The Effect of Flavonoid Aglycones on the CYP1A2, CYP2A6, CYP2C8 and CYP2D6 Enzymes Activity.

Mirza Bojić,Goran Benković,Hrvoje Rimac,Željan Maleš,Martin Kondža

doi:10.3390/molecules24173174

Abstract

Cytochromes P450 are major metabolic enzymes involved in the biotransformation of xenobiotics. The majority of xenobiotics are metabolized in the liver, in which the highest levels of cytochromes P450 are expressed. Flavonoids are natural compounds to which humans are exposed through everyday diet. In the previous study, selected flavonoid aglycones showed inhibition of CYP3A4 enzyme. Thus, the objective of this study was to determine if these flavonoids inhibit metabolic activity of CYP1A2, CYP2A6, CYP2C8, and CYP2D6 enzymes. For this purpose, the O-deethylation reaction of phenacetin was used for monitoring CYP1A2 enzyme activity, coumarin 7-hydroxylation for CYP2A6 enzyme activity, 6-α-hydroxylation of paclitaxel for CYP2C8 enzyme activity, and dextromethorphan O-demethylation for CYP2D6 enzyme activity. The generated metabolites were monitored by high-performance liquid chromatography coupled with diode array detection. Hesperetin, pinocembrin, chrysin, isorhamnetin, and morin inhibited CYP1A2 activity; apigenin, tangeretin, galangin, and isorhamnetin inhibited CYP2A6 activity; and chrysin, chrysin-dimethylether, and galangin inhibited CYP2C8. None of the analyzed flavonoids showed inhibition of CYP2D6. The flavonoids in this study were mainly reversible inhibitors of CYP1A2 and CYP2A6, while the inhibition of CYP2C8 was of mixed type (reversible and irreversible). The most prominent reversible inhibitor of CYP1A2 was chrysin, and this was confirmed by the docking study.

Highlights

Cytochrome P450 (CYP) enzymes are the most significant enzymes for the metabolism of substances foreign to the human body, including drugs [1]
CYP2A6, while the inhibition of CYP2C8 was of mixed type
The iron ion is linked to the heme by four coordinative covalent bonds, while the fifth coordinative covalent bond links iron to the cysteine residue of the apoprotein

Summary

Introduction

Cytochrome P450 (CYP) enzymes are the most significant enzymes for the metabolism of substances foreign to the human body, including drugs [1]. These enzymes are hemoproteins containing heme, which is bound to the apoprotein part. The reactions catalyzed by cytochromes P450 are not limited to one type of reaction or one substrate. Each cytochrome P450 enzyme has numerous substrates and catalyzes chemically diverse reactions. Beside oxidation reactions (e.g., hydroxylations, dealkylations), cytochromes catalyze reduction, desaturation, ester cleavage, ring expansion, ring formation, aldehyde scission, dehydration, ipso attack, one-electron oxidation, coupling reactions, rearrangement of fatty acid, and prostaglandin hydroperoxides [2]

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