Butein suppresses bile acid-induced hepatocyte apoptosis through a JNK-dependent but ERK-independent pathway.

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 microM for 4 h induced apoptosis, and treatment with butein at concentrations of 30 microM 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.