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

Article Details

Citation

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
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
LY-294002ExperimentalGCLC2729
downregulated
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GCLC mRNA6p12.1
LY-294002ExperimentalGCLM2730
downregulated
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GCLM mRNA1p22.1
LY-294002ExperimentalGSS2937
downregulated
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in decreased expression of GSS mRNA20q11.22
IronApprovedGCLC2729
downregulated
Iron results in decreased expression of GCLC mRNA6p12.1
IronApprovedGCLM2730
downregulated
Iron results in decreased expression of GCLM mRNA1p22.1
IronApprovedGSS2937
downregulated
Iron results in decreased expression of GSS mRNA20q11.22
Ursodeoxycholic acidApproved InvestigationalGCLC2729
upregulated
Ursodeoxycholic Acid results in increased expression of GCLC mRNA6p12.1
Ursodeoxycholic acidApproved InvestigationalGCLM2730
upregulated
Ursodeoxycholic Acid results in increased expression of GCLM mRNA1p22.1
Ursodeoxycholic acidApproved InvestigationalGSS2937
upregulated
Ursodeoxycholic Acid results in increased expression of GSS mRNA20q11.22