黑水缬草提取物及其活性成分对肝脏药物代谢酶活性的影响  

Effects of Valeriana amurensis Roots and Rhizomes Extract and Its Active Constituents on Activities of Drug Metabolism Enzymes in Liver

作　　者：薛娟 魏晴 梁珊珊 刘龙江 柴慧芳 XUE Juan;WEI Qing;LIANG Shan-shan;LIU Long-jiang;CHAI Hui-fang(Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China)

机构地区：[1]贵州中医药大学,贵阳550025

出　　处：《中国实验方剂学杂志》2020年第9期106-112,共7页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：国际科技合作项目(2010DFA32440);贵州省2017年一流大学(一期)重点建设项目一流平台建设(培育)项目(3411-4110000520110)。

摘　　要：目的:评价黑水缬草提取物及其活性成分对人肝微粒体6种细胞色素P450(CYP450)主要亚型酶活性的影响。方法:分别以香豆素、丁氨苯丙酮、甲苯磺丁脲、奥美拉唑、右美沙芬、睾酮作为CYP2A6,CYP2B6,CYP2C9,CYP2C19,CYP2D6,CYP3A4的探针底物,以其羟基化或去甲基化的专一性代谢产物7-羟基香豆素,羟基丁氨苯丙酮,4-羟基甲苯磺丁脲,5-羟基奥美拉唑,右菲烷,6β-羟基睾酮作为酶活性的分析指标,建立Cocktail探针底物人肝微粒体体外模型,运用该方法评价黑水缬草提取物及其活性成分对人肝微粒体酶的影响。结果:黑水缬草提取物对CYP2B6,CYP2C9,CYP2D6和CYP3A4共4种亚型酶均有不同程度的抑制作用,半抑制浓度(IC50)分别为87.49,1.73,68.29,2.80 mg·L^-1;在9个木脂素成分中,左旋马尾松树脂醇-3α-O-β-D-吡喃葡萄糖苷对CYP2A6具有中等的抑制作用,IC50=8.51μmol·L-1;8,8'-二羟基-松脂素-4,4'-二-O-β-D-吡喃葡萄糖苷对CYP2D6具有中等抑制作用,IC50=8.73μmol·L-1;(+)-梣皮树脂醇-4,4'-O-β-D-双葡萄吡喃糖苷对CYP2B6和CYP2C9具有中等抑制作用,IC50分别为5.41,8.20μmol·L^-1。结论:黑水缬草提取物及其活性成分对肝脏CYP450酶存在抑制作用,在进行新药临床研究时,需要对联合用药可能会带来药物相互作用的风险进行充分评估。Objective:To evaluate the effects of Valeriana amurensis roots and rhizomes extract and its active constituents on the activities of six major cytochrome P450(CYP450)enzymes in human liver microsomes.Method:Coumarin,bupropion,tolbutamide,omeprazole,dextromethorphan and testosterone were used as probe substrates for CYP2A6,CYP2B6,CYP2C9,CYP2C19,CYP2D6 and CYP3A4,respectively.Taking their specific metabolites of hydroxylation or demethylation(7-hydroxycoumarin,hydroxybupropion,4-hydroxytolbutamide,5-hydroxyomeprazole,dextromethorphan,6β-hydroxytestosterone)as indicators of enzyme activities.The analytical indexes were used to establish an in vitro model of human liver microsomes of Cocktail probe substrates.This method was applied to evaluate the effects of V.amurensis roots and rhizomes extract and its active constituents on human liver microsomal enzymes.Result:The V.amurensis roots and rhizomes extract had different inhibitory effects on CYP2B6,CYP2C9,CYP2D6 and CYP3A4,their half-inhibitory concentration(IC50)values were 87.49,1.73,68.29,2.80 mg·L-1,respectively.Among the 9 lignans,(-)-massoniresinol-3α-O-β-D-glucopyranoside had a moderate inhibitory effect on CYP2A6 with an IC50 value of 8.51μmol·L^-1,8,8'-dihydroxypinoresinol-4,4'-di-O-β-D-glucopyranoside had a moderate inhibitory effect on CYP2D6 with an IC50 value of 8.73μmol·L-1,(+)-medioresinol-4,4'-O-di-β-D-glucopyranoside had a moderate inhibitory effect on CYP2B6 and CYP2C9 with IC50 values of 5.41μmol·L-1 and 8.20μmol·L-1.Conclusion:The V.amurensis roots and rhizomes extract and its active constituents have inhibitory effects on liver CYP450 enzymes.Therefore,in the clinical study of new drugs,it is necessary to fully evaluate the risk of drug interactions caused by combination therapy.

关 键 词：黑水缬草 醇提物 木脂素类 COCKTAIL探针药物法 药物相互作用 细胞色素P450 半抑制浓度 

分 类 号：R22[医药卫生—中医基础理论] R96[医药卫生—中医学]