PF2401-SF, standardized fraction of Salvia miltiorrhiza and its constituents, tanshinone I, tanshinone IIA, and cryptotanshinone, protect primary cultured rat hepatocytes from bile acid-induced apoptosis by inhibiting JNK phosphorylation.
Bile acid-induced hepatocyte apoptosis plays an important role in cholestatic liver disease, and the role of apoptosis may be of therapeutic interest in preventing liver disease. The dried root of Salvia miltiorrhiza Bunge (Labiatae) has been used traditionally to treat liver diseases. We investigated the antiapoptotic effects of a standardized fraction of S. miltiorrhiza (PF2401-SF) and its components, tanshinone I, tanshinone IIA, and cryptotanshinone, in primary cultured rat hepatocytes. PF2401-SF was enriched with tanshinone I (11.5%), tanshinone IIA (41.0%), and cryptotanshinone (19.1%). Glycochenodeoxycholic acid (GCDC)-induced apoptosis, as shown by DNA fragmentation, poly(ADP-ribose) polymerase cleavage, and activation of caspases-8, -9, and -3. PF2401-SF and its components, tanshinone I, tanshinone IIA, and cryptotanshinone showed antiapoptotic activity. Treatment with PF2401-SF or with its components significantly inhibited the generation of intracellular reactive oxygen species. Hydrophobic bile acids activate c-Jun-NH(2)-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPK), and extracellular signal-regulated kinase 1/2, and PF2401-SF inhibited the phosphorylation of JNK and p38. All three components of PF2401-SF inhibited JNK phosphorylation. Addition of inhibitors of MAPK showed that inhibition of JNK decreased apoptosis. These data indicate that PF2401-SF and its components protect hepatocytes from GCDC-induced apoptosis in vitro by inhibiting JNK.
Park
Eun-Jeon
EJ
Department of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Zhao
Yu-Zhe
YZ
Kim
Youn-Chul
YC
Sohn
Dong Hwan
DH
D045784:Abietanes; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000037:antagonists & inhibitors / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003124:Colorimetry; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005999:Glycochenodeoxycholic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D027544:Salvia / Q000737:chemistry*
D045784:Abietanes; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D010616:Phenanthrenes; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C021751:tanshinone; D005999:Glycochenodeoxycholic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases