Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2017.11.01
  • Accepted : 2018.01.12
  • Published : 2018.11.01
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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.

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References

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