Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner
- 주제(키워드) Fasiglifam , Hepatotoxicity , Zebrafish , Reactive oxygen species , GPR40 , G-protein coupled receptor 40
- 주제(기타) Biochemistry & Molecular Biology; Pharmacology & Pharmacy
- 설명문(일반) [Kim, Minjeong; Koh, Yun-Sook; Lim, Kyung-Min] Ewha Womans Univ, Coll Pharmacol, Seoul 03760, South Korea; [Gu, Gyo Jeong; Na, Yi Rang; Seok, Seung Hyeok] Seoul Natl Univ, Dept Microbiol & Immunol, Coll Med, Seoul 03080, South Korea; [Gu, Gyo Jeong; Na, Yi Rang; Seok, Seung Hyeok] Seoul Natl Univ, Inst Endem Dis, Coll Med, Seoul 03080, South Korea; [Lee, Su-Hyun] Biosolut Co, Seoul 01811, South Korea
- 등재 SCIE, SCOPUS, KCI등재
- 발행기관 KOREAN SOC APPLIED PHARMACOLOGY
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156631
- 본문언어 영어
- Published As http://dx.doi.org/10.4062/biomolther.2017.225
초록/요약
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.
more