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http://dx.doi.org/10.4062/biomolther.2017.225

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

Kim, MinJeong (College of Pharmacology, Ewha Womans University)
Gu, Gyo Jeong (Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine)
Koh, Yun-Sook (College of Pharmacology, Ewha Womans University)
Lee, Su-Hyun (Biosolutions Co.)
Na, Yi Rang (Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine)
Seok, Seung Hyeok (Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine)
Lim, Kyung-Min (College of Pharmacology, Ewha Womans University)
Publication Information
Biomolecules & Therapeutics / v.26, no.6, 2018 , pp. 599-607 More about this Journal
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.
Keywords
Fasiglifam; Hepatotoxicity; Zebrafish; Reactive oxygen species; GPR40; G-protein coupled receptor 40;
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