title: Mechanism of CYP2C9 inhibition by flavones and flavonols.
abstract: This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4'-hydroxylation in the CYP2C9 RECO system, with K(i) value <or= 2.2 microM. In terms of the mechanism of inhibition, 6-hydroxyflavone was found to be a noncompetitive inhibitor of CYP2C9, whereas the other flavonoids were competitive inhibitors. Computer docking simulation and constructed mutants substituted at residue 100 of CYP2C9.1 indicate that the noncompetitive binding site of 6-hydroxyflavone lies beside Phe100, similar to the reported allosteric binding site of warfarin. The other flavonoids exert competitive inhibition through interaction with the substrate binding site of CYP2C9 accessed by flurbiprofen. These results suggest flavonoids can participate in interactions with drugs that act as substrates for CYP2C9 and provide a possible molecular basis for understanding cooperativity in human P450-mediated drug-drug interactions.
authors.affiliation: College of Life Science, Jilin University, Changchun, 130023, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Si
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Zhou
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guo
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Ze-Sheng
authors.initials: ZS
authors.lastname: Li
authors.forename: J Paul
authors.initials: JP
authors.lastname: Fawcett
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D047309:Flavones / Q000493:pharmacokinetics / Q000494:pharmacology*; D044948:Flavonols / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D013056:Spectrophotometry, Ultraviolet
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D047309:Flavones; D044948:Flavonols; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases