Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites
| Autor: | Jens Atzrodt, Friedemann Schmidt, Kerstin Wäse, Jacquelyn Dwyer, Wolfgang Holla, Martina Dorau, Alexander Amberg, Volker Derdau, József Pánczél, Angela Dudda, Ulrich Kürzel, Dietmar Weitz, Elisabeth Defossa, Catherine Arabeyre, Markus Kohlmann, Timothy Ackerson, Jens Riedel, Thomas Kissner, Shibani Rajanna |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Health Toxicology and Mutagenesis Metabolite Mitochondria Liver Caspase 3 Fatty Acids Nonesterified Pharmacology Toxicology Biochemistry Receptors G-Protein-Coupled 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Free fatty acid receptor 1 medicine Animals Humans Sulfones Cytotoxicity Molecular Biology Cells Cultured Benzofurans 030102 biochemistry & molecular biology General Medicine Metabolism Glutathione Rats Liver chemistry 030220 oncology & carcinogenesis Hepatocytes Microsomes Liver Molecular Medicine Adenosine triphosphate |
| Zdroj: | Journal of Biochemical and Molecular Toxicology. 33 |
| ISSN: | 1099-0461 1095-6670 |
| DOI: | 10.1002/jbt.22345 |
| Popis: | For fasiglifam (TAK875) and its metabolites the substance-specific mechanisms of liver toxicity were studied. Metabolism studies were run to identify a putatively reactive acyl glucuronide metabolite. In vitro cytotoxicity and caspase 3/7 activation were assessed in primary human and dog hepatocytes in 2D and 3D cell culture. Involvement of glutathione (GSH) detoxication system in mediating cytotoxicity was determined by assessing potentiation of cytotoxicity in a GSH depleted in vitro system. In addition, potential mitochondrial liabilities of the compounds were assessed in a whole-cell mitochondrial functional assay. Fasiglifam showed moderate cytotoxicity in human primary hepatocytes in the classical 2D cytotoxicity assays and also in the complex 3D human liver microtissue (hLiMT) after short-term treatment (24 hours or 48 hours) with TC50 values of 56 to 68 µM (adenosine triphosphate endpoint). The long-term treatment for 14 days in the hLiMT resulted in a slight TC50 shift over time of 2.7/3.6 fold lower vs 24-hour treatment indicating possibly a higher risk for cytotoxicity during long-term treatment. Cellular GSH depletion and impairment of mitochondrial function by TAK875 and its metabolites evaluated by Seahorse assay could not be found being involved in DILI reported for TAK875. The acyl glucuronide metabolites of TAK875 have been finally identified to be the dominant reason for liver toxicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text