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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 |
doi: 10.3389/fphar.2025.1522857
Typical and Atypical Metabolic Characteristics of Three Iridaceae Isoflavone Components: In Vitro and In Silico Studies
Provisionally accepted- 1 Eye and Ent Hospital, Fudan University, Shanghai, Shanghai Municipality, China
- 2 Shanghai University of Traditional Chinese Medicine, Shanghai, China
- 3 University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, United States
- 4 Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
Background: Belamcanda chinensis (L.) DC. (Chinese name Shegan) has been widely used because of its pharmacological activity and remarkable therapeutic effects in sore throat. Tectorigenin, irigenin, and irisflorentin have been recognized as important quality indicators in Shegan. However, the metabolic characteristics of isoflavone aglycones remain unclear. Methods: In this study, human liver microsomes (HLMs) and Cytochrome P450 (CYP) recombinant enzymes were used to study the metabolic stability, identify the metabolic pathways and enzyme kinetics of these three components, and elucidate their possible binding sites through molecular docking. Results: When tectorigenin, irigenin, and irisflorentin were co-incubated with HLMs and CYP recombinant enzymes, hydroxylation metabolite for tectorigenin, demethylated metabolite for irigenin, and 6,7-dihydroxy-5,3,4,5-tetramethoxy isoflavone originating from irisflorentin were identified. CYP2E1 and CYP3A4 have high metabolic rates for tectorigenin, whereas CYP3A4 and CYP1A2 are the most important metabolic enzymes for irigenin and irisflorentin, respectively. The kinetics showed that the metabolism of tectorigenin and irigenin conformed to the Michaelis-Menten model, while the Eadie-Hofstee plot of irisflorentin yielded a convex curve with a unique "hooked" characteristic, and it conformed to the sigmoidal kinetics characteristic. Furthermore, molecular simulations showed that tectorigenin and irigenin bind to the orthosteric site of CYP isoforms via hydrogen bonds and π-π stacking, whereas irisflorentin is principally bound to CYP1A2 via π-π stacking and hydrophobic interactions. Conclusions: Collectively, these Iridaceae isoflavone aglycones can be metabolized by CYP enzymes with typical or atypical kinetic characteristics. These results lay a foundation for a better understanding of the in vivo processes of these components.
Keywords: Tectorigenin, irigenin, Irisflorentin, atypical kinetics, Metabolism, human liver microsomes Abbreviation Table α-Naph α-naphthoflavone Clint
Received: 05 Nov 2024; Accepted: 22 Jan 2025.
Copyright: © 2025 Gu, Zhang, Wang, Zhou, Deng and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jifeng Gu, Eye and Ent Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
Huishan Zhang, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Mei Wang, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Zhipeng Deng, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, China
Rong Shi, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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