【摘 要】
：
目的 阐明知母皂苷(A3)的肝毒性机制,为临床上知母的合理用药提供科学指导,避免潜在的药物安全性隐患。方法 体外细胞实验,采用大鼠肝原代三明治培养技术,分别在mRNA、蛋白质和功能水平研究了A3对于肝细胞胆酸相关转运体和代谢酶的影响；考察了实验组和对照组之间在肝细胞活力、氧化应激(ROS)、乳酸脱氢酶(LDH)释放、线粒体膜电位(MMP)变化等方面的差异；体内动物实验,SD大鼠连续灌胃给药A3(1
【机 构】
：
中国科学院上海药物研究所药物安全评价研究中心,上海200000 中国科学院上海药物研究所中药现代化
论文部分内容阅读
目的 阐明知母皂苷(A3)的肝毒性机制,为临床上知母的合理用药提供科学指导,避免潜在的药物安全性隐患。方法 体外细胞实验,采用大鼠肝原代三明治培养技术,分别在mRNA、蛋白质和功能水平研究了A3对于肝细胞胆酸相关转运体和代谢酶的影响；考察了实验组和对照组之间在肝细胞活力、氧化应激(ROS)、乳酸脱氢酶(LDH)释放、线粒体膜电位(MMP)变化等方面的差异；体内动物实验,SD大鼠连续灌胃给药A3(100 mg·kg-1)7d后,与对照组在血液生化学、病理学方面进行比较。结果 细胞实验中,A3可以引起胆酸摄取和外排型转运体、胆酸合成酶的下调,并降低肝细胞对胆酸的外排,而N-乙酰半胱氨酸(NAC)能够减弱这种作用；A3能够剂量依赖性致使肝细胞活力下降,并导致ROS的发生和LDH的释放。大鼠在连续给药7天后,其血液中总胆酸、总胆红素含量明显上升,ALT和AST亦有升高,病理组织切片显示有空泡化和肝细胞凋亡现象。结论 A3能够致使肝损伤,而这种作用是由于导致了肝胆酸淤积的发生,继而引发ROS的产生,造成了肝细胞的凋亡。
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