3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity studies
3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity studies
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DOI：
10.1016/j.tiv.2013.06.024
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发表时间：
2014-02-01
影响因子：
3.2
通讯作者：
Noor, Fozia
中科院分区：
文献类型：
--
作者：
Mueller, Daniel;Kraemer, Lisa;Noor, Fozia
替代体内动物模型的体外预测模型将对毒理学产生重大影响。传统的2D模型不能反映3D器官的复杂性，导致体外和体内实验数据之间的差异。使用3D HepaRG器官型培养物，我们测试了四种药物（黄曲霉毒素91、胺碘酮、丙戊酸和氯丙嗪）的毒性作用，并将结果与20种HepaRG和HepG 2培养物进行了比较。我们发现，3D HepaRG培养物比其他测试的培养物对黄曲霉毒素B1更敏感，黄曲霉毒素B1仅在肝脏代谢活化时有毒。我们观察到3D HepaRG培养物中的CYP 3A 4活性高于2D HepaRG培养物。此外，我们研究了氯丙嗪的重复剂量毒性，并评估了其对葡萄糖和乳酸代谢的影响。急性和重复剂量（3剂）暴露后，亚毒性浓度的氯丙嗪会诱导2D和3D HepaRG培养物发生显着的代谢变化。总之，我们的数据支持3D细胞培养模型更好地模拟体内组织并改善细胞功能的假设。3D HepaRG器官型培养代表了用于药物毒性筛选的高通量系统。因此，该系统是人类相关性的临床前测试中有前途的工具，可以减少和/或取代药物不良反应的动物测试。(C)2013爱思唯尔有限公司保留所有权利。
Predictive in vitro models alternative to in vivo animal will have a significant impact in toxicology. Conventional 2D models do not reflect the complexity of a 3D organ resulting in discrepancies between experimental in vitro and in vivo data. Using 3D HepaRG organotypic cultures we tested four drugs (aflatoxin 91, amiodarone, valproic acid and chlorpromazine) for toxic effects and compared the results with 20 HepaRG and HepG2 cultures. We show that 3D HepaRG cultures are more sensitive than the other tested cultures to aflatoxin B1 which is only toxic upon metabolic activation in the liver. We observed that CYP3A4 activity is higher in the 3D HepaRG cultures compared to the 2D HepaRG cultures. Furthermore, we investigated repeated dose toxicity of chlorpromazine and assessed its effects on glucose and lactate metabolism. Sub-toxic concentrations of chlorpromazine induced significant metabolic changes in both 2D and 3D HepaRG cultures upon acute and repeated dose (3 doses) exposure. In summary, our data support the hypothesis that 3D cell culture models better mimic the in vivo tissue and improve cellular functionality. The 3D HepaRG organotypic cultures represent a high throughput system for drug toxicity screening. This system is therefore a promising tool in preclinical testing of human relevance which can allow reducing and/or replacing animal testing for drug adverse effects. (C) 2013 Elsevier Ltd. All rights reserved.