Inhibitory effect of active ingredients of Tripterygium wilfordii *** human carboxylesterases

作     者：LIANG Jiahong GONG Jiamin DU Zuo 梁佳鸿;龚家敏;杜佐

作者机构：School of Public HealthNorth Sichuan Medical CollegeNanchong 637100China School of Clinical MedicineNorth Sichuan Medical CollegeNanchong 637100China 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2024年第38卷第9期

页      面：652-660页

学科分类：1008[医学-中药学(可授医学、理学学位)] 1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：川北医学院博士科研启动基金(CBY20-QD02) 南充市市校科技战略合作专项资金项目(20SXQT0318) 

主　　题：Tripterygium wilfordii Hook.F. celastrol carboxylesterases enzyme inhibition 

摘      要：OBJECTIVE The inhibitory effect of active ingredients of Tripterygium wilfordii Hook.F.(TWHF)(celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine)on human carboxylester⁃ase 1(CES1)and CES2 was detected to investigate the herb-drug interactions(HDIs)of *** Human liver microsomes catalysed hydrolysis of 2-(2-benzoyl-3-methoxyphenyl)benzothi⁃azole(BMBT)and fluorescein diacetate(FD)were used as the probe reaction to phenotype the activity of CES1 and CES2,*** residual activities of CES1 and CES2 were detected by ultrahigh performance liquid chromatography(UPLC)after intervention with celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine(100μmol·L^(-1)).Kinetics analysis,involving half inhibitory concentra⁃tion(IC_(50)),inhibition type and kinetic parameter(Ki),and in vitro-in vivo extrapolation(IVIVE),was carried out to predict the HDIs between these compounds and CES-metabolizing *** docking was performed to analyze the ligand-enzyme *** Out of the six main con⁃stituents of TWHF,only celastrol exhibited strong inhibition towards both CES1 and CES2,with the inhibitory rates of 97.45%(P0.05)and 95.62%(P0.05),*** IC_(50)was 9.95 and 4.02 mol·L^(-1),respectively,and the types of inhibition were all non-competitive *** on the kinetics analysis,the Ki values were calculated to be 5.10 and 10.55μmol·L^(-1)for the inhibition of celastrol on CES1 and CES2,*** indicated that celastrol might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting *** docking results showed that hydrogen bonds and hydrophobic contacts contributed to the interaction of celastrol and *** The inhibitory effect of celastrol on CES1 and CES2 might cause HDIs with clinical drugs hydrolysed by CESs.