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-7-glucuronide 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.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Dietary Supplements , Flavonoids/pharmacokinetics , Organic Anion Transporters/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Organic Anion Transporters/metabolismABSTRACT
BACKGROUND/AIM: N. sativa essential oil (EO) and its compounds (thymoquinone, carvacrol and p-cymene) have a broad antimicrobial spectrum. The aim of this study was to investigate the antimicrobial and resistance modifying activity of N. sativa EO, thymoquinone, carvacrol and p-cymene against Listeria monocytogenes. MATERIALS AND METHODS: N. sativa EO, thymoquinone, carvacrol and p-cymene was assessed for its antimicrobial activity, modulation of antimicrobial resistance, inhibition of antimicrobial efflux and membrane integrity by broth microdilution, ethidium bromide accumulation and LIVE/DEAD BacLight™ assays. RESULTS: L. monocytogenes showed substantial susceptibility toward N. sativa EO, thymoquinone, and carvacrol. A significant reduction in MIC's of EtBr and ciprofloxacin was noticed when tested in combination with N. sativa EO, thymoquinone, carvacrol and reserpine. In the presence of each compound the membrane integrity was disintegrated, and the EtBr accumulation increased which was comparable to positive control reserpine. CONCLUSION: N. sativa EO might have a potential for controlling the antibiotic resistance in Listeria.