【摘要】：建立及評(píng)價(jià)體外肝臟3D模型在藥物肝毒性評(píng)價(jià)中的優(yōu)勢(shì)。本研究利用懸滴技術(shù)構(gòu)建Hepa RG3D多細(xì)胞聚球體模型,并檢測(cè)其肝功能水平,最后用該模型評(píng)價(jià)2個(gè)肝毒性陽(yáng)性藥重復(fù)給藥毒性,并與2D模型下單次給藥毒性進(jìn)行比較。Hepa RG細(xì)胞聚集生長(zhǎng)形成微組織體,該模型的細(xì)胞白蛋白表達(dá)水平、尿素分泌水平和CYP3A4活性誘導(dǎo)水平均顯著高于2D模型。鹽酸胺碘酮在2D和3D培養(yǎng)模型下IC_(50)分別為50和100μmol·L~(-1);異煙肼在2D模型下IC_(50)1 mmol·L~(-1),3D模型下IC_(50)為700μmol·L~(-1)。兩個(gè)藥物在3D模型下LDH活性均呈現(xiàn)明顯的時(shí)間/給藥次數(shù)依賴性和劑量正相關(guān)性。結(jié)果提示成功建立體外肝臟3D懸滴培養(yǎng)模型,與2D模型比較,該模型可用于準(zhǔn)確評(píng)價(jià)肝毒性陽(yáng)性藥,并為將來(lái)體外準(zhǔn)確、高通量和多次長(zhǎng)期給藥評(píng)價(jià)藥物肝臟毒性提供可能。
[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.
【作者單位】： 中國(guó)食品藥品檢定研究院國(guó)家藥物安全評(píng)價(jià)監(jiān)測(cè)中心藥物非臨床安全評(píng)價(jià)研究北京市重點(diǎn)實(shí)驗(yàn)室;中山大學(xué)藥學(xué)院;
【基金】：“十二五”國(guó)家科技重大專項(xiàng)符合中藥特點(diǎn)的有毒中藥安評(píng)關(guān)鍵技術(shù)(2015ZX09501004-002);“十二五”國(guó)家科技重大專項(xiàng)生物大分子藥物特殊評(píng)價(jià)關(guān)鍵技術(shù)研究(2015ZX09501007-004)
【分類號(hào)】：R96

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 王世俊;;利福平的肝毒性[J];中國(guó)藥學(xué)雜志;1984年11期

2 趙杰,趙娟;立復(fù)欣肝毒性臨床觀察[J];河北醫(yī)學(xué);2004年05期

3 李立,李克;化學(xué)品(藥品)肝毒性的體外篩選試驗(yàn)[J];河南中醫(yī)學(xué)院學(xué)報(bào);2003年04期

4 李瑾翡;黎e，

本文編號(hào)：2258467