Inhibition of UDP-glucuronosyltransferases by different furoquinoline alkaloids

Abstract

1. 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).

2. 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 in silico docking was employed to elucidate the inhibition difference of furoquinoline alkaloids towards UGTs.

3. 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 (K_i) was determined to be 8.3, 7.2, 3.7 and 33.9 μM, respectively. In vitro–in vivo extrapolation (IVIVE) was employed to demonstrate the inhibition possibility for four alkaloids. Skimmianine was proved to be more suitable for clinical application. In silico 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.

Keywords:

• Furoquinoline alkaloids
• herb–drug interactions (HDIs)
• UDP-glucuronosyltransferases (UGTs)
• dictamnine
• haplopine
• γ-fagarine
• skimmianine

Acknowledgements

The authors are grateful to Prof. Fang and Li for helpful suggestions towards this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Key program of Tianjin Union Medical Center [2016YJZD006]; Tianjin Key R&D Plan of Science and Technology program [19YFZCSY00420]; Tianjin Health and Family Planning Commission [2017057, 16KG154 and 2014kZ053]; and the National Key Laboratory Open Research Project [2018094].