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Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450

Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-dr...

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Autores principales: Lin, Fei, Lin, Xinhua, Wang, Xuewen, Mei, Guanghui, Chen, Bing, Yao, Hong, Huang, Lingyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975586/
https://www.ncbi.nlm.nih.gov/pubmed/36874034
http://dx.doi.org/10.3389/fphar.2023.1108867
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author Lin, Fei
Lin, Xinhua
Wang, Xuewen
Mei, Guanghui
Chen, Bing
Yao, Hong
Huang, Lingyi
author_facet Lin, Fei
Lin, Xinhua
Wang, Xuewen
Mei, Guanghui
Chen, Bing
Yao, Hong
Huang, Lingyi
author_sort Lin, Fei
collection PubMed
description Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS. Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms. Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC(50) ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC(50) < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC(50) < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes. Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition.
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spelling pubmed-99755862023-03-02 Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450 Lin, Fei Lin, Xinhua Wang, Xuewen Mei, Guanghui Chen, Bing Yao, Hong Huang, Lingyi Front Pharmacol Pharmacology Introduction: Selaginella doederleinii Hieron is a traditional Chinese herbal medicine, the ethyl acetate extract from Selaginella doederleinii (SDEA) showed favorable anticancer potentials. However, the effect of SDEA on human cytochrome P450 enzymes (CYP450) remains unclear. To predict the herb-drug interaction (HDI) and lay the groundwork for further clinical trials, the inhibitory effect of SDEA and its four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) on seven CYP450 isoforms were investigated by using the established CYP450 cocktail assay based on LC-MS/MS. Methods: Appropriate substrates for seven tested CYP450 isoforms were selected to establish a reliable cocktail CYP450 assay based on LC-MS/MS. The contents of four constituents (Amentoflavone, Palmatine, Apigenin, Delicaflavone) in SDEA were determined as well. Then, the validated CYP450 cocktail assay was applied to test the inhibitory potential of SDEA and four constituents on CYP450 isoforms. Results: SDEA showed strong inhibitory effect on CYP2C9 and CYP2C8 (IC(50) ≈ 1 μg/ml), moderate inhibitory effect against CYP2C19, CYP2E1 and CYP3A (IC(50) < 10 μg/ml). Among the four constituents, Amentoflavone had the highest content in the extract (13.65%) and strongest inhibitory effect (IC(50) < 5 μM), especially for CYP2C9, CYP2C8 and CYP3A. Amentoflavone also showed time-dependent inhibition on CYP2C19 and CYP2D6. Apigenin and Palmatine both showed concentration-dependent inhibition. Apigenin inhibited CYP1A2, CYP2C8, CYP2C9, CYP2E1 and CYP3A. Palmatine inhibited CYP3A and had a weak inhibitory effect on CYP2E1. As for Delicaflavone, which has the potential to develop as an anti-cancer agent, showed no obvious inhibitory effect on CYP450 enzymes. Conclusion: Amentoflavone may be one of the main reasons for the inhibition of SDEA on CYP450 enzymes, the potential HDI should be considered when SDEA or Amentoflavone were used with other clinical drugs. On the contrast, Delicaflavone is more suitable to develop as a drug for clinical use, considering the low level of CYP450 metabolic inhibition. Frontiers Media S.A. 2023-02-15 /pmc/articles/PMC9975586/ /pubmed/36874034 http://dx.doi.org/10.3389/fphar.2023.1108867 Text en Copyright © 2023 Lin, Lin, Wang, Mei, Chen, Yao and Huang. https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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.
spellingShingle Pharmacology
Lin, Fei
Lin, Xinhua
Wang, Xuewen
Mei, Guanghui
Chen, Bing
Yao, Hong
Huang, Lingyi
Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title_full Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title_fullStr Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title_full_unstemmed Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title_short Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450
title_sort inhibitory effect of selaginella doederleinii hieron on human cytochrome p450
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975586/
https://www.ncbi.nlm.nih.gov/pubmed/36874034
http://dx.doi.org/10.3389/fphar.2023.1108867
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