Skip to main content
SpringerLink
Log in

Effects of triterpene compounds on cytotoxicity, apoptosis, and immune response in cultured cells

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

To identify a candidate compound for therapy of chronic viral hepatitis, we screened a series of oleanene-type triterpenoids for their ability to alleviate aflatoxin B1 (AFB)-induced cytotoxicity, protect against actinomycin-tumor necrosis factor-induced apoptosis, and modulate the mixed lymphocyte reaction (MLR) in cultured cells. Glycyrrhizin at 200 μg/ml showed the strongest inhibitory effects on cytotoxicity without an immunomodulatory effect on MLR. In comparison, glycyrrhetic acid, the aglycone of glycyrrhizin, prevented apoptosis dose dependently and markedly decreased MLR with concomitant increases in concentration, but this compound failed to inhibit cytotoxicity. Among the compounds tested, soyasapogenol B at 100 μg/ml best alleviated cytotoxicity; it also protected against apoptosis at 50 μg/ml, and beginning at 1.0 μg/ml, this compound significantly increased MLR. At 25 μg/ml, soyasapogenol A, a group A saponin of soybean, showed maximum inhibition of cytotoxicity, but this inhibition rate tended to decrease with increasing dose rate. Uvaol markedly increased MLR with concomitant increases in concentration, and inhibited AFB-induced cytotoxicity, although it showed no protective effect on apoptosis. These screening data suggest that soyasapogenol B is a candidate therapeutic agent for chronic hepatitis because this compound can concomitantly (1) ameliorate cytotoxicity, (2) act as an antiapoptotic agent, and (3) increase MLR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Yoshizawa K (2000) Guidelines for the treatment of chronic hepatitis. Japan Society of Hepatology, The Institute, Tokyo

    Google Scholar 

  2. Japan Society of Hepatology (2001) Aiming at eradicating hepatic cancer caused by hepatitis C. The Institute, Tokyo

  3. Rehermann B (2000) Immunology of hepatitis C. Update on viral hepatitis. American Association for the Study of Liver Diseases Postgraduate Course, Dallas

    Google Scholar 

  4. Iino S (2000) Treatment of chronic hepatitis. Japan Society of Hepatology, The Institute, Tokyo

    Google Scholar 

  5. van Rossum TG, Vulto AG, Hop WCJ, Schalm SW (2001) Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C. Am J Gastroenterol 96:2432–2437

    Article  PubMed  Google Scholar 

  6. 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

    Article  PubMed  Google Scholar 

  7. Tarao K, Rino Y, Ohkawa S, Shimizu A, Tamai S, Miyakawa K, Aoki H, Imada T, Shindo K, Okamoto N, Totsuka S (1999) Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer 86:589–595

    Article  PubMed  Google Scholar 

  8. Shimizu I (2000) Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma. J Gastroenterol Hepatol 15:84–90

    Article  Google Scholar 

  9. Patrick L (1999) Hepatitis C: epidemiology and review of complementary/alternative medicine treatments. Altern Med Rev 4:220–238

    PubMed  Google Scholar 

  10. Taira Z, Yabe K, Hamaguchi Y, Hirayama K, Kishimoto M, Ishida S, Ueda Y (2004) Effects of sho-saiko-to extract and its components, baicalin, baicalein, glycyrrhizin and glycyrrhetic acid, on pharmacokinetic behavior of salicylamide in carbon tetrachloride intoxicated rats. Food Chem Toxicol 42:803–807

    Article  PubMed  Google Scholar 

  11. Sasaki K, Minowa N, Kuzuhara H, Nishiyama S, Omoto S (1998) Derivatization of soyasapogenol A and their hepatoprotective activities. Bioorg Med Chem Lett 8:607–612

    Article  PubMed  Google Scholar 

  12. Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G, Wendel A (1994) Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol 153:1778–1788

    PubMed  Google Scholar 

  13. Nissen MH, Bregenholt S, Nording JA, Claesson MH (1998) C1-esterase inhibitor blocks T lymphocyte proliferation and cytotoxic T lymphocyte generation in vitro. Int Immunol 10:167–173

    Article  PubMed  Google Scholar 

  14. Ballow M, Nelson R (1997) Immunopharmacology: immunomodulation and immunotherapy. JAMA 278:2008–2017

    Article  PubMed  Google Scholar 

  15. Horigome H, Hirano T, Oka K (2001) Therapeutic effect of glycyrrhetinic acid in MRL lpr/lpr mice: implications of alteration of corticosteroid metabolism. Life Sci 69:2429–2438

    Article  PubMed  Google Scholar 

  16. Liu J, Liu Y, Mao Q, Klaassen CD (1994) The effects of 10 triterpenoid compounds on experimental liver injury in mice. Fundam Appl Toxicol 22:34–40

    Article  PubMed  Google Scholar 

  17. Jeong HG, You HJ, Park SJ, Moon AR, Chung YC, Kang SK, Chun HK (2002) Hepatoprotective effects of 18beta-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol Res 46:221–227

    Article  PubMed  Google Scholar 

  18. Kitagawa I, Yoshikawa M, Wang HK, Saito M, Tosirisuk V, Fujiwara T, Tomita K (1982) Revised structures of soyasapogenols A, B, and E, oleanene-sapogenols from soybean. Structures of soyasaponins I, II, and III. Chem Pharm Bull 30:2294–2297

    Google Scholar 

  19. Ohminami H, Kimura Y, Okuda H, Arichi S, Yoshikawa M, Kitagawa I (1984) Effects of soyasaponins on liver injury induced by highly peroxidized fat rats. Planta Med 50:440–441

    PubMed  Google Scholar 

  20. Hu J, Reddy MB, Hendrich S, Murphy PA (2004) Soyasaponin I and sapongenol B have limited absorption by Caco-2 intestinal cells and limited bioavailability in women. J Nutr 134:1867–1873

    PubMed  Google Scholar 

  21. Guidotti LG, Borrow P, Hobbs MV, Matzke B, Gressert I, Oldstone MBA, Chisari FV (1996) Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver. Proc Natl Acad Sci USA 93:4589–4594

    Article  PubMed  Google Scholar 

  22. Rupasinghe HPV, Jackson C-JC, Poysa V, Di Berardo C, Bewley JD, Jenkinson J (2003) Common active site architecture and binding strategy of four phenylpropanoid P450s from Arabidopsis thaliana as revealed by molecular modeling. J Agric Food Chem 51:5888–5894

    Article  PubMed  Google Scholar 

  23. Kuzuhara H, Nishiyama S, Minowa N, Sasaki K, Omoto S (2000) Protective effects of soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model. Eur J Pharmacol 391:175–181

    Article  PubMed  Google Scholar 

  24. Robertson A, Soliman G, Owen EC (1939) Polyterpenoid compounds. Part I. Betulic acid from Cornus florida L. J Chem Soc 1267–1273

    Article  Google Scholar 

  25. Meiji Seika Kaisha (2005) ME3738: Brochure of New Investigational Drug Information Package

Download references

Acknowledgements

We thank Dr. Isao Kitagawa (Professor Emeritus, Osaka University, Japan), Dr. Akira Naganuma (Professor, Tohoku University, Japan), and Dr. Hiroshi Yamamoto (Professor, Osaka University, Japan) for their critical review of the manuscript.

Author information

Author notes

  1. Shoji Nishiyama

    Present address: Project Planning and Development Pharmaceuticals, Meiji Seika Kaisha, 2-4-16 Kyobashi, Chuo, Tokyo 104-8002, Japan

Authors and Affiliations

  1. Pharmaceutical Research Center, Meiji Seika Kaisha, 760 Morooka, Kouhoku, Yokohama, Kanagawa 222-8567, Japan

    Hiroyuki Kuzuhara, Shoji Nishiyama, Nobuto Minowa & Kazue Sasaki

Authors
  1. Hiroyuki Kuzuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoji Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuto Minowa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazue Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shoji Nishiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuzuhara, H., Nishiyama, S., Minowa, N. et al. Effects of triterpene compounds on cytotoxicity, apoptosis, and immune response in cultured cells. J Nat Med 60, 113–120 (2006). https://doi.org/10.1007/s11418-005-0022-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-005-0022-2

Keywords

Search

Navigation