五味子诱导的CYPs和Nrf2活化对对乙酰氨基酚急性肝损伤的影响  

Effects of Schisandrae Chinensis Fructus induced CYPs and Nrf2 activation on acute liver injury induced by acetaminophen

作　　者：邱炳勋 刘珂[1] 邹利[1,2] 祝慧凤 俸珊[1] QIU Bing-xun;LIU Ke;ZOU Li;ZHU Hui-feng;FENG Shan(College of Pharmaceutical Sciences and Chinese Medicine,Southwest University,Chongqing 400715,China;Sichuan Vocational College of Health and Rehabilitation,Zigong 543000,China)

机构地区：[1]西南大学药学院,重庆400715 [2]四川卫生康复职业学院,四川自贡643000

出　　处：《中国中药杂志》2018年第24期4908-4915,共8页China Journal of Chinese Materia Medica

基　　金：重庆市基础科学与前沿技术研究项目(cstc2017jcyjAX0137);教育部博士后面上项目(2016M602641);西南大学博士后项目(102060-20750902);西南大学基本科研业务费(XDJK2015C155)

摘　　要：五味子为临床常用保肝药,研究表明其对CYP450s酶活性具有双向调控作用,即短期给药可抑制CYP450s活性,而长期给药可诱导CYP450s活性。异常高表达的CYP450s活性是活性代谢产物致肝损伤发生的危险因素。而五味子长期用药后对活性代谢产物致肝损伤的影响还未见报道。因此,该研究选择对乙酰氨基酚(APAP,可经活性代谢产物导致药物性肝损伤)为模型药物。通过动物整体实验评价五味子长期给药后对APAP急性肝损伤的影响及其机制。五味子提取物(0. 5~2. 0g·kg-1)灌胃给予SD大鼠21 d后,大鼠肝脏组织5种CYP450s酶活性有不同程度的上调,同时Nrf2及其信号通路下游基因如GLCc,GLCm,GST,HO-1的mRNA表达均显著增加,GST和SOD活性也呈剂量依赖性增加。五味子提取物给药结束后,单次灌胃给予APAP(500 mg·kg-1,诱发急性肝损伤剂量)后,五味子呈剂量依赖性逆转APAP导致的急性肝损伤,主要表现为:逆转ALT,AST,MDA水平升高(P <0. 05),升高GSH水平,改善肝脏组织病理学损伤以及降低肝细胞中cleaved caspase-3表达。此外,LC-MS/MS含量检测显示五味子呈剂量依赖性增加肝组织中APAP活性代谢产物N-乙酰-对苯醌亚胺生成量(P <0. 05)。上述结果表明五味子(0. 5~2. 0 g·kg-1)长期给药虽然可上调CYP450s活性,导致APAP活性代谢产物生成量增加;但其同时激活Nrf2信号通路,上调GST等抗氧化酶表达,增强抗氧化酶活性及GSH水平,最终可保护APAP导致的急性肝损伤。Schisandra chinensis is a commonly used hepatoprotective medicine in clinic. Previous studies have showed that Schisandrae Chinensis Fructus has dual effects on the activity of CYPs. Short-term administration of Schisandrae Chinensis Fructus may inhibit CYP450 s activity,while long-term administration may up-regulate CYP activity. High CYP450 s activity level may increase the frequency of reactive metabolites-induced liver injury. It remains unclear how long-term administration of Schisandrae Chinensis Fructus may affect acetaminophen-induced acute hepatotoxicity. After oral administration of Schisandrae Chinensis Fructus extract( 0. 5-2. 0 g·kg-1) for 21 d,the activity of CYPs,Nrf2,HO-1,GST expressions,SOD and GST activity as well as glutathione level of SD rats were up-regulated. Besides,Schisandrae Chinensis Fructus extract ameliorated APAP( 500 mg·kg-1)-induced acute hepatotoxicity in a dose-dependent manner,as evidenced by decrease in ALT,AST,and MDA level and increase in GSH level( P < 0. 05). What’ s more,the liver histopathology was alleviated,and cleaved caspase-3 expression was decreased. Besides,the increase of N-acetyl-pbenzoquinoneimine-GSH( reactive metabolite of acetaminophen) formation was observed in Schisandrae Chinensis Fructus extract groups. In conclusion,the present study indicated that the effects of Schisandrae Chinensis Fructuson acetaminophen-induced hepatotoxicity may rely on the Nrf2 signal pathway activation,and less depends on the increase in CYP450 s activity.

关 键 词：五味子 对乙酰氨基酚 肝毒性 CYP450s N-乙酰-对苯醌亚胺 

分 类 号：R285.5[医药卫生—中药学]