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.
[1]Shanghai Univ Tradit Chinese Med, Translat Med Ctr, Yueyang Hosp Integrated Tradit Chinese & Western, Shanghai 200473, Peoples R China.
[2]Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai 200473, Peoples R China.
[3]Dalian Med Univ, Coll Basic Med Sci, Dept Biotechnol, Dalian 116044, Peoples R China.
[4]Dalian Univ Technol, Sch Life Sci & Med, Panjin 124221, Peoples R China.
[5]Univ Helsinki, Fac Pharm, Div Pharmaceut Chem & Technol, Helsinki 00014, Finland.
[6]Dalian Runsheng Kangtai Med Lab Co Ltd, Dalian, Peoples R China.
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