Evaluation of Drugs With Specific Organ Toxicities in Organ-Specific Cell Lines
Evaluation of Drugs With Specific Organ Toxicities in Organ-Specific Cell Lines
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DOI：
10.1093/toxsci/kfr339
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发表时间：
2012-03-01
影响因子：
3.8
通讯作者：
Will, Yvonne
中科院分区：
文献类型：
--
作者：
Lin, Zhiwu;Will, Yvonne
由于患者福利和财务原因，临床前开发以及后期临床试验期间药物的安全性损耗仍然是制药行业面临的挑战。肝脏、心脏和肾毒性仍然是化合物终止的主要原因。近年来，已作出努力，以确定这样的负债在药物开发过程中，通过利用在硅片和细胞毒性模型。一些出版物旨在预测特定的器官毒性。例如，已经对肝毒性化合物进行了两次大规模评价。相比之下，只有小的心脏毒性和肾毒性化合物集进行了评价。在这里，我们研究了肝、心和肾来源的细胞系在（1）准确预测细胞毒性和（2）准确预测特定器官毒性方面的效用。我们在HepG 2（肝细胞癌）、H9 c2（胚胎心肌）和NRK-52 E（肾近端小管）细胞中测试了273种肝毒性、191种心脏毒性和85种肾毒性化合物的细胞毒性。我们发现，大多数化合物，无论其指定的器官毒性，在所有三种细胞系中具有相似的效果。只有大约5%的化合物在细胞系中显示出不同的毒性反应，与已知的体内器官毒性没有明显的相关性。我们的研究结果表明，从一般筛选的角度来看，不同的细胞系在评估一般细胞毒性方面具有相对相等的价值，并且使用这种简单的方法无法准确预测特定的器官毒性。选择器官毒性可能由特定组织中的化合物蓄积、器官内的细胞类型、代谢和脱靶效应引起。然而，我们的分析表明，当纳入人类C-max值时，预测可以显着改善。
Safety attrition of drugs during preclinical development as well as in late-stage clinical trials continues to be a challenge for the pharmaceutical industry for patient welfare and financial reasons. Hepatic, cardiac, and nephrotoxicity remain the main reasons for compound termination. In recent years, efforts have been made to identify such liabilities earlier in the drug development process, through utilization of in silico and cytotoxicity models. Several publications have aimed to predict specific organ toxicities. For example, two large-scale evaluations of hepatotoxic compounds have been conducted. In contrast, only small cardiotoxic and nephrotoxic compound sets have been evaluated. Here, we investigated the utility of hepatic-, cardiac-, and kidney-derived cell lines to (1) accurately predict cytotoxicity and (2) to accurately predict specific organ toxicities. We tested 273 hepatotoxic, 191 cardiotoxic, and 85 nephrotoxic compounds in HepG2 (hepatocellular carcinoma), H9c2 (embryonic myocardium), and NRK-52E (kidney proximal tubule) cells for their cytotoxicity. We found that the majority of compounds, regardless of their designated organ toxicities, had similar effects in all three cell lines. Only approximately 5% of compounds showed differential toxicity responses in the cell lines with no obvious correlation to the known in vivo organ toxicity. Our results suggest that from a general screening perspective, different cell lines have relatively equal value in assessing general cytotoxicity and that specific organ toxicity cannot be accurately predicted using such a simple approach. Select organ toxicity potentially results from compound accumulation in a particular tissue, cell types within organs, metabolism, and off-target effects. Our analysis, however, demonstrates that the prediction can be improved significantly when human C-max values are incorporated.