Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

Abstract

Chrysin is an abundant flavonoid in nature, and it is also contained by several dietary supplements. Chrysin is highly biotransformed in the body, during which conjugated metabolites chrysin-7-sulfate and chrysin-7-glucuronide are formed. These conjugates appear at considerably higher concentrations in the circulation than the parent compound. Based on previous studies, chrysin can interact with biotransformation enzymes and transporters; however, the interactions of its metabolites have been barely examined. In this in vitro study, the effects of chrysin, chrysin-7-sulfate, and chrysin-7glucuronide on cytochrome P450 enzymes (2C9, 2C19, 3A4, and 2D6) as well as on organic anion-transporting polypeptides (OATPs; 1A2, 1B1, 1B3, and 2B1) and ATP binding cassette [P-glycoprotein, multidrug resistance-associated protein 2, and breast cancer resistance protein (BCRP)] transporters were investigated. Our observations revealed that chrysin conjugates are strong inhibitors of certain biotransformation enzymes (e.g., CYP2C9) and transporters (e.g., OATP1B1, OATP1B3, OATP2B1, and BCRP) examined. Therefore, the simultaneous administration of chrysin-containing dietary supplements with medications needs to be carefully considered due to the possible development of pharmacokinetic interactions. SIGNIFICANCE STATEMENT Chrysin-7-sulfate and chrysin-7-glucuronide are the major metabolites of flavonoid chrysin. In this study, we examined the effects of chrysin and its conjugates on cytochrome P450 enzymes and on organic anion-transporting polypeptides and ATP binding cassette transporters (P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2). Our results demonstrate that chrysin and/or its conjugates can significantly inhibit some of these proteins. Since chrysin is also contained by dietary supplements, high intake of chrysin may interrupt the transport and/or the biotransformation of drugs.

Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters

“…Inhibition of CYP2C19 [ 47 ], 3A4 [ 48 ], and 2D6 [ 49 ] by Q and its conjugates was tested based on our previously reported methods, without modifications.…”

Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

“…Chrysin, a flavonoid contained in honey and many dietary supplements, undergoes extensive phase II conjugation in humans, producing chrysin-7-sulfate and chrysin-7-glucuronide. Mohos et al (2020) compared the inhibitory effects of the two conjugated metabolites with chrysin on CYP2C9, CYP2C19, CYP2D6, and CYP3A4 using CypExpress kits, which are permeabilized and stabilized dried yeast powder preparations containing full length, unmodified, human P450s and recombinant human NADPH oxidoreductase (https:// www.oxfordbiomed.com/tech-resources/resources/cypexpress). The sulfate conjugate was a strong inhibitor of CYP2C9, whereas the glucuronide conjugate showed minimal to no inhibition of the P450s tested (Mohos et al, 2020).…”

“…Mohos et al (2020) compared the inhibitory effects of the two conjugated metabolites with chrysin on CYP2C9, CYP2C19, CYP2D6, and CYP3A4 using CypExpress kits, which are permeabilized and stabilized dried yeast powder preparations containing full length, unmodified, human P450s and recombinant human NADPH oxidoreductase (https:// www.oxfordbiomed.com/tech-resources/resources/cypexpress). The sulfate conjugate was a strong inhibitor of CYP2C9, whereas the glucuronide conjugate showed minimal to no inhibition of the P450s tested (Mohos et al, 2020). Because systemic peak concentrations of chrysin-7-sulfate have been reported to greatly exceed chrysin concentrations in humans after oral administration of chrysin (Walle et al, 2001;Mohos et al, 2020), the authors concluded that chronic consumption of dietary supplements containing high amounts of chrysin could precipitate pharmacokinetic interactions with CYP2C9 substrates.…”

“…The sulfate conjugate was a strong inhibitor of CYP2C9, whereas the glucuronide conjugate showed minimal to no inhibition of the P450s tested (Mohos et al, 2020). Because systemic peak concentrations of chrysin-7-sulfate have been reported to greatly exceed chrysin concentrations in humans after oral administration of chrysin (Walle et al, 2001;Mohos et al, 2020), the authors concluded that chronic consumption of dietary supplements containing high amounts of chrysin could precipitate pharmacokinetic interactions with CYP2C9 substrates.…”

“…In addition to examining the inhibitory effects of chrysin-7-sulfate and chrysin-7-glucuronide on the P450s described earlier, Mohos et al (2020) tested the effects of these conjugates on human transporters using A431 cells transfected with uptake transporters and inside-out membrane vesicles expressing efflux transporters. Both conjugates were shown to inhibit the uptake transporters organic anion transporting polypeptide (OATP) 1A2, OATP1B1, OATP1B3, and OATP2B1 and the efflux transporter BCRP.…”