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Article

Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids

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Faculty of Pharmacy, University of Mostar, Matice Hrvatske bb, 88000 Mostar, Bosnia and Herzegovina
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University of Zagreb Faculty of Pharmacy and Biochemistry, Ante Kovačića 1, 10000 Zagreb, Croatia
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Farmavita d.o.o., Igmanska 5A, 71000 Sarajevo, Bosnia and Herzegovina
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Faculty of Medicine, University of Mostar, Zrinskog Frankopana 34, 88000 Mostar, Bosnia and Herzegovina
*
Author to whom correspondence should be addressed.
Academic Editor: Armando Zarrelli
Molecules 2021, 26(10), 3018; https://doi.org/10.3390/molecules26103018
Received: 22 April 2021 / Revised: 14 May 2021 / Accepted: 17 May 2021 / Published: 19 May 2021
Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically. View Full-Text
Keywords: acacetin; apigenin; chrysin; pinocembrin; inhibition; CYP3A4; flavonoid-drug interaction acacetin; apigenin; chrysin; pinocembrin; inhibition; CYP3A4; flavonoid-drug interaction
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MDPI and ACS Style

Kondža, M.; Bojić, M.; Tomić, I.; Maleš, Ž.; Rezić, V.; Ćavar, I. Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids. Molecules 2021, 26, 3018. https://doi.org/10.3390/molecules26103018

AMA Style

Kondža M, Bojić M, Tomić I, Maleš Ž, Rezić V, Ćavar I. Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids. Molecules. 2021; 26(10):3018. https://doi.org/10.3390/molecules26103018

Chicago/Turabian Style

Kondža, Martin, Mirza Bojić, Ivona Tomić, Željan Maleš, Valentina Rezić, and Ivan Ćavar. 2021. "Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids" Molecules 26, no. 10: 3018. https://doi.org/10.3390/molecules26103018

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