替芬泰对HepG2细胞的线粒体毒性  

The mitochondrial toxicity of bentysrepinine on HepG2 cells

作　　者：冯玥[1] 霍璇[1] 胡金芳[1] 邸志权[1] 张宗鹏[1] 申秀萍[1] 

机构地区：[1]天津药物研究院新药评价有限公司,天津300301

出　　处：《中国药理学通报》2017年第9期1248-1252,共5页Chinese Pharmacological Bulletin

基　　金：国家科技重大专项课题(No 2015ZX09501004-002-003)

摘　　要：目的采用HepG2细胞来评价首次合成的马蹄金素衍生物替芬泰在抗乙肝病毒的同时对肝细胞的线粒体毒性,为临床试验剂量设计和合理用药提供参考。方法测定替芬泰对HepG2细胞增殖的抑制率,对培养上清液乳酸含量、细胞活性氧含量、线粒体膜电位变化及线粒体呼吸链复合物酶Ⅰ~Ⅳ活性的影响,综合评价替芬泰的线粒体毒性。结果替芬泰对HepG2细胞增殖的半数抑制浓度为359μmol·L^(-1)。与对照组比较,替芬泰400μmol·L^(-1)(196 mg·L^(-1))时明显降低HepG2细胞的线粒体膜电位,明显增加细胞活性氧含量,升高乳酸生成水平,降低线粒体呼吸链复合物酶Ⅰ、Ⅱ、Ⅲ的活性,具有明显的线粒体毒性。与拉米夫定、阿德福韦酯比较,同为100μmol·L^(-1)的替芬泰对上述指标均无影响。结论替芬泰的线粒体毒性安全范围较大,实验结果对临床试验剂量设计和临床用药具有一定的指导意义。Aim To provide references for clinical trials dose and rational drug use by evaluating mitochondrial toxicity of bentysrepinine on HepG2 cells. Methods Mitochondrial toxicity of bentysrepinine on HepG2 cells was cmomprehensively evaluated by measuring proliferation inhibition rate,lactic acid content in culture supernatant,reactive oxygen species（ ROS）content,mitochondrial membrane potential（ MMP）variation and the activity of mitochondrial respiratory chain complex enzymes Ⅰ to Ⅳ. Results The half inhibitory concentration of bentysrepinine of HepG2 cells was 359 μmol · L^-1. Compared with the control group,bentysrepinine could reduce the MMP,raise the level of lactic acid,increase the content of ROS and lower the activity of mitochondrial respiratory chain complex enzymes Ⅰ to Ⅲ with the concentration of400 μmol·L^-1（ 196 mg·L^-1）,showing an obvious mitochondrial toxicity. Compared with lamivudine and adefovir dipivoxil,bentysrepinine exerted no influence on indexes above with the same concentration 100μmol · L^-1. Conclusions Bentysrepinine shows an obvious mitochondrial toxicity on HepG2 cells with the concentration of 400 μmol · L^-1. This mitochondrial toxicity is not presented with the concentration of 200μmol·L^-1. It shows that the safety range of bentysrepinine about mitochondrial toxicity is relatively wide.The test plays a guiding role in clinical trial dose design as well as clinical treatment.

关 键 词：替芬泰 线粒体毒性 线粒体膜电位 活性氧 线粒体呼吸链复合物酶 乳酸 

分 类 号：R322.47[医药卫生—人体解剖和组织胚胎学] R329.24[医药卫生—基础医学]