基于分子对接和实验验证的五味子乙素在人肝微粒体中的代谢酶表型研究  

Investigation of Metabolic Enzyme Phenotypes of Schisandrin B in Human Liver Microsomes Based on Molecular Docking and Experimental Verification

作　　者：王晓艳[1,2] 李伟霞[1,2,3] 张辉 冯科冉[3] 张明亮 吴娅丽 陈毓龙 李琨 王星 唐进法[1,2,3] WANG Xiaoyan;LI Weixia;ZHANG Hui;FENG Keran;ZHANG Mingliang;WU Yali;CHEN Yulong;LI Kun;WANG Xing;TANG Jinfa(Henan Province Engineering Research Center of Clinical Application,Evaluation and Transformation of Traditional Chinese Medicine,Henan Provincial Key Laboratory for Clinical Pharmacy of Traditional Chinese Medicine,The First Affiliated Hospital of Henan University of Chinese Medicine,Zhengzhou 450000;Provincial and Ministerial Co-construction Collaborative Innovation Center for Prevention and Treatment of Respiratory Diseases with Traditional Chinese Medicine of Henan University of Chinese Medicine,Zhengzhou 450046;School of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046;School of Traditional Chinese Medicine,Capital Medical University,Beijing 100069)

机构地区：[1]河南中医药大学第一附属医院河南省中药临床应用、评价与转化工程研究中心河南省中药临床药学中医药重点实验室,郑州1450000 [2]河南中医药大学呼吸疾病中医药防治省部共建协同创新中心,郑州450046 [3]河南中医药大学药学院,郑州450046 [4]首都医科大学中医药学院,北京100069

出　　处：《中药药理与临床》2023年第3期47-52,共6页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家自然科学基金资助项目(编号:81803702);河南省卫生健康委国家中医临床研究基地科研专项(编号:2021JDZY079);河南省中医药拔尖人才培养项目(豫中医科教[2018]35号);河南中医药大学研究生“科研创新”类项目。

摘　　要：目的:基于分子对接和肝微粒体体外实验分析参与五味子乙素(Sch B)代谢的CYP450酶,确定其在人肝微粒体中的代谢表型。方法:首先利用分子对接方法从人体内9种重要的CYP450酶筛选出与Sch B亲和力强的药物代谢酶,其次采用体外人肝微粒体温孵体系,结合CYP450亚酶特异性抑制剂实验验证参与Sch B代谢的CYP450亚型。结果:分子对接研究结果发现CYP2A6、CYP2C8、CYP2C19、CYP2E1等代谢酶具有较高的得分,表明这些酶可能与Sch B具有较强的结合。体外抑制实验结果显示甲氧沙林(CYP2A6特异性抑制剂)、盐酸噻氯吡啶(CYP2C19特异性抑制剂)和4-甲基吡唑(CYP2E1特异性抑制剂)在一定程度上抑制了人肝微粒体对Sch B的代谢,表明CYP2A6、CYP2C19、CYP2E1可能在参与Sch B代谢中发挥重要作用,并对其与Sch B的结合模式进行分析。结论:本研究初步探索了参与Sch B代谢的CYP450酶亚型,为进一步研究Sch B的体内代谢及五味子的临床合理配伍提供参考。Objective:To explore the CYP450 enzymes involved in schisandrin B(Sch B) metabolism based on molecular docking and in vitro experiments of human liver microsomes, and predict the metabolic phenotypes of Sch B in human liver microsomes. Methods:Firstly, strong affinity drug metabolic enzymes of Sch B were screened out in nine human CYP450 subtypes by the molecular docking method. Then, based on in vitro human liver microparticle temperature incubation system combined with the exclusive CYP450 inhibitors experiment, the CYP450 subtypes involved in Sch B metabolism were verified. Results:The results of molecular docking showed that CYP2A6,CYP2C8,CYP2C19,CYP2E1,and other enzymes had high scores, which suggested strong affinity with Sch B. The results of inhibition experiment in vitro showed that 8-methoxypsoralen(CYP2A6 specific inhibitor),ticlopidine(CYP2C19 specific inhibitor),and 4-methylprazole(CYP2E1 specific inhibitor) partly inhibited the metabolism of Sch B,indicating that CYP2A6,CYP2C19,and CYP2E1 played important roles in the metabolism of Sch B,and the combination mode with Sch B was analyzed. Conclusion:This study preliminarily explores CYP450 enzyme subtypes involved in Sch B metabolism, to provide references for further study of Sch B metabolism in vivo and reasonable clinical compatibility of Schisandra chinensis.

关 键 词：五味子乙素 肝药酶亚型 分子对接 人肝微粒体 

分 类 号：R285[医药卫生—中药学]