Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms
Creators: name: Gao, Wei-Feng
name: Li, Yi-Xuan
name: Zhang, Wei-Hua
name: Tao, Ran
name: Yin, Ting-Ting
name: Wang, Yi-Jia
name: Liu, Li-Na
name: Fu, Zhi-Wei
name: Li, Sai-Nan
name: Liu, Nai-Rong
name: Zhang, Heng
name: Liu, Guang
name: Zhao, Li-Zhong
name: Zhang, Xi-Peng
name: Zhang, Chun-Ze
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Cancer
subject: Hematology
subject: Virology

description: Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs).<i>In vitro</i> incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and <i>in silico</i> docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1.MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC<sub>50</sub>) of PTL on the activity of UGT1A1 was determined to be 64.4 μM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (<i>K</i><sub>i</sub>) was determined to be 12.1 μM. <i>In silico</i> docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug–drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation. Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). <i>In vitro</i> incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and <i>in silico</i> docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC<sub>50</sub>) of PTL on the activity of UGT1A1 was determined to be 64.4 μM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (<i>K</i><sub>i</sub>) was determined to be 12.1 μM. <i>In silico</i> docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug–drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.