Inhibition of UDP-glucuronosyltransferases by different furoquinoline alkaloids
Creators: name: Li, Yixuan
name: Zhang, Weihua
name: Yin, Tingting
name: Wang, Ce
name: Wang, Feige
name: Sun, Jing
name: Liu, Lina
name: Zhang, Qinghuai
name: Zhang, Chunze
Publisher: name: Taylor & Francis
Year: 2020
Subjects: Biochemistry
Pharmacology
Biotechnology
Chemical Sciences not elsewhere classified
Biological Sciences not elsewhere classified
Information Systems not elsewhere classified
Cancer
Hematology
Virology

description: Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb–drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs).The recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition type and parameters were determined, and <i>in silico</i> docking was employed to elucidate the inhibition difference of furoquinoline alkaloids towards UGTs.Dictamine, haplopine, γ-fagarine and skimmianine strongly inhibited UGT1A3, UGT1A7, UGT1A9 and UGT2B4, respectively. Among them, dictamnine inhibited more than 70% of the four UGTs. Inhibition kinetics determination showed that they all exerted competitive inhibition, and the inhibition kinetic constant (<i>K<sub>i</sub></i>) was determined to be 8.3, 7.2, 3.7 and 33.9 μM, respectively. <i>In vitro–in vivo</i> extrapolation (IVIVE) was employed to demonstrate the inhibition possibility for four alkaloids. Skimmianine was proved to be more suitable for clinical application. <i>In silico</i> docking study indicated that the hydrophobic interactions played a key role in the inhibition of furoquinoline alkaloids towards three of the four UGTs. In conclusion, monitoring the interactions between furoquinoline alkaloids and drugs mainly undergoing UGTs-catalyzed metabolism is necessary. Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb–drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs). The recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition type and parameters were determined, and <i>in silico</i> docking was employed to elucidate the inhibition difference of furoquinoline alkaloids towards UGTs. Dictamine, haplopine, γ-fagarine and skimmianine strongly inhibited UGT1A3, UGT1A7, UGT1A9 and UGT2B4, respectively. Among them, dictamnine inhibited more than 70% of the four UGTs. Inhibition kinetics determination showed that they all exerted competitive inhibition, and the inhibition kinetic constant (<i>K<sub>i</sub></i>) was determined to be 8.3, 7.2, 3.7 and 33.9 μM, respectively. <i>In vitro–in vivo</i> extrapolation (IVIVE) was employed to demonstrate the inhibition possibility for four alkaloids. Skimmianine was proved to be more suitable for clinical application. <i>In silico</i> docking study indicated that the hydrophobic interactions played a key role in the inhibition of furoquinoline alkaloids towards three of the four UGTs. In conclusion, monitoring the interactions between furoquinoline alkaloids and drugs mainly undergoing UGTs-catalyzed metabolism is necessary.