Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells

Biochem Pharmacol. 2009 Mar 1;77(5):858-66. doi: 10.1016/j.bcp.2008.11.012. Epub 2008 Nov 25.


Ursodeoxycholic acid (UDCA) is widely recognized as an effective compound in the treatment of chronic hepatitis and is known to modulate the redox state of the liver accompanied by an increase of GSH. In the present study, to access the antioxidative effect of UDCA and to clarify the molecular basis of the action on GSH level, we evaluated its effects in HepG2 cells exposed to excessive iron. UDCA inhibited both a decrease in the GSH level and an increase in the reactive oxygen species caused by excessive iron in the cells. UDCA increased the gene expression of the catalytic- and modifier-units of glutamine-cysteine ligase (GCL), which is a key enzyme in GSH synthesis. We further investigated the effect of UDCA on the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and obtained results showing that UDCA-induced increase in the GSH level was prevented by LY294002, a PI3K inhibitor. In addition, Western blot analysis of Akt showed that, while the total Akt level remained unchanged, the phosphorylated Akt level was increased by UDCA, and this increase was also prevented by LY294002. Moreover, UDCA promoted the translocation of a transcription factor, nuclear factor-E2-related factor-2 (Nrf2), into the nucleus, and this action was inhibited by LY294002. From these results, it was indicated that UDCA increased the GSH synthesis through an activation of the PI3K/Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of UDCA concerned with its therapeutic effectiveness in chronic hepatitis.

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Chromones / pharmacology
  • DNA Primers
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Glutathione / biosynthesis*
  • Humans
  • Morpholines / pharmacology
  • NF-E2-Related Factor 2 / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ursodeoxycholic Acid / pharmacology*


  • Chromones
  • DNA Primers
  • Enzyme Inhibitors
  • Morpholines
  • NF-E2-Related Factor 2
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Ursodeoxycholic Acid
  • Proto-Oncogene Proteins c-akt
  • Glutathione