Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 임경민 | * |
dc.date.accessioned | 2019-01-02T16:30:20Z | - |
dc.date.available | 2019-01-02T16:30:20Z | - |
dc.date.issued | 2018 | * |
dc.identifier.issn | 1976-9148 | * |
dc.identifier.issn | 2005-4483 | * |
dc.identifier.other | OAK-23994 | * |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/248096 | - |
dc.description.abstract | Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 mu M) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 mu M. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 mu M. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner. | * |
dc.language | English | * |
dc.publisher | KOREAN SOC APPLIED PHARMACOLOGY | * |
dc.subject | Fasiglifam | * |
dc.subject | Hepatotoxicity | * |
dc.subject | Zebrafish | * |
dc.subject | Reactive oxygen species | * |
dc.subject | GPR40 | * |
dc.subject | G-protein coupled receptor 40 | * |
dc.title | Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner | * |
dc.type | Article | * |
dc.relation.issue | 6 | * |
dc.relation.volume | 26 | * |
dc.relation.index | SCIE | * |
dc.relation.index | SCOPUS | * |
dc.relation.index | KCI | * |
dc.relation.startpage | 599 | * |
dc.relation.lastpage | 607 | * |
dc.relation.journaltitle | BIOMOLECULES & THERAPEUTICS | * |
dc.identifier.doi | 10.4062/biomolther.2017.225 | * |
dc.identifier.wosid | WOS:000449738500011 | * |
dc.author.google | Kim, Minjeong | * |
dc.author.google | Gu, Gyo Jeong | * |
dc.author.google | Koh, Yun-Sook | * |
dc.author.google | Lee, Su-Hyun | * |
dc.author.google | Na, Yi Rang | * |
dc.author.google | Seok, Seung Hyeok | * |
dc.author.google | Lim, Kyung-Min | * |
dc.contributor.scopusid | 임경민(8916551700) | * |
dc.date.modifydate | 20240220115649 | * |