Mechanism of CYP2C9 Inhibition by Flavones and Flavonols

Abstract

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 <2.2 M. 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.Flavonoids are polyphenolic secondary metabolites that are widely distributed in higher plants and ingested by humans in their regular food (Kuhnau, 1976;Bravo, 1998). Flavones and flavonols are two major classes of flavonoids (Table 1). Flavonols are present in a variety of fruits and vegetables, whereas flavones are mainly found in cereals and herbs (Hertog et al., 1993;Bravo, 1998;Peterson and Dwyer, 1998). In the West, the estimated daily intake of both flavonols and flavones is in the range 20 to 50 mg per day (Cermak and Wolffram, 2006). However, given the growing demand for food supplements or herbal remedies containing flavonoids, and given that in some countries flavonoids are commonly used as therapeutic agents (2008 State Food and Drug Administration RPC, http://app1.sfda.gov. cn/datasearch/face3/dir.html), it is likely that some individuals are exposed to relatively high levels of flavonoids. This points to a need for more information on the safety and potential toxicity of flavonoids.In the early 1980s, several studies reported the effects of flavonoids on the activity of hepatic cytochrome P450 (P450) enzymes (Buening et al., 1981;Lasker et al., 1982). Since then, the ability of flavonoids to inhibit isoforms of CYP450, particularly CYP1A1 and CYP1A2, has been extensively confirmed (Cermak and Wolffram, 2006). Several clinical studies have reported that some flavonoids have the capacity to alter drug metabolism in vivo (Peng et al., 2003;Rajnarayana et al., 2003;Choi et al., 2004). However, for CYP2C9, which ranks among the most important drug-metabolizing enzymes in humans and hydroxylates 10 to 20% of commonly prescribed drugs (Kirchheiner and Brockmöller, 2005), only two flavones, luteolin and baicalein, and one flavonol, quercetin, have been found to ...

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

“…This indicated that tamarixetin may improve fluvastatin bioavailability by affecting the drug absorption phase, without altering pharmacokinetic properties relating to its distribution, metabolism, or elimination. These findings suggested that, as expected, tamarixetin may interacted with CYP2C in the gut and liver in a short-term and reversible manner before they passage into the circulatory system (17,41). Nevertheless, we still cannot rule out the possibility that the effects of tamarixetin on fluvastatin oral bioavailability could be mediated by inhibition of other P450 isozymes or even non-CYP metabolic enzymes (e.g., phase II enzymes or membrane transporters).…”

In Vitro Inhibition of Multiple Cytochrome P450 Isoforms by Xanthone Derivatives from Mangosteen Extract

“…The xanthones found in mangosteen have multiple phenolic groups, which may contribute to both their efficacious and inhibitory effects. Phenolcontaining compounds such as the flavanol quercetin have been shown to be potent competitive inhibitors of CYP2C9 by occupying the flurbiprofen binding site of CYP2C9 (Si et al, 2009). The polyphenolic substructures of the xanthones found in mangosteen may suggest a similar mechanism of inhibition for these compounds.…”

Molecular docking simulation analysis of the interaction of dietary flavonols with heat shock protein 90

“…Some preliminary reports showed that flavonoids are involved in the modification of allergens, viruses and carcinogens [4][5] . Moreover, several in vitro studies showed that flavonoids also have anti-allergic, anti-inflammatory [6] , anti-microbial [7][8] , anti-cancer [9] and anti-diarrheal activities [10] .…”