Inhibition of human carboxylesterases by magnolol : Kinetic analyses and mechanism

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Song , Y-Q , Weng , Z-M , Dou , T-Y , Finel , M , Wang , Y-Q , Ding , L-L , Jin , Q , Wang , D-D , Fang , S-Q , Cao , Y-F , Hou , J & Ge , G-B 2019 , ' Inhibition of human carboxylesterases by magnolol : Kinetic analyses and mechanism ' , Chemico-Biological Interactions , vol. 308 , pp. 339-349 .

Title: Inhibition of human carboxylesterases by magnolol : Kinetic analyses and mechanism
Author: Song, Yun-Qing; Weng, Zi-Miao; Dou, Tong-Yi; Finel, Moshe; Wang, Ya-Qiao; Ding, Le-Le; Jin, Qiang; Wang, Dan-Dan; Fang, Sheng-Quan; Cao, Yun-Feng; Hou, Jie; Ge, Guang-Bo
Contributor organization: Division of Pharmaceutical Chemistry and Technology
Drug Research Program
Pharmaceutical Design and Discovery group
Moshe Finel / Principal Investigator
Date: 2019-08-01
Language: eng
Number of pages: 11
Belongs to series: Chemico-Biological Interactions
ISSN: 0009-2797
Abstract: Magnolol, the most abundant bioactive constituent of the Chinese herb Magnolia officinalis, has been found with multiple biological activities, including anti-oxidative, anti-inflammatory and enzyme-regulatory activities. In this study, the inhibitory effects and inhibition mechanism of magnolol on human carboxylesterases (hCEs), the key enzymes responsible for the hydrolytic metabolism of a variety of endogenous esters as well as ester-bearing drugs, have been well-investigated. The results demonstrate that magnolol strongly inhibits hCE1-mediated hydrolysis of various substrates, whereas the inhibition of hCE2 by magnolol is substrate-dependent, ranging from strong to moderate. Inhibition of intracellular hCE1 and hCE2 by magnolol was also investigated in living HepG2 cells, and the results showed that magnolol could strongly inhibit intracellular hCE1, while the inhibition of intracellular hCE2 was weak. Inhibition kinetic analyses and docking simulations revealed that magnolol inhibited both hCE1 and hCE2 in a mixed manner, which could be partially attributed to its binding at two distinct ligand-binding sites in each carboxylesterase, including the catalytic cavity and the regulatory domain. In addition, the potential risk of the metabolic interactions of magnolol via hCE1 inhibition was predicted on the basis of a series of available pharmacokinetic data and the inhibition constants. All these findings are very helpful in deciphering the metabolic interactions between magnolol and hCEs, and also very useful for avoiding deleterious interactions via inhibition of hCEs.
Subject: Magnolol
Human carboxylesterases (hCEs)
Inhibition potential
Herb-drug interactions (HDIs)
1182 Biochemistry, cell and molecular biology
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion

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