体外肝脏3D模型在药物肝毒性评价中的优势

发布时间：2018-10-09 07:24

【摘要】：建立及评价体外肝脏3D模型在药物肝毒性评价中的优势。本研究利用悬滴技术构建Hepa RG3D多细胞聚球体模型,并检测其肝功能水平,最后用该模型评价2个肝毒性阳性药重复给药毒性,并与2D模型下单次给药毒性进行比较。Hepa RG细胞聚集生长形成微组织体,该模型的细胞白蛋白表达水平、尿素分泌水平和CYP3A4活性诱导水平均显著高于2D模型。盐酸胺碘酮在2D和3D培养模型下IC_(50)分别为50和100μmol·L~(-1);异烟肼在2D模型下IC_(50)1 mmol·L~(-1),3D模型下IC_(50)为700μmol·L~(-1)。两个药物在3D模型下LDH活性均呈现明显的时间/给药次数依赖性和剂量正相关性。结果提示成功建立体外肝脏3D悬滴培养模型,与2D模型比较,该模型可用于准确评价肝毒性阳性药,并为将来体外准确、高通量和多次长期给药评价药物肝脏毒性提供可能。
[Abstract]:To establish and evaluate the advantages of in vitro liver 3D model in the evaluation of drug hepatotoxicity. In this study, the Hepa RG3D multicellular globular model was constructed by hanging drop technique, and its liver function was measured. Finally, the model was used to evaluate the repeated administration toxicity of two hepatotoxic positive drugs. The cytotoxicity of Hepa RG cells was compared with that of 2D model. The cell albumin expression level, urea secretion level and CYP3A4 activity induction level of the model were significantly higher than that of 2D model. The IC_ _ (50) of amiodarone hydrochloride was 50 渭 mol / L ~ (-1) in 2D model and 100 渭 mol / L ~ (-1) of isoniazid in 2D model and IC_ (50) was 700 渭 mol L ~ (-1) in 3D model of isoniazid. The LDH activity of the two drugs in 3D model was time-dependent and dose-dependent. The results suggested that the 3D suspension culture model of liver in vitro was successfully established. Compared with 2D model, the model could be used to accurately evaluate the hepatotoxicity positive drugs, and provide the possibility for the evaluation of liver toxicity in the future with accurate, high-throughput and multiple long-term administration in vitro.
【作者单位】：中国食品药品检定研究院国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室;中山大学药学院;
【基金】：“十二五”国家科技重大专项符合中药特点的有毒中药安评关键技术(2015ZX09501004-002);“十二五”国家科技重大专项生物大分子药物特殊评价关键技术研究(2015ZX09501007-004)
【分类号】：R96

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