Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity
Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity
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DOI：
10.1016/j.taap.2009.04.002
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发表时间：
2009-06-15
影响因子：
3.8
通讯作者：
Lauffenburger, Douglas A.
中科院分区：
文献类型：
--
作者：
Cosgrove, Benjamin D.;King, Bracken M.;Lauffenburger, Douglas A.
由于目前临床前筛选试验的不足，特异性药物肝毒性是药物开发中的一个主要问题，但最近建立的利用细菌内毒素联合给药诱导炎症背景的啮齿动物模型已成功地再现了某些药物的特异性肝毒性特征。然而，这些模型的低通量性质使得它们作为临床前筛查分析的使用存在问题。在这里，我们呈现一个类似的。但这是一种高通量的体外方法，在这种方法中，药物被注射到各种类型的细胞(原代人和大鼠肝细胞以及人HepG2细胞系)，跨越含有内毒素和细胞因子肿瘤坏死因子、干扰素-γ、白介素1α和白介素6的炎症环境。使用这种方法，我们观察到了多种特殊肝毒剂(雷尼替丁、曲瓦沙星、奈法唑酮、尼美舒利、克拉霉素和泰利霉素)的药物-细胞因子肝毒性协同作用，但没有观察到相应的无毒对照化合物(法莫替丁、左氧氟沙星、丁螺环酮和阿司匹林)的药物-细胞因子肝毒性协同作用。一份更大的药物-细胞因子混合肝毒性数据概要显示，在多细胞因子混合的背景下，肿瘤坏死因子、IL-1α和脂多糖在很大程度上增强了肝毒性的协同作用。然后，我们筛选了90种在人类肝细胞中发挥细胞因子协同作用的药物，发现与单一细胞因子混合物协同作用的特殊肝毒药物比例(19%)显著高于非肝毒性药物(3%)。最后，我们使用信息论的方法来确定最有效地构建药物和细胞因子混合诱导的这些细胞系统的肝毒性回归模型的细胞因子治疗的信息量亚组。我们的结果表明，这种药物-细胞因子共同治疗的方法可以为研究炎症相关的特异性药物肝毒性提供一个有用的临床前工具。(C)2009 Elsevier Inc.保留所有权利。
Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous. but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFN gamma, IL-1 alpha, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1 alpha, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity. (C) 2009 Elsevier Inc. All rights reserved.