Butein Suppresses Bile Acid-Induced Hepatocyte Apoptosis through a JNK-Dependent but ERK-Independent Pathway

 

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Abstract

We investigated the protective effect of butein on glycochenodeoxycholic acid (GCDC)-induced apoptosis in primary cultured rat hepatocytes. Treatment with GCDC at a concentration of 100 μM for 4 h induced apoptosis, and treatment with butein at concentrations of 30 μM inhibited the GCDC-induced apoptosis as shown by the reduced cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and activation of caspases-3, -8, and -9. c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) play fundamental roles in cell survival, proliferation, and apoptosis. GCDC alone induced ERK and JNK phosphorylation. Butein alone induced ERK activation, and ERK activation was greater in hepatocytes treated with butein and GCDC than in hepatocytes exposed to GCDC alone. Butein treatment reduced JNK activation induced by GCDC. Addition of U0126, an inhibitor of ERK, did not alter the proapoptotic effect of GCDC or the antiapoptotic effect of butein. Addition of SP600125, a specific JNK inhibitor, protected hepatocytes against GCDC-induced apoptosis. These data suggest that butein has a protective effect against GCDC-induced hepatocyte apoptosis and that the protective effect of butein is JNK dependent but ERK independent.

Abbreviations

ERK:extracellular signal regulated kinase 1/2

GCDC:glycochenodeoxycholic acid

JNK:c-Jun N-terminal kinase

MAPKs:mitogen-activated protein kinases

PARP:poly(ADP-ribose) polymerase

References

• 1 Lee J C, Lee K Y, Kim J, Na C S, Jung N C, Chung G H. et al . Extract from Rhus verniciflua Stokes is capable of inhibiting the growth of human lymphoma cells.  Food Chem Toxicol. 2004;  42 1383-8.
  PubMedGoogle Scholar
• 2 Lee J C, Lim K T, Jang Y S. Identification of Rhus verniciflua Stokes compounds that exhibit free radical scavenging and antiapoptotic properties.  Biochim Biophys Acta. 2002;  1570 181-91.
  PubMedGoogle Scholar
• 3 Chan S C, Chang Y S, Wang J P, Chen S C, Kuo S C. Three new flavonoids and antiallergic, anti-inflammatory constituents from the heartwood of Dalbergia odorifera .  Planta Med. 1998;  64 153-8.
  PubMedGoogle Scholar
• 4 Sogawa S, Nihro Y, Ueda H, Miki T, Matsumoto H, Satoh T. Protective effects of hydroxychalcones on free radical-induced cell damage.  Biol Pharm Bull.. 1994;  17 251-6.
  PubMedGoogle Scholar
• 5 Woo S W, Lee S H, Kang H C, Park E J, Zhao Y Z, Kim Y C. et al . Butein suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture.  J Pharm Pharmacol. 2003;  55 347-52.
  CrossrefPubMedGoogle Scholar
• 6 Lee S H, Nan J X, Zhao Y , Woo S W, Park E J, Kang T H. et al . The chalcone butein from Rhus verniciflua shows antifibrogenic activity.  Planta Med. 2003;  69 990-4.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Elsharkawy A M, Oakley F, Mann D A. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis.  Apoptosis. 2005;  10 927-39.
  CrossrefPubMedGoogle Scholar
• 8 Qiao L, Yacoub A, Studer E, Gupta S, Pei X Y, Grant S. et al . Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes.  Hepatology. 2002;  35 779-89.
  CrossrefPubMedGoogle Scholar
• 9 Zeid I M, Bronk S F, Fesmier P J, Gores G J. Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes.  Hepatology. 1997;  25 81-6.
  CrossrefPubMedGoogle Scholar
• 10 Gumpricht E, Dahl R, Devereaux M W, Sokol R J. Licorice compounds glycyrrhizin and 18β-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes.  J Biol Chem. 2005;  280 10 556-63.
  PubMedGoogle Scholar
• 11 Graf D, Kurz A K, Fischer R, Reinehr R, Haussinger D. Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.  Gastroenterology. 2002;  122 1411-27.
  CrossrefPubMedGoogle Scholar
• 12 Satoh M S, Lindahl T. Role of poly (ADP-ribose) formation in DNA repair.  Nature. 1992;  356 356-8.
  PubMedGoogle Scholar
• 13 Allen R T, Hunter W J, Agrawal D K. Morphological and biochemical characterization and analysis of apoptosis.  Pharmacol Toxicol Methods. 1997;  37 215-8.
  CrossrefPubMedGoogle Scholar
• 14 Rao Y P, Studer E J, Stravitz R T, Gupta S, Qiao L, Dent P. et al . Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes.  Hepatology. 2002;  35 307-14.
  CrossrefPubMedGoogle Scholar
• 15 Zhuang S, Schnellmann R G. A death-promoting role for extracellular signal-regulated kinase.  J Pharmacol Exp Ther. 2006;  319 91-7.
  PubMedGoogle Scholar
• 16 Czaja M J. The future of GI and liver research: editorial perspectives. III. JNK/AP-1 regulation of hepatocyte death.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G875-9.
  PubMedGoogle Scholar
• 17 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.
  CrossrefPubMedGoogle Scholar
• 18 Jung C H, Kim J H, Hong M H, Seog H M, Oh S H, Lee P J. et al . Phenolic-rich fraction from Rhus verniciflua Stokes (RVS) suppress inflammatory response via NF-kappaB and JNK pathway in lipopolysaccharide-induced RAW 264.7 macrophages.  J Ethnopharmacol. 2007;  110 490-7.
  CrossrefPubMedGoogle Scholar
• 19 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 20 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.
  Article in Thieme ConnectPubMedGoogle Scholar

Dong Hwan Sohn

Department of Pharmacy

Wonkwang University

Iksan

Jeonbuk 570-749

Republic of Korea

Phone: +82-63-850-6822

Fax: +82-63-854-6038

Email: dhsohn@wonkwang.ac.kr