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. 2010 Feb 18;60(1):91–97. doi: 10.1211/jpp.60.1.0012

Glycyrrhizin prevents of lipopolysaccharide/D‐galactosamine‐induced liver injury through down‐regulation of matrix metalloproteinase‐9 in mice

Kazuki Abe 1, Tadayuki Ikeda 2, Kenjiro Wake 2,3, Tetsuji Sato 2, Toshitsugu Sato 1, Hideo Inoue 1,✉
PMCID: PMC7166488  PMID: 18251086

ABSTRACT

Glycyrrhizin, a biological active compound isolated from the liquorice root, has been used as a treatment for chronic hepatitis. We have examined the involvement of matrix metalloproteinase (MMP)‐9 in the development of lipopolysaccharide (LPS) and D‐galactosamine (GalN)‐induced liver injury in mice. We also investigated the effect of glycyrrhizin on expression of MMP‐9 in this model. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased after LPS/GalN treatment. Expression of MMP‐9 mRNA and protein was markedly up‐regulated in liver tissues 6–8 h after LPS/GalN treatment. Pretreatment with glycyrrhizin (50 mg kg−1) and the MMP inhibitor (5 mg kg−1) suppressed increases in serum levels of ALT and AST in mice treated with LPS/GalN. Furthermore, glycyrrhizin inhibited levels of both mRNA and protein for MMP‐9. Immunohistochemical reaction for MMP‐9 was observed in macrophages/monocytes infiltrated in the inflammatory area of liver injury. Glycyrrhizin reduced the infiltration of inflammatory cells and immunoreactive MMP‐9 in liver injury. The results indicated that MMP‐9 played a role in the development of LPS/GalN‐induced mouse liver injury, and suggested that an inhibition by glycyrrhizin of the acute liver injury may have been due to a down‐regulation of MMP‐9.

REFERENCES

  1. Arase, Y. , Ikeda, K. , Murashima, N. , Chayama, K. , Tsubota, A. , Koida, I. , Suzuki, Y. , Saitoh, S. , Kobayashi, M. , Kumada, H. (1997) The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer 79: 1494–1500. [DOI] [PubMed] [Google Scholar]
  2. Chosay, J. S. , Essani, N. A. , Dunn, C. J. , Jaeschke, H. (1997) Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin‐induced injury. Am. J. Physiol. 272: G1195–G1200. [DOI] [PubMed] [Google Scholar]
  3. Cinatl, J. , Morgenstern, B. , Bauer, G. , Chandra, P. , Rabenau, H. , Doerr, H. W. (2003) Glycyrrhizin, an active component of liquorice roots, and replication of SARS‐associated coronavirus. Lancet 361: 2045–2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Endo, Y. , Shibazaki, M. , Yamaguchi, K. , Kai, K. , Sugawara, S. , Takada, H. , Kikuchi, H. , Kumagai, K. (1999) Enhancement by galactosamine of lipopolysaccharide (LPS)‐induced tumour necrosis factor production and lethality: its suppression by LPS pretreatment. Br. J. Pharmacol. 128: 5–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ikeda, K. , Arase, Y. , Kobayashi, M. , Saitoh, S. , Someya, T. , Hosaka, T. , Sezaki, H. , Akuta, N. , Suzuki, Y. , Suzuki, F. , Kumada, H. (2006) A long‐term glycyrrhizin injection therapy reduces hepato‐cellular carcinogenesis rate in patients with interferon‐resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig. Dis. Sci. 51: 603–609. [DOI] [PubMed] [Google Scholar]
  6. Ito, Y. , Abril, E. R. , Bethea, N. W. , McCuskey, R. S. (2005) Inhibition of matrix metalloproteinases minimizes hepatic microvascular injury in response to acetaminophen in mice. Toxicol. Sci. 83: 190–196. [DOI] [PubMed] [Google Scholar]
  7. Ito, Y. , Abril, E. R. , Bethea, N. W. , McCuskey, M. K. , Cover, C. , Jaeschke, H. , McCuskey, R. S. (2006) Mechanisms and patho‐physiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice. Am. J. Physiol. Gastrointest. Liver. Physiol. 291: G211–218. [DOI] [PubMed] [Google Scholar]
  8. Itokazu, Y. , Segawa, Y. , Omata, T. , Inoue, N. , Tsuzuike, N. , Nagasawa, M. , Nishioka, H. , Kobayashi, T. , Nakano, Y. , Kanda, T. (2000) Effects of ZNC‐2381, a new oral compound, on several hepatic injury models and on hepatocellular apoptosis in mice and rat. J. Pharm. Pharmacol. 52: 531–538. [DOI] [PubMed] [Google Scholar]
  9. Kimura, M. , Inoue, H. , Hirabayashi, K. , Natsume, H. , Ogihara, M. (2001) Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors. Eur. J. Pharmacol. 431: 151–161. [DOI] [PubMed] [Google Scholar]
  10. Knittel, T. , Mehde, M. , Kobold, D. , Saile, B. , Dinter, C. Ramadori, G. (1999) Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non‐parenchymal cells of rat liver: Regulation by TNF‐α and TGF‐β1. J. Hepatol. 30: 48–60. [DOI] [PubMed] [Google Scholar]
  11. Leist, M. , Gantner, F. , Bohlinger, I. , Tiegs, G. , Germann, P. G. , Wendel, A. (1995) Tumor necrosis factor‐induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am. J. Pathol. 146: 1220–1234. [PMC free article] [PubMed] [Google Scholar]
  12. Morikawa, A. , Sugiyama, T. , Kato, Y. , Koide, N. , Jiang, G. , Takahashi, K. , Tamada, Y. , Yokochi, T. (1996) Apoptotic cell death in the response of D‐galactosamine‐sensitized mice to lipopolysac‐charide as an experimental endotoxic shock model. Infect. Immun. 64: 734–738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nakanishi, K. , Yoshimoto, T. , Tsutsui, H. , Okamura, H. (2001) Interleukin‐18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 19: 423–474. [DOI] [PubMed] [Google Scholar]
  14. Nagai, T. , Egashira, T. , Yamanaka, Y. , Kohno, M. (1991) The protective effect of glycyrrhizin against injury of the liver caused by ischemia‐reperfusion. Arc. Environ. Contam. Toxicol. 20: 432–436. [DOI] [PubMed] [Google Scholar]
  15. Nose, M. , Ito, M. , Kamimura, K. , Shimizu, M. , Ogihara, Y. (1994) A comparison of the antihepatotoxic activity between glycyrrhizin and glycyrrhetinic acid. Planta Med. 60: 136–139. [DOI] [PubMed] [Google Scholar]
  16. Nowak, M. , Gaines, G. C. , Rosenberg, J. , Minter, R. , Bahjat, F. R. , Rectenwald, J. , MacKay, S. L. , Edwards, C. K. , Moldawer, L. L. (2000) LPS‐induced liver injury in D‐galactosamine‐sensitized mice requires secreted TNF‐alpha and the TNF‐p55 receptor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278: 1202–1209. [DOI] [PubMed] [Google Scholar]
  17. Ohuchi, K. , Kamada, Y. , Levine, L. , Tsurufuji, S. (1981) Glycyrrhizin inhibits prostaglandin E2 production by activated peritoneal macrophages from rats. Prostaglandins Med. 7: 457–463. [DOI] [PubMed] [Google Scholar]
  18. Okamoto, T. (2000) The protective effect of glycyrrhizin on anti‐Fas antibody‐induced hepatitis in mice. Eur. J. Pharmacol. 387: 229–232. [DOI] [PubMed] [Google Scholar]
  19. Okamoto, T. , Kanda, T. (1999) Glycyrrhizin protects mice from concanavalin A‐induced hepatitis without affecting cytokine expression. Int. J. Mol. Med. 4: 149–152. [DOI] [PubMed] [Google Scholar]
  20. Okimasu, E. , Moromizato, Y. , Watanabe, S. , Sasaki, J. , Shiraishi, N. , Morimoto, Y. M. , Miyahara, M. , Utsumi, K. (1983) Inhibition of phospholipase A2 and platelet aggregation by glycyrrhizin, an antiinflammation drug. Acta Med. Okayama 37: 385–391. [DOI] [PubMed] [Google Scholar]
  21. Pagenstecher, A. , Stalder, A. K. , Kincaid, C. L. , Volk, B. , Campbell, I. L. (2000) Regulation of matrix metalloproteinases and their inhibitor genes in lipopolysaccharide‐induced endotoxemia in mice. Am. J. Pathol. 157: 197–210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pugin, J. , Widmer, M. C. , Kossodo, S. , Liang, C. M. , Preas, H. L. , Suffredini, A. F. (1999) Human neutrophils secrete gelatinase B in vitro and in vivo in response to endotoxin and proinflammatory mediators. Am. J. Respir. Cell. Mol. Biol. 20: 458–464. [DOI] [PubMed] [Google Scholar]
  23. Sakano, Y. , Takeda, K. , Tsutsui, H. , Kaisho, T. , Nomura, F. , Okamura, H. , Nakanishi, K. , Akira, S. (1999) IL‐18‐deficient mice are resistant to endotoxin‐induced liver injury but highly susceptible to endotoxin shock. Int. Immunol. 11: 471–480. [DOI] [PubMed] [Google Scholar]
  24. Sass, G. , Heinlein, S. , Agli, A. , Bang, R. , Schumann, J. , Tiegs, G. (2002) Cytokine expression in three mouse model of experimental hepatitis. Cytokine 19: 115–120. [DOI] [PubMed] [Google Scholar]
  25. Shibayama, Y. (1989) Prevention of hepatotoxic responses to chemicals by glycyrrhizin in rats. Exp. Mol. Pathol. 51: 48–55. [DOI] [PubMed] [Google Scholar]
  26. Shiki, Y. , Shirai, K. , Saito, Y. , Yoshida, S. , Mori, Y. , Wakashin, M. (1992) Effects of glycyrrhizin on lysis of hepatocyte membranes induced by anti‐liver cell membrane antibody. J. Gastroenterol. Hepatol. 7: 12–16. [DOI] [PubMed] [Google Scholar]
  27. Shin, Y. W. , Bae, E. A. , Lee, B. , Lee, S. H. , Kim, J. A. , Kim, Y. S. , Kim, D. H. (2007) In vitro and in vivo antiallergic effects of glycyrrhiza glabra and its components. Planta Med. 73: 257–261. [DOI] [PubMed] [Google Scholar]
  28. Tiegs, G. (1994) Immunotoxicology of host‐response‐mediated experimental liver injury. J. Hepatol. 21: 890–903. [DOI] [PubMed] [Google Scholar]
  29. Tiegs, G. , Wolter, M. , Wendel, A. (1989) Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin‐induced hepatitis in mice. Biochem. Pharmacol. 38: 627–631. [DOI] [PubMed] [Google Scholar]
  30. Vaillant, B. , Chiaramonte, M. G. , Cheever, A. W. , Soloway, P. D. , Wynn, T. A. (2001) Regulation of hepatic fibrosis and extracellular matrix genes by the Th response: new insight into the role of tissue inhibitors of matrix metalloproteinases. J. Immunol. 167: 7017–7026. [DOI] [PubMed] [Google Scholar]
  31. van Rossum, T. G. , Vulto, A. G. , Hop, W. C. , Brouwer, J. T. , Niesters, H. G. , Schalm, S. W. (1999a) Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double‐blind, randomized, placebo‐controlled phase I/II trial. J. Gastroenterol. Hepatol. 14: 1093–1099. [DOI] [PubMed] [Google Scholar]
  32. van Rossum, T. G. , Vulto, A. G. , Hop, W. C. , Schalm, S. W. (1999b) Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection. Clin. Ther. 21: 2080–2090. [DOI] [PubMed] [Google Scholar]
  33. van Rossum, T. G. , Vulto, A. G. , Hop, W. C. , Schalm, S. W. (2001) Glycyrrhizin‐induced reduction of ALT in European patients with chronic hepatitis C. Am. J. Gastroenterol. 96: 2432–2437. [DOI] [PubMed] [Google Scholar]
  34. Visse, R. , Nagase, H. (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92: 827–839. [DOI] [PubMed] [Google Scholar]
  35. Wielockx, B. , Lannoy, K. , Shapiro, S. D. , Itoh, T. , Itohara, S. , Vandekerckhove, J. , Libert, C. (2001) Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy. Nat. Med. 7: 1202–1208. [DOI] [PubMed] [Google Scholar]
  36. Xiong, Q. , Hase, K. , Tezuka, Y. , Namba, T. , Kadota, S. (1999) Acteoside inhibits apoptosis in D‐galactosamine and lipopolysaccharide‐induced liver injury. Life. Sci. 65: 421–430. [DOI] [PubMed] [Google Scholar]
  37. Yoshida, T. , Abe, K. , Ikeda, T. , Matsushita, T. , Wake, K. , Sato, T. , Sato, T. , Inoue, H. (2007) Inhibitory effect of glycyrrhizin on lipopolysaccharide and D‐galactosamine‐induced mouse liver injury. Eur. J. Pharmacol. 576: 136–142. [DOI] [PubMed] [Google Scholar]
  38. Yumoto, E. , Higashi, T. , Nouso, K. , Nakatsukasa, H. , Fujiwara, K. , Hanafusa, T. , Yumoto, Y. , Tanimoto, T. , Kurimoto, M. , Tanaka, N. , Tsuji, T. (2002) Serum gamma‐interferon‐inducing factor (IL‐18) and IL‐10 levels in patients with acute hepatitis and fulminant hepatic failure. J. Gastroenterol. Hepatol. 17: 285–294. [DOI] [PubMed] [Google Scholar]

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