游离脂肪酸受体1激动剂fasiglifam（TAK875）及其主要代谢物的肝毒性机理研究。,Journal of Biochemical and Molecular Toxicology

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游离脂肪酸受体1激动剂fasiglifam（TAK875）及其主要代谢物的肝毒性机理研究。
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2019-05-08 , DOI: 10.1002/jbt.22345
Timothy Ackerson ₁ , Alexander Amberg ₂ , Jens Atzrodt ₃ , Catherine Arabeyre ₄ , Elisabeth Defossa ₃ , Martina Dorau ₂ , Angela Dudda ₅ , Jacquelyn Dwyer ₁ , Wolfgang Holla ₃ , Thomas Kissner ₂ , Markus Kohlmann ₅ , Ulrich Kürzel ₆ , József Pánczél ₆ , Shibani Rajanna ₁ , Jens Riedel ₆ , Friedemann Schmidt ₂ , Kerstin Wäse ₂ , Dietmar Weitz ₆ , Volker Derdau ₃

Affiliation

对于法西格坦（TAK875）及其代谢物，研究了该物质特异性肝毒性机制。进行了代谢研究，以鉴定出假定的反应性酰基葡萄糖醛酸苷代谢物。在2D和3D细胞培养中，在原代人和狗肝细胞中评估了体外细胞毒性和caspase 3/7激活。谷胱甘肽（GSH）脱毒系统通过介导GSH耗尽的体外系统中的细胞毒性增强作用来确定其介导的细胞毒性作用，此外，还通过全细胞线粒体功能分析评估了化合物的潜在线粒体功能。在传统的2D细胞毒性试验中，法西格芬对人原代肝细胞显示中等程度的细胞毒性，在短期（24小时或48小时）TC治疗后，在复杂的3D人肝显微组织（hLiMT）中也显示出中度细胞毒性_50个值介于56至68μM之间（三磷酸腺苷终点）。与24小时治疗相比，在hLiMT中进行14天的长期治疗可使TC ₅₀随时间推移轻微变化2.7 / 3.6倍，这表明长期治疗期间细胞毒性的风险可能更高。TAK875报道的DILI中未发现TAK875引起的细胞GSH耗竭和线粒体功能受损，以及通过Seahorse分析评估的代谢产物。TAK875的酰基葡糖醛酸苷代谢物最终被确定为肝毒性的主要原因。

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Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites.

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.

更新日期：2019-05-08

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