Planta Med 2006; 72(7): 661-664
DOI: 10.1055/s-2006-931571
Letter
© Georg Thieme Verlag KG Stuttgart · New York

Honokiol Reduces Oxidative Stress, c-jun-NH2-Termial Kinase Phosphorylation and Protects against Glycochenodeoxycholic Acid-Induced Apoptosis in Primary Cultured Rat Hepatocytes

Eun-Jeon Park1 , So-yeon Kim1 , Yu-Zhe Zhao1 , Dong Hwan Sohn1
  • 1Department of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Korea
Further Information

Publication History

Received: October 6, 2005

Accepted: January 24, 2006

Publication Date:
29 May 2006 (online)

Abstract

Hydrophobic bile acid-induced apoptosis plays an important role in cholestatic liver disease, and its prevention may be of therapeutic interest. The aim of this study was to investigate the protective effect of honokiol on glycochenodeoxycholic acid-induced apoptosis in primary cultured rat hepatocytes. Glycochenodeoxycholic acid is a hydrophobic bile salt that accumulates intrahepatically during cholestasis and induces hepatocyte apoptosis at pathophysiological concentrations. Primary rat hepatocytes were pretreated with honokiol at concentrations of 40, 20 and 10 μM 5 min before glycochenodeoxycholic acid treatment. Incubation of hepatocytes with glycochenodeoxycholic acid at a concentration of 100 μM for 4 h induced apoptosis as shown by DNA fragmentation, chromatin condensation and cleavage of poly(ADP-ribose) polymerase. Pretreatment with honokiol at concentrations of 40, 20 and 10 μM significantly inhibited the generation of intracellular reactive oxygen species and reduced activation of caspases-8, -9, and -3 and cleavage of poly-(ADP-ribose) polymerase. Glycochenodeoxycholic acid treatment up-regulated phosphorylation of stress-activated protein kinase/c-jun-NH2-terminal kinase which was inhibited by honokiol treatment. Inhibition of stress-activated protein kinase/c-jun-NH2-terminal kinase phosphorylation by SP600125 protected hepatocytes from apoptosis induced by glycochenodeoxycholic acid. These data indicate that honokiol protects hepatocytes from apoptosis induced by glycochenodeoxycholic acid in vitro and this protection may be due to reduced oxidative stress and inhibition of stress-activated protein kinase/c-jun-NH2-terminal kinase phosphorylation.

References

  • 1 Rust C, Gores G J. Apoptosis and liver disease.  Am J Med. 2000;  108 567-74
  • 2 Miyoshi H, Rust C, Roberts P J, Burgart L J, Gores G J. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas.  Gastroenterology. 1999;  117 669-77
  • 3 Reinehr R, Becker S, Wettstein M, Haussinger D. Involvement of the Src family kinase yes in bile salt-induced apoptosis.  Gastroenterology. 2004;  127 1540-57
  • 4 Fujita M, Itokawa H, Sashida Y. Studies on the components of Magnolia obovata Thunb. II. On the components of the methanol extract of the bark.  Yakugaku Zasshi. 1973;  93 422-8
  • 5 Chiu J H, Ho C T, Wei Y H, Lui W Y, Hong C Y. In vitro and in vivo protective effect of honokiol on rat liver from peroxidative injury.  Life Sci. 1997;  61 1961-71
  • 6 Park E J, Zhao Y Z, Na M, Bae K, Kim Y H, Lee B H. et al . Protective effects of honokiol and magnolol on tertiary butyl hydroperoxide- or D-galactosamine-induced toxicity in rat primary hepatocytes.  Planta Med. 2003;  69 33-7
  • 7 Faubion W A, Guicciardi M E, Miyoshi H, Bronk S F, Roberts P J, Svingen P A. et al . Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas.  J Clin Invest. 1999;  103 137-45
  • 8 Allen R T, Hunter W J, Agrawal D K. Morphological and biochemical characterization and analysis of apoptosis.  Pharmacol Toxicol Methods. 1997;  37 215-8
  • 9 Czaja M J. The future of GI and liver research: editorial perspectives III. JNK/AP-1 regulation of hepatocyte death.  Am J Physiol Gatrointest Liver Physiol. 2003;  284 G875-9
  • 10 Marderstein E L, Bucher B, Guo Z, Feng X, Reid K, Geller D A. Protection of rat hepatocytes from apoptosis by inhibition of c-Jun N-terminal kinase.  Surgery. 2003;  134 280-4
  • 11 Yang S E, Hsieh M T, Tsai T H, Hsu S L. Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells.  Biochem Pharmacol. 2002;  63 1641-51
  • 12 Fong W F, Tse A K, Poon K , Wang C. Magnolol and honokiol enhance HL-60 human leukemia cell differentiation induced by 1,25-dihydroxyvitamin D3 and retinoic acid.  Int J Biochem Cell Biol. 2005;  37 427-41
  • 13 Park E J, Zhao Y Z, Kim Y H, Lee B H, Sohn D H. Honokiol induces apoptosis via cytochrome c release and caspase activation in activated rat hepatic stellate cells in vitro .  Planta Med. 2005;  71 82-4

Prof. Dong Hwan Sohn

Department of Pharmacy

Wonkwang University

Iksan

Jeonbuk 570-749

Republic of Korea

Fax: +82-63-854-6038

Email: dhsohn@wonkwang.ac.kr