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首页> 外文期刊>Journal of biochemical and molecular toxicology >Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites
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Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

机译：机械研究对游离脂肪酸受体1激动剂Fasiglifam（Tak875）及其原代代谢物的肝脏毒性

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Abstract 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 TC 50 values of 56 to 68?μM (adenosine triphosphate endpoint). The long‐term treatment for 14 days in the hLiMT resulted in a slight TC 50 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.
机译：Fasiglifam（Tak875）及其代谢物研究了肝脏毒性的物质特异性机制。运行代谢研究以鉴定辅助活性酰葡糖苷代谢物代谢物。在2D和3D细胞培养中，在原发性人和狗肝细胞中评估体外细胞毒性和Caspase 3/7活化。通过评估在体外系统中的GSH中的细胞毒性的增强来确定谷胱甘肽（GSH）解毒系统介导细胞毒性的诱导。此外，在全细胞线粒体功能测定中评估化合物的潜在线粒体负债。 Fasiglifam在古典2D细胞毒性测定中的人母原发性肝细胞中显示中等细胞毒性，并且在短期处理（24小时或48小时）后的复合3D人肝脏微仪（HLIMT）中，TC 50值为56至68Ωμm（腺苷三磷酸终点）。在HLIMT中的长期处理14天导致略微的TC 50随时间转移为2.7 / 3.6倍，与24小时治疗表明长期治疗期间细胞毒性的风险更高。 TAK875的细胞GSH消耗和线粒体功能损伤及其由海马测定评估的其代谢产物涉及TAK875报告的帝力。最终鉴定了Tak875的酰氨基葡萄糖代谢物是肝脏毒性的主要原因。

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