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首页> 外文期刊>Applied in vitro toxicology. >Fit-For-Purpose Hepatocyte Models Enable the Identification of Early Events Contributing to Idelalisib-Induced Liver Injury
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Fit-For-Purpose Hepatocyte Models Enable the Identification of Early Events Contributing to Idelalisib-Induced Liver Injury

机译：定制使肝细胞模型识别导致的早期事件Idelalisib-Induced肝损伤

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Introduction: Idelalisib is a phosphatidylinositol 3-delta kinase inhibitor that has shown good efficacy in treating some hematologic malignancies. Rare, but potentially serious liver toxicity was associated with idelalisib use in clinical trials. The objective of this study was to evaluate the early idelalisib-induced changes in human hepatocytes using a combination of in vitro models and techniques to identify mechanisms contributing to overt liver injury observed in the clinic.Materials and Methods: Primary human hepatocytes from two donors and the HepaRG cell line were cultured as three-dimensional (3D) liver models, with and without primary human nonparenchymal cells. A panel of high-content imaging endpoints was used to evaluate responses across six concentrations of idelalisib (0.6–180 μM) and three timepoints of exposure (1, 7, and 14 days). Primary human hepatocytes from three donors were also sandwich cultured in two-dimensional (2D) format and assayed for cytotoxicity, global gene expression, and exosome responses across similar concentrations of idelalisib after a 1-day exposure.Results: In 3D liver models, the most sensitive endpoints to idelalisib were ATP and glutathione depletion and longer exposures resulted in a more robust response. In 2D hepatocytes, statistically significant decreases in albumin secretion were observed at both the 60 and 180 μM concentrations and the most significantly enriched pathway among genes upregulated in response to idelalisib was “Endoplasmic Reticulum Stress.”Discussion and Conclusion: Taken together, these data suggest that oxidative stress is an early event contributing to idelalisib-induced liver injury and demonstrate how fit-for-purpose in vitro models can be used to investigate mechanisms of drug toxicity.
机译：作品简介:Idelalisib磷脂酰肌醇3-delta激酶抑制剂所示好疗效在治疗一些血液恶性肿瘤。毒性与idelalisib使用临床试验评估早期idelalisib-induced变化在人类肝细胞使用的组合体外模型和技术来识别造成明显的肝损伤机制观察在诊所。主要从两个捐助者和人类肝细胞HepaRG细胞系被培养三维(3 d)肝脏模型,和没有主要的人类nonparenchymal细胞。使用高含量成像小组端点评估在6个浓度的反应idelalisib(0.6 -180μM)和三个时间点接触(1、7和14天)。肝细胞从三个捐助者也三明治在二维(2 d)格式和培养化验的细胞毒性,全球基因表达,和外来体反应相似一天后idelalisib浓度曝光。敏感的端点idelalisib ATP和谷胱甘肽耗竭和长时间曝光导致一种更健壮的反应。肝细胞,显著减少在白蛋白分泌观察60和180μM浓度和最大大丰富了通路中基因调节响应idelalisib“内质网压力。”结论:综上所述,这些数据显示氧化应激是一个早期事件导致idelalisib-induced肝损伤并演示如何定制体外模型可以用来调查机制药物毒性。

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