| 引用本文: | 薛涛,郭璐,莫建明,吴娟萍,何俏军,管建明.DJ-1蛋白稳定剂干预厄洛替尼诱导的肝脏毒性研究[J].中国现代应用药学,2021,38(24):3064-3070. |
| XUE Tao,GUO Lu,MO Jianming,WU Juanping,HE Qiaojun,GUAN Jianming.Study on the Intervention Effect of DJ-1-binding Compound on Erlotinib-induced Hepatotoxicity[J].Chin J Mod Appl Pharm(中国现代应用药学),2021,38(24):3064-3070. |
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| DJ-1蛋白稳定剂干预厄洛替尼诱导的肝脏毒性研究 |
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薛涛1, 郭璐2, 莫建明2, 吴娟萍2, 何俏军3, 管建明4
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1.湖州师范学院附属第一医院, 分子医学实验中心, 浙江 湖州 313000;2.湖州师范学院附属第一医院, 药学部, 浙江 湖州 313000;3.浙江大学药物安全评价研究中心, 杭州 310058;4.湖州师范学院附属第一医院, 爱山医学体检中心, 浙江 湖州 313000
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| 摘要: |
| 目的 考察小分子酪氨酸激酶抑制剂厄洛替尼诱导的肝脏毒性，研究DJ-1蛋白稳定剂Compound-23的肝脏保护作用。方法 培养Chang liver细胞研究厄洛替尼对细胞的体外毒性作用，氧化应激的影响，以及细胞内DJ-1蛋白氧化还原状态的改变。SD大鼠随机分为对照组，厄洛替尼肝损伤造模组及其合用Compound-23的高、低剂量组共4组，研究厄洛替尼的体内肝脏毒性，并通过对大鼠体质量，肝功能AST、ALT、LDH值，肝脏GSH、SOD、MDA值，肝脏坏死及凋亡程度的检测，评价DJ-1蛋白稳定剂Compound-23对厄洛替尼诱导的肝脏毒性的干预作用。结果 厄洛替尼在体内外均有肝脏毒性作用，诱导细胞内ROS水平的升高，DJ-1蛋白等电点降低，二聚体的解离，呈现氧化应激状态。合用DJ-1蛋白稳定剂Compound-23高剂量组能显著改善厄洛替尼诱导的细胞凋亡损伤，细胞增殖抑制，大鼠体质量下降，肝功能值升高，氧化应激状态（P<0.05或P<0.01），以及肝脏坏死和凋亡的程度。结论 厄洛替尼通过诱导氧化应激，抑制DJ-1蛋白还原态活性产生肝脏毒性，DJ-1蛋白稳定剂Compound-23通过减轻细胞损伤、改善肝功能、缓解氧化应激，对肝脏起保护作用。 |
| 关键词: 酪氨酸激酶抑制剂 厄洛替尼 肝脏毒性 DJ-1 氧化应激 |
| DOI：10.13748/j.cnki.issn1007-7693.2021.24.002 |
| 分类号:R965.3 |
| 基金项目:浙江省卫生健康科技计划（2021RC030）；浙江省自然科学基金项目（LQ15H310004） |
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| Study on the Intervention Effect of DJ-1-binding Compound on Erlotinib-induced Hepatotoxicity |
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XUE Tao1, GUO Lu2, MO Jianming2, WU Juanping2, HE Qiaojun3, GUAN Jianming4
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1.First People's Hospital Affiliated to Huzhou University, Center for Molecular Medicine, Huzhou 313000, China;2.First People's Hospital Affiliated to Huzhou University, Department of Pharmacy, Huzhou 313000, China;3.Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, China;4.First People's Hospital Affiliated to Huzhou University, Center for Aishan Medical Examination, Huzhou 313000, China
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| Abstract: |
| OBJECTIVE To investigate the hepatotoxicity induced by erlotinib, which was a small molecular tyrosine kinase inhibitor, and to observe the protective effect of DJ-1-binding compound Compound-23 on liver. METHODS To study the cytotoxic effect of erlotinib on cells in vitro, the effect on oxidative stress, and the changes of DJ-1 redox status in cultured Chang liver cell line. SD rats were randomly divided into 4 groups, including control group, erlotinib-induced liver injury model group, high dose and low dose of Compound-23 groups. The hepatotoxicity of erlotinib was studied in vivo, and the intervention effect of DJ-1-binding compound Compound-23 on erlotinib-induced hepatotoxicity was evaluated by detecting body weight of rats, the level of liver function index such as AST, ALT, LDH, the level of GSH, SOD, MDA in liver, liver necrosis, and apoptosis in rats. RESULTS Erlotinib caused hepatotoxicity both in vitro and in vivo, and induced the increase in ROS level, the decrease in isoelectric point of DJ-1, and the dissociation of DJ-1 dimer in cells, which indicated the oxidative stress status. High dose of DJ-1-binding compound Compound-23 group could significantly improve erlotinib-induced cell apoptosis damage, proliferation inhibition, weight loss, increase levels of liver function index and oxidative stress(P<0.05 or P<0.01), as well as necrosis and apoptosis degree in rats. CONCLUSION Erlotinib induce hepatotoxicity by induce oxidative stress and inhibit reduced activity of DJ-1 protein, DJ-1-binding compound Compound-23 protect the liver by reducing cell damage, improving liver function, and attenuating oxidative stress. |
| Key words: tyrosine kinase inhibitors erlotinib hepatotoxicity DJ-1 oxidative stress |
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