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Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid

Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to dete...

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Autores principales: Li, Ke, Yu, Xiu-Hua, Maskey, Anish R., Musa, Ibrahim, Wang, Zhen-Zheng, Garcia, Victor, Guo, Austin, Yang, Nan, Srivastava, Kamal, Dunkin, David, Li, Jun-Xiong, Guo, Longgang, Cheng, Yung-Chi, Yuan, Haoliang, Tiwari, Raj, Li, Xiu-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922998/
https://www.ncbi.nlm.nih.gov/pubmed/36793921
http://dx.doi.org/10.3389/fphar.2022.1042756
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author Li, Ke
Yu, Xiu-Hua
Maskey, Anish R.
Musa, Ibrahim
Wang, Zhen-Zheng
Garcia, Victor
Guo, Austin
Yang, Nan
Srivastava, Kamal
Dunkin, David
Li, Jun-Xiong
Guo, Longgang
Cheng, Yung-Chi
Yuan, Haoliang
Tiwari, Raj
Li, Xiu-Min
author_facet Li, Ke
Yu, Xiu-Hua
Maskey, Anish R.
Musa, Ibrahim
Wang, Zhen-Zheng
Garcia, Victor
Guo, Austin
Yang, Nan
Srivastava, Kamal
Dunkin, David
Li, Jun-Xiong
Guo, Longgang
Cheng, Yung-Chi
Yuan, Haoliang
Tiwari, Raj
Li, Xiu-Min
author_sort Li, Ke
collection PubMed
description Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to determine the effects of epimedium on CYP3A4 and whether it affects the anti-inflammatory function of CS and identify the active compound responsible for this effect. Methods: The effect of epimedium on CYP3A4 activity was evaluated using the Vivid CYP high-throughput screening kit. CYP3A4 mRNA expression was determined in human hepatocyte carcinoma (HepG2) cells with or without epimedium, dexamethasone, rifampin, and ketoconazole. TNF-α levels were determined following co-culture of epimedium with dexamethasone in a murine macrophage cell line (Raw 264.7). Active compound (s) derived from epimedium were tested on IL-8 and TNF-α production with or without corticosteroid, on CYP3A4 function and binding affinity. Results: Epimedium inhibited CYP3A4 activity in a dose-dependent manner. Dexamethasone enhanced the expression of CYP3A4 mRNA, while epimedium inhibited the expression of CYP3A4 mRNA and further suppressed dexamethasone enhancement of CYP3A4 mRNA expression in HepG2 cells (p < 0.05). Epimedium and dexamethasone synergistically suppressed TNF-α production by RAW cells (p < 0.001). Eleven epimedium compounds were screened by TCMSP. Among the compounds identified and tested only kaempferol significantly inhibited IL-8 production in a dose dependent manner without any cell cytotoxicity (p < 0.01). Kaempferol in combination with dexamethasone showed complete elimination of TNF-α production (p < 0.001). Furthermore, kaempferol showed a dose dependent inhibition of CYP3A4 activity. Computer docking analysis showed that kaempferol significantly inhibited the catalytic activity of CYP3A4 with a binding affinity of −44.73kJ/mol. Discussion: Inhibition of CYP3A4 function by epimedium and its active compound kaempferol leads to enhancement of CS anti-inflammatory effect.
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spelling pubmed-99229982023-02-14 Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid Li, Ke Yu, Xiu-Hua Maskey, Anish R. Musa, Ibrahim Wang, Zhen-Zheng Garcia, Victor Guo, Austin Yang, Nan Srivastava, Kamal Dunkin, David Li, Jun-Xiong Guo, Longgang Cheng, Yung-Chi Yuan, Haoliang Tiwari, Raj Li, Xiu-Min Front Pharmacol Pharmacology Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to determine the effects of epimedium on CYP3A4 and whether it affects the anti-inflammatory function of CS and identify the active compound responsible for this effect. Methods: The effect of epimedium on CYP3A4 activity was evaluated using the Vivid CYP high-throughput screening kit. CYP3A4 mRNA expression was determined in human hepatocyte carcinoma (HepG2) cells with or without epimedium, dexamethasone, rifampin, and ketoconazole. TNF-α levels were determined following co-culture of epimedium with dexamethasone in a murine macrophage cell line (Raw 264.7). Active compound (s) derived from epimedium were tested on IL-8 and TNF-α production with or without corticosteroid, on CYP3A4 function and binding affinity. Results: Epimedium inhibited CYP3A4 activity in a dose-dependent manner. Dexamethasone enhanced the expression of CYP3A4 mRNA, while epimedium inhibited the expression of CYP3A4 mRNA and further suppressed dexamethasone enhancement of CYP3A4 mRNA expression in HepG2 cells (p < 0.05). Epimedium and dexamethasone synergistically suppressed TNF-α production by RAW cells (p < 0.001). Eleven epimedium compounds were screened by TCMSP. Among the compounds identified and tested only kaempferol significantly inhibited IL-8 production in a dose dependent manner without any cell cytotoxicity (p < 0.01). Kaempferol in combination with dexamethasone showed complete elimination of TNF-α production (p < 0.001). Furthermore, kaempferol showed a dose dependent inhibition of CYP3A4 activity. Computer docking analysis showed that kaempferol significantly inhibited the catalytic activity of CYP3A4 with a binding affinity of −44.73kJ/mol. Discussion: Inhibition of CYP3A4 function by epimedium and its active compound kaempferol leads to enhancement of CS anti-inflammatory effect. Frontiers Media S.A. 2023-01-30 /pmc/articles/PMC9922998/ /pubmed/36793921 http://dx.doi.org/10.3389/fphar.2022.1042756 Text en Copyright © 2023 Li, Yu, Maskey, Musa, Wang, Garcia, Guo, Yang, Srivastava, Dunkin, Li, Guo, Cheng, Yuan, Tiwari and Li. 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
Li, Ke
Yu, Xiu-Hua
Maskey, Anish R.
Musa, Ibrahim
Wang, Zhen-Zheng
Garcia, Victor
Guo, Austin
Yang, Nan
Srivastava, Kamal
Dunkin, David
Li, Jun-Xiong
Guo, Longgang
Cheng, Yung-Chi
Yuan, Haoliang
Tiwari, Raj
Li, Xiu-Min
Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title_full Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title_fullStr Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title_full_unstemmed Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title_short Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
title_sort cytochrome p450 3a4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922998/
https://www.ncbi.nlm.nih.gov/pubmed/36793921
http://dx.doi.org/10.3389/fphar.2022.1042756
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