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Flavonoids as cytochrome CYP3A4 inhibitors: how significant is their inhibition potential?

Flavonoids are a big class of polyphenol compounds characterised with a phenyl chromane core. Their diversity comes from hydroxylation and subsequent methylation and glycosylation of the basic skeleton. These compounds are widely distributed in plant kingdom, mainly as the secondary metabolites of higher plants, and antioxidant activity is their major pharmacological effect. However, the list of biological effects of individual flavonoids is much more extensive and includes antibacterial, virustatic, fungistatic, and hepatoprotective effects among others. CYP3A4 is the most significant enzyme for the metabolism of xenobiotics, namely medicinal drugs, and potential interactions of flavonoids with drugs whose metabolism is mediated by this enzyme are of our interest. Direct inhibition of CYP3A4 can be avoided by simple discontinuation of one drug that interacts with another, whereas irreversible inhibition leads to inactivation of the enzyme. To evaluate the potential of flavonoid inhibition of CYP3A4 we have conducted a screening of 30 flavonoid aglycones. Enzyme activity was tested on bicistronic membranes with CYP3A4 coexpressed with NADPH reductase for electron transfer from NADPH. The RP-HPLC-DAD method was used to monitor marker reaction of CYP3A4 (6β- hydroxylation of testosterone) and determine residual enzyme activity. Out of 30 flavonoids analysed, 7 have shown the potential to inhibit CYP3A4 atmicromolar concentrations. Chrysin, apigenin, and acacetin showed direct inhibition. Irreversible inhibiton of CYP3A4 was observed with pinocembrin, isorhamnetin, tangeretin, and chrysin- dimethylether. Although antioxidant activity is desirable, preliminary results suggest caution when high amounts of vegetables and fruits rich in aforementioned flavonoids are consumed with drugs that are mainly metabolised by CYP3A4 (e.g. erythromycin, cyclosporine, simvastatin) as this can result in high concentrations of drugs leading to undesirable, even toxic effects.

cytochrome CYP3A4 ; flavonoids ; metabolic interactions

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