Eupatilin attenuates bile acid-induced hepatocyte apoptosis.

Abstract

BACKGROUND:

In cases of cholestasis, bile acids induce hepatocyte apoptosis by activating death receptor-mediated apoptotic signaling cascades. Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a pharmacologically active ingredient found in Artemisia asiatica and exhibits cytoprotective effects against experimentally induced gastrointestinal, pancreatic, and hepatic damage. This study was undertaken to examine if eupatilin modulates bile acid-induced hepatocyte apoptosis.

METHODS:

Huh-BAT cells, a human hepatocellular carcinoma cell line stably transfected with a bile acid transporter, were used in this study. Apoptosis was quantified using 4',6-diamidino-2-phenylindole dihydrochloride staining, and its signaling cascades were explored by immunoblot analysis. Kinase signaling was evaluated by immunoblotting and by using selective inhibitors. Eupatilin's in vivo effect on bile acid-induced hepatocyte apoptosis was explored in bile duct-ligated rats.

RESULTS:

Eupatilin significantly reduced bile acid-mediated hepatocyte apoptosis by attenuating bile acid-induced caspase 8 cleavage. Eupatilin diminished the bile acid-induced activation of mitogen-activated protein kinases, including p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In particular, the eupatilin-mediated inhibition of bile acid-induced c-Jun N-terminal kinase activation was found to be responsible for attenuating caspase 8 cleavage. Moreover, eupatilin diminished hepatocyte apoptosis in bile duct-ligated rats.

CONCLUSIONS:

Eupatilin attenuates bile acid-induced hepatocyte apoptosis by suppressing bile acid-induced kinase activation. Therefore, eupatilin might be therapeutically efficacious in a variety of human liver diseases associated with cholestasis.

• Authors: Su Cheol Park, Jung-Hwan Yoon, Won Kim, Geum-Youn Gwak, Kang Mo Kim, Sung-Hee Lee, Soo-Mi Lee, Hyo-Suk Lee
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 41 Issue 8 Pg. 772-8 (Aug 2006) ISSN: 0944-1174 [Print] Japan
• PMID: 16988766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Deoxycholic Acid
• eupatilin
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspase 8

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cholestasis (drug therapy)
• Deoxycholic Acid (pharmacology)
• Flavonoids (pharmacology)
• Hepatocytes (drug effects)
• Humans
• Immunoblotting
• In Situ Nick-End Labeling
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Microscopy, Fluorescence
• Models, Animal
• Rats
• Rats, Sprague-Dawley
• p38 Mitogen-Activated Protein Kinases (metabolism)