Heterotropic activation of flavonoids on cytochrome P450 3A4: A case example of alleviating dronedarone-induced cytotoxicity.
Toxicol Lett
; 319: 187-196, 2020 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-31756459
ABSTRACT
The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Flavonoides
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Supervivencia Celular
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Activadores de Enzimas
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Citocromo P-450 CYP3A
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Dronedarona
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Antiarrítmicos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Toxicol Lett
Año:
2020
Tipo del documento:
Article