheimer's Disease 병태모델에 미치는 영향. 동의생리병리학회지 16: 279-288, 2002.
  16. 서부일. 산사가 알콜 투여로 유발된 흰쥐의 고지혈증과 간 손상의 예방에 미치는 영향. 대한본초학회지 20: 35-43, 2005.
  17. 심재영, 조영미, 김영경, 이헌옥, 엄애선. 대두 이소플라본의 카드뮴 독성 완화작용에 미치는 영향. 한국콩연구회지 22: 19-24, 2005.
  18. Samarawickrama, G.P. Biological effects of cadm-ium in mammals, In Webb M(ed):"The chemistry, bioc-hemistry and biology of cadmium", Elsevier-North Holland Biomedical Press, Amsterdam, pp 341-422, 1979.
  19. Rajanna, B., Hobson, M., Reese, J., Sample, E. and Chapatwala, K.D. Chronic Hepatic and renal toxicity by cadmium in rats, Drug Chem. Toxicol 7: 229-241, 1984. https://doi.org/10.3109/01480548409035105
  20. Kunimoto, M., Miysaka, K. and Miura, T. Changes in membrane properties of rat blood cells induced by cadmium accumulating in the membrane fraction, J. Biochem 99: 397-406, 1986. https://doi.org/10.1093/oxfordjournals.jbchem.a135494
  21. Chapatwala, K.D., Rajanna, B. and Desaiah, D. Cadmium-induced changes in gluconeogenic enzymes in rat kidney and liver, Drug Chem. Toxicol 3: 407-420, 1980. https://doi.org/10.3109/01480548009030129
  22. Manca, D., Ricard, A.C., Trottier, B. and Chevalier, G. Studies on lipid proxidation in rat tissues following administration of low and moderate doses of cadmium chloride, Toxicology 67: 303-323, 1991. https://doi.org/10.1016/0300-483X(91)90030-5
  23. Sarkar, S., Yadav, P., Trivedi, R., Bansal, A.K. and Bhatnagar, D. Cadmium-induced lipid peroxi-dation and the status of the antioxidant system in rat tissues, J. Trace Element Med. Biol 9: 144-149, 1995. https://doi.org/10.1016/S0946-672X(11)80038-6
  24. Dalton, T., Fu, K., Enders, G.C., Palmiter, R.D. and Andrews, G.K. Analysis of the effects of overex-pression of metallothionein-I in transgenic mice on the reproductive toxicology of cadmium, Environ. Health Persp 104: 68-76, 1996. https://doi.org/10.1289/ehp.9610468
  25. Kim, J.H., Chough, N.J. and Park, S.B. Studies on the heavy metals of cammon restaurant meals. J. Korean Soc. Food Nutr 18: 316-320, 1989.
  26. Song, M.R. and Lee, S.R. Assessment of total dictary intake of some heavy metals from common res-taurant meals in Seoul area. Korean J. Food Sci. Technol 18: 458-467, 1986.
  27. Whelton, B.D., Peterson, D.P., Moretti, E.S., Mauser, R.W. and Bhattacharyya, M.H. Hepatic levels of cadmium, zinc and copper in multiparous, nulliparous and ovariectomized mice fed either a nutrient-sufficient or-deficient diet containing cadmium. Toxicology 119: 141-153, 1997. https://doi.org/10.1016/S0300-483X(96)03612-8
  28. Kim, S.C., Byun, S.H., Yang, C.H., Kim, C.Y., Kim, J.W., Kim, S.G. Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage). Toxicology 197: 239-251, 2004. https://doi.org/10.1016/j.tox.2004.01.010
  29. Cho, M.K., Suh, S.H., Kim, S.G. JunB/AP-1 and NF-$\kappa$ B-mediated induction of nitric oxide synthase by bovine type I collagen in serumstimulated murine macrophages. Nitric Oxide 6: 319-332, 2002. https://doi.org/10.1006/niox.2001.0415
  30. Sauer, J.M., Waalkes, M.P., Hooser, S.B., Kuester, R.K., McQueen, C.A., Sipes, I.G. Suppression of Kupffer cell function prevents cadmium induced hepatocellular necrosis in the male Sprague-Dawley rat. Toxicology 121: 155-164, 1997. https://doi.org/10.1016/S0300-483X(97)00062-0
  31. Srivastava, R.K., Sharma, S., Verma, S., Arora, B., Lal, H. Influence of diabetes on liver injury induced by antitubercular drugs and on silymarin hepatoprotection in rats. Methods Find Exp Clin Pharmacol 30: 731-737, 2008. https://doi.org/10.1358/mf.2008.30.10.1316824
  32. Belyaeva, E.A., Dymkowska, D., Więckowski, M.R., Wojtczak, L. Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. Toxicology and Applied pharmacology 231: 34-42, 2008. https://doi.org/10.1016/j.taap.2008.03.017
  33. Soldani, C., Scovassi, A.I. Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7: 321-328, 2002. https://doi.org/10.1023/A:1016119328968
  34. Tan, K.K., Bang, S.L., Vijayan, A., Chiu, M.T. Hepatic enzymes have a role in the diagnosis of hepatic injury after blunt abdominal trauma. Injury 40: 978-983, 2009. https://doi.org/10.1016/j.injury.2009.02.023
  35. 김순호, 손한철, 이은엽, 장철훈. 최신임상검사진단학. 서울, 계축문화사, pp 150-157, 1996.
  36. Sherlock, S., Dooley, J. Diseases of the Liver and Biliary System, 11th ed., London, Blackwell Science, p 23, 2002.
  37. Tzirogiannis, K.N., Panoutsopoulos, G.I., Demonakou, M.D., Hereti, R.I., Alexandropoulou, K.N., Mykoniatis, M.G. Effect of hepatic stimulator substance (HSS) on cadmium-induced acute hepatotoxicity in the rat liver. Dig Dis Sci 49: 1019-1028, 2004. https://doi.org/10.1023/B:DDAS.0000034566.43582.53
  38. 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 174: 225-234, 2001. https://doi.org/10.1006/taap.2001.9218
  39. Arjmandi, B.H., Khalil, D.A. and Hollis, B.W. Soy protein: Its effects on intestinal calcium transport, serum vitamin D, and insulin-like growth factor-1 in ovariectomized rats. Calcifeid Tissue Int 70: 483-487, 2002. https://doi.org/10.1007/s00223-001-1100-4
  40. Valencia, R., Gerpe, M., Trimmer, J., Buckman, T., Mason, A.Z. and Olsson, P. The effet of estrogen on cadmium distribution in Rainvow Trout(Oncorhynchus mykiss). Marine Environmental Research 46: 167-171, 1998. https://doi.org/10.1016/S0141-1136(97)00125-6
  41. 최정화, 이순재. 만성카드뮴 중독 쥐에서 카드뮴 축적에 미치는 녹차 Catechin의 영향. 한국영양학회지 34: 384-392, 2001.
  42. 임태진. 랫드 간세포 일차배양에서 셀레늄이 카드뮴에 의해 유도된 독성 및 지질과산화에 미치는 영향. 한국환경농학회지 22: 94-99, 2003.
  43. 이치호, 한규호, 최일신, 김충용, 조진국. 인진쑥의 열수 추출물이 흰쥐의 카드뮴 독성에 미치는 영향. 한국축산식품학회지 19: 188-197, 1999.
  44. 김민지, 홍정희, 이순재. 만성 카드뮴 중독 흰쥐에서 카드뮴 축적과 배설에 미치는 Vitamin E의 영향. 한국영양학회지 36: 691-698, 2003.
  45. Belyaeva, E.A., Dymkowska, D., Więckowski, M.R., Wojtczak, L. Reactive oxygen species produced by the mitochondrial respiratory chain are involved in Cd2+-induced injury of rat ascites hepatoma AS-30D cells. Biochemica et Biophysica Acta 1757: 1568-1574, 2006. https://doi.org/10.1016/j.bbabio.2006.09.006
  46. Russmann, S., Kullak-Ublick, G.A., Grattagliano, I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 16: 3041-3053, 2009. https://doi.org/10.2174/092986709788803097
  47. Ueda, H. Prothymosin alpha and cell death mode switch, a novel target for the prevention of cerebral ischemia-induced damage. Pharmacol Ther 123: 323-333, 2009. https://doi.org/10.1016/j.pharmthera.2009.05.007
  48. Geoffrey M. Cooper 저, 전국분자생물학교수 역, 세포학 (The Cell), 서울, 한우리, pp 599-636, 2000.
  49. Elmore, S. Apoptosis: a review of programmed cell death. Toxicol Pathol 35: 495-516, 2007. https://doi.org/10.1080/01926230701320337
  50. Nagata, S. Fas-mediated apoptosis. Adv Exp Med Biol 406: 119-124, 1996.
  51. 손윤희, 조현정, 김미경, 정은정, 남경수. 단삼 에탄올추출물이 유방암 예방 및 전이에 미치는 영향. 생약학회지 38:62-66, 2007.
  52. van Wijk, S.J., Hageman, G.J. Poly(ADP-ribose) polymerase-1 mediated caspase-independent cell death after ischemia/reperfusion. Free Radic Biol Med 39: 81-90, 2005.
  53. Skilleter, D., Cain, K., Dinsdale, D., Paine, A. Biochemical mechanisms and morphology selectivity in hepatotoxicity: Studies in cultures of hepatic-parenchymal and non-parenchymal cells, Xenobiotica 15: 687-693, 1985. https://doi.org/10.3109/00498258509047428
  54. Lee, J.R., Park, S.J., Lee, H.S., Jee, S.Y., Seo, J., Kwon, Y.K., Kwon, T.K., Kim, S.C. Hepatoprotective Activity of Licorice Water Extract against Cadmium-induced Toxicity in Rats. Evid Based Complement Alternat Med 6: 195-201, 2009 https://doi.org/10.1093/ecam/nem078
  55. Park Eun Young. Hepatoprotective and renoprotective effects of liquiritigenin, a component of licorice, on cadmium-induced toxicity in rats. 대구한의대학교 대학원, 석사학위논문, 2008.