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Planta Med 2023; 89(04): 397-407
DOI: 10.1055/a-1936-4807
Biological and Pharmacological Activity
Original Papers

Comparative Inhibitory Effects of Natural Biflavones from Ginkgo against Human CYP1B1 in Recombinant Enzymes and MCF-7 Cells

Xiaodong Chen‡
1   College of Pharmacy, Dalian Medical University, Dalian, China
,
Tingting Zhao‡
1   College of Pharmacy, Dalian Medical University, Dalian, China
,
Jie Du‡
1   College of Pharmacy, Dalian Medical University, Dalian, China
,
Xintong Guan‡
2   College of Basic Medicine, Dalian Medical University, Dalian, China
,
Hong Yu
3   Department of Pharmacy, Dalian Municipal Women and Childrenʼs Medical Center, Liaoning Dalian, China
,
Dalong Wang
1   College of Pharmacy, Dalian Medical University, Dalian, China
,
Changyuan Wang
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
,
Qiang Meng
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
,
Jialin Yao
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
,
Huijun Sun
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
,
Kexin Liu
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
,
Jingjing Wu 
1   College of Pharmacy, Dalian Medical University, Dalian, China
4   Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University, Dalian, Liaoning, China
› InstitutsangabenGefördert durch: National Natural Science Foundation of China 81403003
Gefördert durch: National Natural Science Foundation of China 81702995
Gefördert durch: National Natural Science Foundation of China U1608283
Gefördert durch: Liaoning Revitalization Talents Program XLYC1907103
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Abstract

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.

Key words

CYP1B1 - Ginkgo biloba - biflavones - inhibition - AhR - structure-inhibition relationship

Supporting Information

    The inhibition of α-naphthoflavone as a positive control on CYP1B1 (Fig. 1S) and the kinetics of resorufin O-deethylation catalyzed by human recombinant CYP1B1 (Fig. 2S) are available as Supporting Information.

  • Ergänzendes Material


Publikationsverlauf

Eingereicht: 12. April 2022

Angenommen nach Revision: 25. August 2022

Accepted Manuscript online:
05. September 2022

Artikel online veröffentlicht:
05. Dezember 2022

© 2022. Thieme. All rights reserved.

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