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Open AccessArticle

The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme

PDS Biology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4, 10000 Zagreb, Croatia
Institute of Clinical Laboratory Diagnostics, Osijek University Hospital Center, Josipa Huttlera 4, 31000 Osijek, Croatia
Department of Pharmacology, School of Medicine, University of Osijek, Cara Hadrijana 10/E, 31000 Osijek, Croatia
Department of Pharmaceutical Botany, Faculty of Pharmacy and Biochemistry, University of Zagreb, Schrottova 39, 10000 Zagreb, Croatia
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia
Author to whom correspondence should be addressed.
Molecules 2018, 23(10), 2553;
Received: 7 September 2018 / Revised: 29 September 2018 / Accepted: 5 October 2018 / Published: 7 October 2018
(This article belongs to the Section Natural Products Chemistry)
Flavonoids are natural compounds that have been extensively studied due to their positive effects on human health. There are over 4000 flavonoids found in higher plants and their beneficial effects have been shown in vitro as well as in vivo. However, data on their pharmacokinetics and influence on metabolic enzymes is scarce. The aim of this study was to focus on possible interactions between the 30 most commonly encountered flavonoid aglycones on the metabolic activity of CYP3A4 enzyme. 6β-hydroxylation of testosterone was used as marker reaction of CYP3A4 activity. Generated product was determined by HPLC coupled with diode array detector. Metabolism and time dependence, as well as direct inhibition, were tested to determine if inhibition was reversible and/or irreversible. Out of the 30 flavonoids tested, 7 significantly inhibited CYP3A4, most prominent being acacetin that inhibited 95% of enzyme activity at 1 µM concentration. Apigenin showed reversible inhibition, acacetin, and chrysin showed combined irreversible and reversible inhibition while chrysin dimethylether, isorhamnetin, pinocembrin, and tangeretin showed pure irreversible inhibition. These results alert on possible flavonoid–drug interactions on the level of CYP3A4. View Full-Text
Keywords: flavonoids; CYP3A4; HPLC-DAD; testosterone flavonoids; CYP3A4; HPLC-DAD; testosterone
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Šarić Mustapić, D.; Debeljak, Ž.; Maleš, Ž.; Bojić, M. The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme. Molecules 2018, 23, 2553.

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