Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies
BackgroundBelamcanda 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 metaboli...
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Frontiers Media S.A.
2025-02-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1522857/full |
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| author | Jifeng Gu Jifeng Gu Huishan Zhang Mei Wang Yuyang Zhou Yuyang Zhou Zhipeng Deng Rong Shi |
| author_facet | Jifeng Gu Jifeng Gu Huishan Zhang Mei Wang Yuyang Zhou Yuyang Zhou Zhipeng Deng Rong Shi |
| author_sort | Jifeng Gu |
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| description | BackgroundBelamcanda 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.MethodsIn 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.ResultsWhen 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 CYP2C19 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.ConclusionCollectively, 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. |
| format | Article |
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| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-15a8c681593c4bc4861bbe802d01f6d22025-02-11T05:10:15ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.15228571522857Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studiesJifeng Gu0Jifeng Gu1Huishan Zhang2Mei Wang3Yuyang Zhou4Yuyang Zhou5Zhipeng Deng6Rong Shi7Department of Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaScience and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaScience and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaScience and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Pharmacology, Addiction Science, Toxicology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United StatesSchool of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaScience and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaBackgroundBelamcanda 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.MethodsIn 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.ResultsWhen 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 CYP2C19 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.ConclusionCollectively, 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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1522857/fulltectorigeninirigeninirisflorentinatypical kineticsmetabolismhuman liver microsomes |
| spellingShingle | Jifeng Gu Jifeng Gu Huishan Zhang Mei Wang Yuyang Zhou Yuyang Zhou Zhipeng Deng Rong Shi Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies Frontiers in Pharmacology tectorigenin irigenin irisflorentin atypical kinetics metabolism human liver microsomes |
| title | Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies |
| title_full | Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies |
| title_fullStr | Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies |
| title_full_unstemmed | Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies |
| title_short | Typical and atypical metabolic characteristics of three iridaceae isoflavone components: in vitro and in silico studies |
| title_sort | typical and atypical metabolic characteristics of three iridaceae isoflavone components in vitro and in silico studies |
| topic | tectorigenin irigenin irisflorentin atypical kinetics metabolism human liver microsomes |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1522857/full |
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