Inhibitory effect of active ingredients of Tripterygium wilfordii Hook.F.on human carboxylesterases
10.3867/j.issn.1000-3002.2024.09.002
- VernacularTitle:雷公藤有效成分对人羧酸酯酶的抑制作用
- Author:
Jiahong LIANG
1
,
2
;
Jiamin GONG
;
Zuo DU
Author Information
1. 川北医学院公共卫生学院,四川 南充 637100
2. 川北医学院临床医学院,四川 南充 637100
- Keywords:
Tripterygium wilfordii Hook.F.;
celastrol;
carboxylesterases;
enzyme inhibition
- From:
Chinese Journal of Pharmacology and Toxicology
2024;38(9):652-660
- CountryChina
- Language:Chinese
-
Abstract:
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 TWHF.METHODS 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,respectively.The residual activities of CES1 and CES2 were detected by ultra-high performance liquid chromatography(UPLC)after intervention with celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine(100 μmol·L-1).Kinetics analysis,involving half inhibitory concentra-tion(IC50),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 drugs.Molecular docking was performed to analyze the ligand-enzyme interaction.RESULTS 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%(P<0.05)and 95.62%(P<0.05),respectively.The IC50 was 9.95 and 4.02 mol·L-1,respectively,and the types of inhibition were all non-competitive inhibition.Based on the kinetics analysis,the Ki values were calculated to be 5.10 and 10.55 μmol·L-1 for the inhibition of celastrol on CES1 and CES2,respectively.IVIVE indicated that celastrol might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CES1.Molecular docking results showed that hydrogen bonds and hydrophobic contacts contributed to the interaction of celastrol and CESs.CONCLUSION The inhibitory effect of celastrol on CES1 and CES2 might cause HDIs with clinical drugs hydrolysed by CESs.
