Early Safety Assessment Using Cellular Systems Biology Yields Insights into Mechanisms of Action
Early Safety Assessment Using Cellular Systems Biology Yields Insights into Mechanisms of Action
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DOI：
10.1177/1087057110376413
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发表时间：
2010-08-01
影响因子：
--
通讯作者：
Johnston, Patricia A.
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文献类型：
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作者：
Giuliano, Kenneth A.;Gough, Albert H.;Johnston, Patricia A.
将高含量筛选（HCS）阅读器与器官特异性细胞模型、功能性生物标志物面板和先进的信息学相结合，是在开发过程早期识别化合物毒性的有力方法，并形成“早期安全性评估”的基础。这种细胞系统生物学（CSB (TM)）方法（CellCiphr (R)谱）已被用于将啮齿动物和人类细胞肝脏模型与在多个时间点测量的功能生物标志物组合在一起，以描述细胞毒理学反应的效力和特异性。这些概况也为毒性反应的机制提供了初步的见解。作者在这里描述了机制分析概况，旨在进一步剖析毒性作用机制，并阐明在细胞亚群中明显的微妙影响。他们在活的原代肝细胞和HepG2细胞群体中同时测量了多种生物标志物特征，测量了8种关键的毒性机制。从这些机制剖面中挖掘细胞群体反应揭示了反应的浓度依赖性和异质性的性质，以及功能反应之间的关系。这些更详细的机制概况定义了在平均人群反应中不明显的复合活动的差异。由于细胞和组织在空间和时间上遇到大范围的药物剂量，这些机制谱建立在CellCiphr (R)谱的基础上，更好地反映了体内反应的复杂性。（Journal of biomolmolecular Screening 2010:783-797）
The integration of high-content screening (HCS) readers with organ-specific cell models, panels of functional biomarkers, and advanced informatics is a powerful approach to identifying the toxic liabilities of compounds early in the development process and forms the basis of "early safety assessment." This cellular systems biology (CSB (TM)) approach (CellCiphr (R) profile) has been used to integrate rodent and human cellular hepatic models with panels of functional biomarkers measured at multiple time points to profile both the potency and specificity of the cellular toxicological response. These profiles also provide initial insights on the mechanism of the toxic response. The authors describe here mechanistic assay profiles designed to further dissect the toxic mechanisms of action and elucidate subtle effects apparent in subpopulations of cells. They measured 8 key mechanisms of toxicity with multiple biomarker feature measurements made simultaneously in populations of living primary hepatocytes and HepG2 cells. Mining the cell population response from these mechanistic profiles revealed the concentration dependence and nature of the heterogeneity of the response, as well as relationships between the functional responses. These more detailed mechanistic profiles define differences in compound activities that are not apparent in the average population response. Because cells and tissues encounter wide ranges of drug doses in space and time, these mechanistic profiles build on the CellCiphr (R) profile and better reflect the complexity of the response in vivo. (Journal of Biomolecular Screening 2010:783-797)