何首乌主要成分的肝毒性及其对药物代谢酶的影响  

Hepatotoxicity of Main Components of Polygonum multiflorum and Its Effects on Drug Metabolism Enzyme

作　　者：郑晓媛 余志杰 王璇 周世文 ZHENG Xiaoyuan;YU Zhijie;WANG Xuan;ZHOU Shiwen(Dept,of Pharmacy,the Second Affiliated Hospital of Army Medical University,Chongqing 400037,China;Dept,of Pharmacy,Chongqing Emergency Medical Center,Chongqing 400014,China)

机构地区：[1]陆军军医大学第二附属医院药学部,重庆400037 [2]重庆市急救医疗中心药剂科,重庆400014

出　　处：《中国药房》2021年第21期2619-2623,共5页China Pharmacy

基　　金：重庆市技术创新与应用示范项目(社会民生类一般项目)(No.cstc2018jscx-msybX0172);重庆市卫生计生委医学科研项目(No.2017ZDXM023)

摘　　要：目的:研究何首乌主要成分的肝毒性,并基于代谢酶探讨其毒性机制。方法:采用ADMETlab2.0平台预测何首乌的5种主要成分大黄素、大黄素甲醚、大黄酸、二苯乙烯苷、没食子酸对肝、皮肤、心脏等的毒性或致癌作用,并评估这些成分对细胞色素P450酶系(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4)的影响;检测不同浓度(10、20、40、80μmol/L)的大黄素、大黄酸、二苯乙烯苷、没食子酸对人正常肝细胞L02存活率的影响;以胆红素为底物,采用体外反应体系考察何首乌主要成分对葡糖醛酸基转移酶1家族多肽A1(UGT1A1)活性的影响。结果:何首乌主要成分大黄素、大黄素甲醚、大黄酸、没食子酸对肝的毒性作用均较强。大黄素、大黄素甲醚对CYP1A2的抑制作用较强,对CYP2C9、CYP2D6、CYP3A4的抑制作用为中等;大黄酸对CYP1A2、CYP2C9的抑制作用为中等,二苯乙烯苷和没食子酸对上述各酶的抑制作用均较弱。大黄素(40、80μmol/L)和没食子酸(40、80μmol/L)均可显著降低L02细胞的存活率(P<0.01)。5、10、20、40、80μmol/L的大黄素和没食子酸(5μmol/L的大黄素除外)对UGT1A1酶的抑制率均显著升高(P<0.01),大黄素对UGT1A1酶的抑制作用为可逆的竞争性抑制。结论:何首乌主要成分大黄素、大黄酸、大黄素甲醚等具有肝毒性,其作用机制可能与抑制CYP1A2、CYP2C9活性以及竞争性抑制胆红素代谢限速酶UGT1A1的活性有关。OBJECTIVE:To study the hepatotoxicity of main components of Polygonum multiflorum,and investigate its toxic mechanism based on metabolic enzymes.METHODS:ADMETlab 2.0 platform was used to forecast the toxic or carcinogenic effects of emodin,physcion,rhein,stilbene glycoside and gallic acid on liver,skin and heart.The effects of those components on cytochrome P 450 enzyme system(CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP3A4)were evaluated.The effects of different concentrations of emodin,rhein,stilbene glycoside and gallic acid(10,20,40,80μmol/L)on the survival rate of normal hepatocyte L 02 were detected.The effects of major components of P.multiflorum on the activity of UGT 1A1 enzyme were studied by in vitro reaction system,using bilirubin as substrate.RESULTS:Main components of P.multiflorum,ie.emodin,physcion,rhein and gallic acid,showed strong toxic effects on the liver,while stilbene glycosides possessed weak toxic effects on the liver.Emodin and physcion had strong inhibitory effects on CYP 1A2 and medium inhibitory effects on CYP 2C9,CYP2D6 and CYP3A4;rhein showed medium inhibitory effects on CYP 1A2 and CYP 2C9,while stilbene glycoside and gallic acid possessed weak inhibitory effects on the above enzymes.Emodin(40,80μmol/L)and gallic acid(40,80μmol/L)could significantly reduce the survival rate of L 02 cells(P<0.01).The inhibition rate of 5,10,20,40,80μmol/L emodin and gallic acid(except for 5μmol/L emodin)on UGT 1A1 enzyme increased significantly(P<0.01),and the inhibition effect of emodin on UGT 1A1 enzyme was reversible competitive inhibition.CONCLUSIONS:The main components of P.multiflorum,ie.emodin,rhein and physcion,are hepatotoxic;the mechanism of it may be associated with inhibiting the activity of CYP 1A2 and CYP 2C9 and competitively blocking rate-limiting enzyme UGT 1A1 in the process of bilirubin metabolism.

关 键 词：何首乌 大黄素 二苯乙烯苷 大黄酸 没食子酸 细胞色素P450酶 葡糖醛酸酶 肝毒性 

分 类 号：R285.5[医药卫生—中药学]