Inhibition of human carboxylesterases by ginsenosides: structure–activity relationships and inhibitory mechanism

Abstract

BackgroundHuman carboxylesterases (hCES) are key serine hydrolases responsible for the hydrolysis of a wide range of endogenous and xenobiotic esters. Although it has been reported that some ginsenosides can modulate the activities of various enzymes, the inhibitory effects of ginsenosides on hCES have not been well-investigated.MethodsIn this study, more than 20 ginsenosides were collected and their inhibitory effects on hCES1A and hCES2A were assayed using the highly specific fluorescent probe substrates for each isoenzyme. Molecular docking simulations were also performed to investigate the interactions between ginsenosides and hCES.ResultsAmong all tested ginsenosides, Dammarenediol II (DM) and 20S-O-β-(d-glucosyl)-dammarenediol II (DMG) displayed potent inhibition against both hCES1A and hCES2A, while protopanaxadiol (PPD) and protopanaxatriol (PPT) exhibited strong inhibition on hCES2A and high selectivity over hCES1A. Introduction of O-glycosyl groups at the core skeleton decreased hCES inhibition activity, while the hydroxyl groups at different sites might also effect hCES inhibition. Inhibition kinetic analyses demonstrated that DM and DMG functioned as competitive inhibitors against hCES1A-mediated d-luciferin methyl ester (DME) hydrolysis. In contrast, DM, DMG, PPD and PPT inhibit hCES2A-mediated fluorescein diacetate (FD) hydrolysis via a mixed manner.ConclusionThe structure–inhibition relationships of ginsenosides as hCES inhibitors was investigated for the first time. Our results revealed that DM and DMG were potent inhibitors against both hCES1A and hCES2A, while PPD and PPT were selective and strong inhibitors against hCES2A.

Kinetic conversion of BIOGF1K enriched in compound K from in vitro 3-D human tissue model

“…Carboxylesterases surpass the activity of arylesterase, and betamethasone 17-valerate is a substrate of carboxylesterases ( Bätz et al, 2013 ). Protopanaxadiol(PPD) ginsenosides exhibited strong inhibition on carboxylesterases ( Sun et al, 2019 ). These enzymes and microbiome could probably be involved in the biotransformation of applied ginsenosides in 3-D human tissue model.…”

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“…However, an influence on the half-life of drugs of abuse may also be expected. Furthermore, previous studies showed that several natural products such as cannabis or ginsenosides have an impact on hCES1 activity (Qian et al 2020;Sun et al 2019). For instance, the three major cannabinoids of Cannabis sativa, tetrahydrocannabinol, cannabidiol, and cannabinol, were shown to reduce the hepatic hydrolysis of heroin, which is a substrate of the hCES1 subfamily (Meyer et al 2015;Qian et al 2020).…”

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