View : 51 Download: 0

Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner

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
Authors
Kim, MinjeongGu, Gyo JeongKoh, Yun-SookLee, Su-HyunNa, Yi RangSeok, Seung HyeokLim, Kyung-Min
Ewha Authors
임경민
SCOPUS Author ID
임경민scopus
Issue Date
2018
Journal Title
BIOMOLECULES & THERAPEUTICS
ISSN
1976-9148JCR Link

2005-4483JCR Link
Citation
BIOMOLECULES & THERAPEUTICS vol. 26, no. 6, pp. 599 - 607
Keywords
FasiglifamHepatotoxicityZebrafishReactive oxygen speciesGPR40G-protein coupled receptor 40
Publisher
KOREAN SOC APPLIED PHARMACOLOGY
Indexed
SCIE; SCOPUS; KCI WOS
Document Type
Article
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.
DOI
10.4062/biomolther.2017.225
Appears in Collections:
약학대학 > 약학과 > Journal papers
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE