Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids

Abstract

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.

In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification

“…Flavonoids and their glycosides are the most predominant class in A. judaica L. They are represented by quercetin, rutin, apigenin, rhoifolin, vitexin, kaempferol, fisetin, orientin, luteolin, isorhamnetin, naringenin, diosmetin, and acacetin. The therapeutic potential of these flavonoids has been described as antioxidant, neuroprotective, anti-mutagenic, anti-cancer, and anti-inflammatory agents [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Their anti-cancer activity is related to their ability to induce apoptosis and inhibit the angiogenesis process [ 74 ].…”

Prevention of Anthracycline-Induced Cardiotoxicity: The Good and Bad of Current and Alternative Therapies

“…Previous clinical and pre-clinical experimental studies have demonstrated the good pharmacokinetic profile of Pin, which is highlighted by its rapid absorption and wide distribution with negligible residue accumulation ( 94 , 98 , 99 ). In the context of Dox, Pin being a known inhibitor of CYP3A4 and also being implicated in the inhibition of CYP2D6, suggests that co-administering Dox with Pin might give rise to herb-drug interactions ( 100 ). Depending on how potently Pin inhibits CYP2D6, in comparison to Dox, may either increase the bioavailability of Dox plasma concentration or reduce it.…”

“…These type of inhibitions are based on the inactivation of the CYP enzyme via metabolic intermediates that bind reversibly or irreversibly to the enzyme. The clinical implications of the irreversible inhibition are expected to last longer than those of the reversible inhibitor after multiple treatment doses ( 100 ). This enables clinicians to plan for the appropriate scheduling of sequential regimens that either both inhibit or induce CYP2D6 and CYP3A4.…”

“…This enables clinicians to plan for the appropriate scheduling of sequential regimens that either both inhibit or induce CYP2D6 and CYP3A4. The use of combinational therapy is further supported by the large and flexible active sites of the CYP enzymes, which readily adapt to concurrently accommodate several substrates with distinct structures, without inducing any adverse reactions ( 100 , 109 ). This might explain how Pin, which is known to cause irreversible CYP3A4 inhibition ( 100 ), was able to mitigate Dox-induced cardiotoxicity without reducing the anti-carcinogenic properties of Dox ( 93 ).…”

Network Analysis of the Herb–Drug Interactions of Citrus Herbs Inspired by the “Grapefruit Juice Effect”

“…The regulating effects of the key compounds, which included naringenin, tangeretin, nobiletin, and apigenin, on UGT1A1 and CYP3A4 were also preliminarily observed in vitro. In fact, some recent studies focused on the capability of the compounds to regulate the drug-metabolizing enzymes, although the action tendency might be reversed due to different experimental systems and conditions. − As widely known, CYP450 played a pivotal role in drug metabolism, since the majority of hepatically cleared drugs depended on CYP450 for metabolism . GF inhibited intestinal and hepatic CYP3A4 in an exposure-dependent fashion, and patients taking CYP3A4 substrates are at risk of developing drug-related adverse events if consuming large amounts of GF .…”