Protective Effect of Lithospermum erythrorhizon on Galactosamine Induced Liver Injury

자초(Lithospermum erythrorhizon)추출물의 투여가 Galactosamine으로 유도된 간손상에 미치는 보호 효과

  • 이현화 (조선대학교 자연과학대학 생물학과) ;
  • 윤중식 (생물방제센터) ;
  • 송선영 (광주보건대학 피부미용과)
  • Received : 2010.02.22
  • Accepted : 2010.03.23
  • Published : 2010.03.31

Abstract

The present study was carried out to investigate the hepatoprotective effect of water extract of Lithospermum erythrorhizon on acute hepatotoxicity induced in Sprague-Dawley (SD) rats by a single dose of galactosamine (400 mg/kg, i.p). The animals were divided into four groups. The animals in the Con group were fed basal diet. GalN group were administered with galactosamine. LE200 and LE500 groups treated with water extract of Lithospermum erythrorhizon (such as 200 and 500 mg/kg/day, p.o) for 7 days before galactosamine injection. In the change of AST, ALT, ALP, GGT and LDH contents, as compared with GalN group, LE200 group were significantly decreased. According to the electron microscopical observation, liver cells were increased the lipid droplet, change of mitochondria in the GalN compared with LE200. These results suggest that administration of water extract of Lithospermum erythrorhizon suppress or retard galactosamine induced acute liver injury.

본 연구는 galactosamine 투여로 인해 유발된 흰쥐의 간독성에 미치는 자초추출물의 효과를 알아보기 위해 자초 추출물을 각각 200 mg/kg과 500 mg/kg을 매일 1회씩 7일간 복강내 주사한 후, 마지막 자초 추출물 투여일에 galactosamine을 주사하여 다음과 같은 결론을 얻었다. AST, ALT, ALP, GGT와 LDH의 활성도에서는 LE200군이 GalN군에 비해 유의적으로 감소하였다. 그리고 조직학적 변화에서, GalN군은 염증세포의 침윤과 국소적인 괴사성 변화가 나타났지만, LE군들에서는 GalN 투여에 의한 변화가 상당히 경감되었다. 또한 미세구조적 변화에서는 GalN군은 미토콘드리아의 변형, 지방적의 증가, 조면소포체의 분절 등 세포소기관의 변형을 유발하였다. 그러나 LE군들에서는 대조군과 유사한 소견을 보여 주었다. 이상의 결과들로 보아, 자초추출물은 galactosamine 투여로 간독성을 유발시킨 흰쥐의 간 조직에 장애를 주지 않으면서 간독성을 완화시키는 효과가 있다고 사료된다.

Keywords

References

  1. Bulgakov VP, Kozyrenko MM, Fedoreyev SA, Mischenko NP, Denisenko VA, Zvereva LV, Pokushalova TV, Zhuravlev YN: Shikonin production by p-fluorophenylalanine resistant cells of Lithospermum erythrorhizon. Fitoterapia 72(4) : 394-401, 2001. https://doi.org/10.1016/S0367-326X(00)00343-9
  2. Chen X, Yang L, Oppenheim JJ, Howard MZ: Cellular pharmacology studies of shikonin derivatives. Phytother Res 16(3) : 199-209, 2002. https://doi.org/10.1002/ptr.1100
  3. Cho TH: The effect of N-dimethylnitrosamine and D-galactosamine on the ultrastructural changes of liver and kidney in the rat. J Kor Surg Soc 43(5) : 633-640, 1992. (Korean)
  4. Cho MH, Paik YS, Hahn TR: Physical stability of shikonin derivatives from the roots of Lithospermum erythrorhizon cultivated in Korea. J Agric Food Chem 47(10) : 4117-20, 1999. https://doi.org/10.1021/jf9902853
  5. Choi WH, Hong SS, Lee SA, Han XH, Lee KS, Lee MK, Hwang BY, Ro JS: Monoamine oxidase inhibitory naphthoquinones from the roots of Lithospermum erythrorhizon. Arch Pharm Res 28(4) : 400-404, 2005. https://doi.org/10.1007/BF02977668
  6. Chung HS, Kang M, Cho C, Park S, Kim H, Yoon YS, Kang J, Shin MK, Hong MC, Bae H: Inhibition of lipopolysaccharide and interferon-gamma-induced expression of inducible nitric oxide synthase and tumor necrosis factor-alpha by Lithospermi radix in mouse peritoneal macrophages. J Ethnopharmacol 102(3) : 412-417, 2005. https://doi.org/10.1016/j.jep.2005.06.028
  7. Decker K, Keppler D: Galactosamine hepatitis: key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev Physiol Biochem Pharmacol 71 : 77-106, 1974. https://doi.org/10.1007/BFb0027661
  8. Farber JL, Gill G, Konishi Y: Prevention of galactosamine-induced liver cell necrosis by uridine. Am J Pathol 72(1) : 53-62, 1973.
  9. Hong SS, Gibney GT, Esquilin M, Yu J, Xia Y: Effect of protein kinases on lactate dehydrogenase activity in cortical neurons during hypoxia. Brain Res 1009(1) : 195-202, 2004. https://doi.org/10.1016/j.brainres.2004.03.004
  10. Hsu PC, Huang YT, Tsai ML, Wang YJ, Lin JK, Pan MH: Induction of apoptosis by shikonin through coordinative modulation of the Bcl-2 family, p27, and p53, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells. J Agric Food Chem 52(20) : 6330-6337, 2004. https://doi.org/10.1021/jf0495993
  11. Hwang H, Kim H, Yu H, Oh M, Lee I, Kim S: Gene encoding pathogenesis-related 10 protein of Lithospermum erythrorhizon is responsive to exogenous stimuli related to the plant defense system. Plant Sci 165 : 1297-1302, 2003. https://doi.org/10.1016/S0168-9452(03)00341-8
  12. Hwang SG: Animal models of acute hepatic failure. The Kor J Gastroenter 37(5) : 303-311, 2001. (Korean)
  13. Huh YJ, Shin HH, Lee KH, Suh IS: The role of endotoxin on the galactosamine induced liver injury. Kyungpook Univ Med J 32 (4) : 401-415, 1992. (Korean)
  14. Jin R, Wan LL, Mitsuishi T: Effects of shi-ka-ron and Chinese herbs in mice treated with anti-tumor agent mitomycin C. Zhongguo Zhong Xi Yi Jie He Za Zhi 15(2) : 101-103, 1995.
  15. Keppler D, Lesch R, Reutter W, Decker K: Experimental hepatitis induced by D-galactosamine. Exp Mol Pathol 9(2) : 279-90 1968. https://doi.org/10.1016/0014-4800(68)90042-7
  16. Kim SH, Kang IC, Yoon TJ, Park YM, Kang KS, Song GY, Ahn BZ: Antitumor activities of a newly synthesized shikonin derivative, 2-hyim-DMNQ-S-33. Cancer Lett 172(2) : 171-175, 2001. https://doi.org/10.1016/S0304-3835(01)00665-6
  17. Kim SH, Heo JH, Kim YS, Kang SS, Choi JS, Lee SM: Protective effect of daidzin against D-galactosamine and lipopolysaccharideinduced hepatic failure in mice. Phytother Res 23(5) : 701-706, 2009. https://doi.org/10.1002/ptr.2710
  18. Konoshima T, Kozuka M, Tokuda H, Tanabe M: Anti-tumor promoting activities and inhibitory effects on Epstein-Barr virus activation of Shi-un-kou and its constituents. Yakugaku Zasshi 109(11) : 843-846, 1989. https://doi.org/10.1248/yakushi1947.109.11_843
  19. Lee HJ, Lee HJ, Magesh V, Nam D, Lee EO, Ahn KS, Jung MH, Ahn KS, Kim DK, Kim JY, Kim SH: Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice. Yakugaku Zasshi 128(11) : 1681-1688, 2008. https://doi.org/10.1248/yakushi.128.1681
  20. Padma P, Setty OH: Effect of administration of galactosamine hydrochloride on rat liver mitochondria. Indian J Biochem Biophys 34(3) : 296-301, 1997.
  21. Pan YM, Liang Y, Wang HS, Liang M: Antioxidant activities of several Chinese medicine herbs. Food Chem 88(3) : 347-350, 2004. https://doi.org/10.1016/j.foodchem.2004.02.002
  22. Sankawa U, Otsuka H, Kataoka Y, Iitaka Y, Hoshi A, Kuretani K.: Antitumor activity of shikonin, alkannin and their derivatives. II. X-ray analysis of cyclo-alkannin leucoacetate, tautomerism of alkannin and cyclo-alkannin and antitumor activity of alkannin derivatives. Chem Pharm Bull 29(1) : 116-122, 1981. https://doi.org/10.1248/cpb.29.116
  23. Singh F, Gao D, Lebwohl MG, Wei H: Shikonin modulates cell proliferation by inhibiting epidermal growth factor receptor signaling in human epidermoid carcinoma cells. Cancer Lett 200(2) : 115-121, 2003. https://doi.org/10.1016/S0304-3835(03)00239-8
  24. Staniforth V, Wang SY, Shyur LF, Yang NS: Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor alpha promoter in vivo. J Biol Chem 279 : 5877-5885, 2004. https://doi.org/10.1074/jbc.M309185200
  25. Szasz G: A kinetic photometric method for serum gamma-glutamyl transpeptidase. Clin Chem. 15(2) : 124-136, 1969.
  26. Wang JF, Wendel A: Studies on the hepatotoxicity of galactosamine/endotoxin or galactosamine/ TNF in the perfused mouse liver. Biochem Pharmacol 39(2) : 267-70, 1990. https://doi.org/10.1016/0006-2952(90)90025-G
  27. Weng XC, Xiang GQ, Jiang AL, Liu YP, Wu LL, Dong XW, Duan S: Antioxidant properties of components extracted from puccoon (Lithospermum erythrorhizon Sieb. et Zucc.). Food Chem 69(2) : 143-146, 2000. https://doi.org/10.1016/S0308-8146(99)00236-8
  28. Yamasaki K, Otake T, Mori H, Morimoto M, Ueba N, Kurokawa Y, Shiota K, Yuge T: Screening test of crude drug extract on anti-HIV activity. Yakugaku Zasshi 113(11) : 818-824, 1993. https://doi.org/10.1248/yakushi1947.113.11_818
  29. Zhang ZQ, Cao XC, Zhang L, Zhu WL: Effect of shikonin, a phytocompound from Lithospermum erythrorhizon, on rat vascular smooth muscle cells proliferation and apoptosis in vitro. Zhonghua Yi Xue Za Zhi 85(21) : 1484-1488, 2005.
  30. Zieve L, Anderson WR, Dozeman R: Hepatic regenerative enzyme activity after diffuse injury with galactosamine: relationship to histologic alterations. J Lab Clin Med 112(5) : 575-582, 1988.