A cell-based, multiparametric sensor approach characterises drug-induced cytotoxicity in human liver HepG2 cells
A cell-based, multiparametric sensor approach characterises drug-induced cytotoxicity in human liver HepG2 cells
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DOI：
10.1016/j.tiv.2013.02.001
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发表时间：
2013-04-01
影响因子：
3.2
通讯作者：
Huwyler, Joerg
中科院分区：
文献类型：
--
作者：
Seeland, Swen;Toeroek, Michael;Huwyler, Joerg
药物毒性是药物研发中的一个重要问题，因此，建立一种无标记、实时、多参数的细胞传感器系统用于药物毒性的体外评价，是一种有效的体外评价方法。该系统是基于监测细胞的耗氧量，酸化和阻抗的人肝癌衍生的HepG2细胞。来自多参数cytosensor系统的读出已被优化，并允许敏感，可靠，同时记录细胞的生理信号，如代谢活动，细胞呼吸和形态变化和细胞粘附后暴露于drug.Analysis的8个原型参考药物揭示了不同的模式药物诱导的生理信号。结果表明，这些效应具有严格的浓度依赖性。基于信号模式和观察到的效应的可逆性，化合物可以基于呼吸或代谢应激或导致细胞死亡的病症（坏死样和坏死样）的触发机制进行分类。提出了一种测试标记风险缓解策略，以解决药物诱导细胞毒性的潜在风险。(C)2013爱思唯尔有限公司保留所有权利。
Drug-induced toxicity is of considerable concern in drug discovery and development, placing emphasis on the need for predictive in vitro technologies that identify potential cytotoxic side effects of drugs.A label-free, real-time, multiparametric cytosensor system has therefore been established for in vitro assessment of drug-induced toxicity. The system is based on monitoring cellular oxygen consumption, acidification and impedance of human hepatocarcinoma-derived HepG2 cells. The read-out derived from the multiparametric cytosensor system has been optimised and permits sensitive, reliable, and simultaneous recording of cell physiological signals, such as metabolic activity, cellular respiration and morphological changes and cell adhesion upon exposure to a drug.Analysis of eight prototypic reference drugs revealed distinct patterns of drug-induced physiological signals. Effects proved to be rigidly concentration-dependent. Based on signal patterns and reversibility of the observed effects, compounds could be classified based as triggering mechanisms of respiratory or metabolic stress or conditions leading to cell death (necrosis-like and apoptosis-like). A test-flag-risk mitigation strategy is proposed to address potential risks for drug-induced cytotoxicity. (C) 2013 Elsevier Ltd. All rights reserved.