Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model
Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model
复制标题
DOI：
10.1016/j.tiv.2009.07.026
复制
发表时间：
2009-10-01
影响因子：
3.2
通讯作者：
Ek, Monica
中科院分区：
文献类型：
--
作者：
Edling, Ylva;Sivertsson, Louise K.;Ek, Monica
药物诱导的肝毒性是药物退出开发和市场的主要原因。预测肝毒性的一个主要问题是缺乏合适的体外预测系统。药物诱导的肝毒性通常与免疫细胞向肝脏的募集有关，加速通常由枯否细胞激活引发的炎症反应。为了评估是否引入炎性细胞可以增加药物诱导的细胞毒性的敏感性，我们开发了一种基于两种人细胞系的体外共培养系统;肝细胞瘤（Huh-7）和单核细胞（THP-1）细胞系。作为模型药物，我们选择了两种过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂，肝毒性曲格列酮和非肝毒性罗格列酮。在共同培养中。与任一细胞系的单一培养物相比，曲格列酮引起增强的细胞毒性，而用罗格列酮处理后几乎没有观察到细胞毒性。曲格列酮治疗增加了两种细胞类型中促炎介质和应激相关基因的基因表达，通常在共培养中比在单细胞培养中更明显。基于这些结果，我们认为，人肝癌细胞和单核细胞的共培养可能提供一个重要的体外系统，更好地预测潜在的肝毒素介导的细胞毒性。(C)2009爱思唯尔有限公司版权所有。
Drug-induced hepatotoxicity is a major reason for withdrawal of drugs from development as well as from the market. A major problem predicting hepatotoxicity is the lack of suitable predictive in vitro system. Drug-induced hepatotoxicity is usually associated with the recruitment of immune cells to the liver accelerating an inflammatory response often initiated by activation of the Kupffer cells. In order to evaluate whether the introduction of inflammatory cells could increase the sensitivity for drug-induced cytotoxicity we developed an in vitro co-culture system based on two human cell lines; a hepatoma (Huh-7) and monocytic (THP-1) cell line. As model drugs we chose two peroxisome proliferator activated receptor gamma (PPAR gamma) agonists, the hepatotoxic troglitazone and the non-hepatotoxic rosiglitazone. In the co-cultures. troglitazone caused an enhanced cytotoxicity as compared to single cultures of either cell line, whereas little cytotoxicity was seen after treatment with rosiglitazone. Troglitazone treatment increased gene expression of pro-inflammatory mediators and stress-related genes in both cell types, which in general was more pronounced in co-cultures than in single cell cultures. Based on these results we suggest that co-cultures of human hepatoma cells and monocytes might provide an important in vitro system for better prediction of cytotoxicity mediated by potential hepatotoxins. (C) 2009 Elsevier Ltd. All rights reserved.