The effect of ursodeoxycholic acid on glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes

Toxicology. 2005 Oct 15;214(1-2):77-86. doi: 10.1016/j.tox.2005.05.025.


Ursodeoxycholic acid (UDCA) has been widely used for treating cholestatic liver diseases. However, in a recent review of clinical trial articles, its therapeutic benefits were not proven. Therefore, we investigated whether UDCA prevents or potentiates glycochenodeoxycholic acid (GCDCA)-induced apoptosis in isolated rat hepatocytes. Hepatocellular cytotoxicity was assessed by lactate dehydrogenase (LDH) release, and apoptosis evaluated by DNA fragmentation, caspase activities, release of cytochrome C from mitochondria, and mitochondrial membrane potential change (Deltapsi). When hepatocytes were co-incubated with GCDCA and UDCA for a short time (2-6 h), GCDCA-induced LDH release was significantly reduced, while prolonged co-incubation (12-20 h) increased it. Similarly, the same co-incubation for a short time resulted in the inhibition of caspase activities and cytochrome C release, while prolonged incubation enhanced them compared with the incubation with GCDCA alone. Furthermore, UDCA significantly promoted the GCDCA-induced Deltapsi decline after 4h of incubation. These results demonstrated that UDCA reduced GCDCA-induced apoptosis in short incubation, but potentiated it in prolonged incubation. Based on these, we propose a hypothesis that induction of Deltapsi decrease from earlier stage of incubation may be responsible for the aggravation of GCDCA-induced apoptosis in long-term exposure, and would like to raise caution about clinical long-term use of UDCA.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • Electrophoresis, Agar Gel
  • Glycochenodeoxycholic Acid / pharmacology*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ursodeoxycholic Acid / pharmacology*


  • Glycochenodeoxycholic Acid
  • Ursodeoxycholic Acid
  • Cytochromes c
  • Caspases