Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells.
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Arisawa S, Ishida K, Kameyama N, Ueyama J, Hattori A, Tatsumi Y, Hayashi H, Yano M, Hayashi K, Katano Y, Goto H, Takagi K, Wakusawa S
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.
- PubMed ID
- 19073151 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome LY-294002 Experimental GCLC 2729 downregulated 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GCLC mRNA 6p12.1 LY-294002 Experimental GCLM 2730 downregulated 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GCLM mRNA 1p22.1 LY-294002 Experimental GSS 2937 downregulated 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GSS mRNA 20q11.22 Iron Approved GCLC 2729 downregulated Iron results in decreased expression of GCLC mRNA 6p12.1 Iron Approved GCLM 2730 downregulated Iron results in decreased expression of GCLM mRNA 1p22.1 Iron Approved GSS 2937 downregulated Iron results in decreased expression of GSS mRNA 20q11.22 Ursodeoxycholic acid Approved Investigational GCLC 2729 upregulated Ursodeoxycholic Acid results in increased expression of GCLC mRNA 6p12.1 Ursodeoxycholic acid Approved Investigational GCLM 2730 upregulated Ursodeoxycholic Acid results in increased expression of GCLM mRNA 1p22.1 Ursodeoxycholic acid Approved Investigational GSS 2937 upregulated Ursodeoxycholic Acid results in increased expression of GSS mRNA 20q11.22