Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes.

Violetta Mohos,Csaba Hetényi,Miklós Poór,Balázs Zoltán Zsidó,Přemysl Mladěnka,Milan Pour,Beáta Lemli,Pavel Horký,Eszter Fliszár-Nyúl

doi:10.3390/biom10030409

Violetta Mohos, Csaba Hetényi + Show 7 more

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https://doi.org/10.3390/biom10030409

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Abstract

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

Highlights

Flavonoids, phenolic compounds found in numerous plants [1], have been demonstrated to have beneficial health effects in several in vitro and in vivo studies [2,3]
Some colonic metabolites were previously shown to interact with serum albumin or biotransformation enzymes, such as pyrogallol (PYR) which form a stable complex with albumin [18], and it is a potent inhibitor of xanthine oxidase enzyme [19,20]
S119, E122, P197, and R440 amino acid residues of the enzyme stabilize the binding of both ligands through H bonds. As it has been reported, flavonoids and their conjugated metabolites interact with serum albumin [5,43,44] and with several biotransformation enzymes [45,46,47,48]

Summary

Introduction

Flavonoids, phenolic compounds found in numerous plants (including fruits and vegetables) [1], have been demonstrated to have beneficial health effects in several in vitro and in vivo studies [2,3]. Flavonoid-containing dietary supplements are widely marketed through the Internet Some of these dietary supplements contain extremely high doses of flavonoids (ranging from several hundreds to thousands of milligrams) [4,5]. Flavonoids can interact with proteins involved in drug pharmacokinetics, such as serum albumin, biotransformation enzymes, and drug transporters [6,7,8]. A large fraction of flavonoids, not absorbed from the small intestines, can be biotransformed by the colon microbiota, leading to the degradation of flavonoid ring(s) to smaller phenolic compounds. Some colonic metabolites were previously shown to interact with serum albumin or biotransformation enzymes, such as pyrogallol (PYR) which form a stable complex with albumin [18], and it is a potent inhibitor of xanthine oxidase enzyme [19,20]

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