Bioavailability of Flavonoids: The Role of Cell Membrane Transporters

Čvorović, Jovana; Žiberna, Lovro; Fornasaro, Stefano; Tramer, Federica; Passamonti, Sabina

doi:10.1016/b978-0-12-813006-3.00022-2

Cited by 20 publications

(16 citation statements)

References 254 publications

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“…The interaction between flavonoids and OATPs has been reviewed in several reports (Miron et al, 2017;Cvorovi c et al, 2018). Based on previous studies, chrysin seems to be a weak inhibitor of OATP1B1 (33% inhibition of estrone-3-sulfate uptake was observed by 100 mM chrysin) (Wang et al, 2005;Wu et al, 2012) and a potent inhibitor of OATP2B1 and OATP1A2 (Navrátilová et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Thus, it is important to note that the mechanism of polyphenol transport through the cell membrane is under study. Among polyphenols, flavonoids have been shown to move across the cell membrane through multiple transporters, compatible with their hydrophilic nature, which makes passage through the lipid bilayer of the cell by diffusion rather uncertain [41]. However, the purpose of this study was not to investigate the mechanism of transport of CSE and GA, and thus further experiments will be necessary to confirm this aspect.…”

Section: Discussionmentioning

confidence: 98%

“…This task is performed by an antioxidant defense system represented by two components, both present in the cell: antioxidant enzymes and low-molecular-weight molecules. Antioxidant enzymes include catalase, superoxide dismutase, and glutathione reductase, among others, while the most common low-molecular-weight antioxidants are vitamins C and E (ascorbic acid and tocopherol, respectively), glutathione, carotenoids (Vitamin A or retinol), quinines, and some polyphenols [41,42]. However, polyphenols can also exert pro-oxidant activities, depending on their concentration and the nature of neighboring molecules [42,43].…”

Section: Discussionmentioning

confidence: 99%

Chestnut Shell Extract Modulates Immune Parameters in the Rainbow Trout Oncorhynchus mykiss

Coccia

Siano

Volpe

et al. 2019

Fishes

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In this study, chestnut (Castanea sativa) shell was extracted with different solvents, and immunomodulatory activity was investigated in an in vitro model system using blood and intestinal leukocytes of Oncorhynchus mykiss. Gallic acid (GA) was used as a standard. Chestnut shell extract (CSE) and GA readily entered both blood and intestinal leukocytes. Superoxide anion production and phagocytosis were decreased by low doses of CSE and increased with high doses. CSE and GA differently regulated cytokine expression in blood and intestinal leukocytes. High doses of CSE upregulated IL-1β, TNF-α, and IL-10 in intestinal leukocytes and IL-10 in blood leukocytes. Low doses of CSE upregulated IL-1β and TNF-α in blood leukocytes. GA appeared to be effective only in blood leukocytes. The effects of CSE on pro- and anti-inflammatory cytokines seemed to suggest an alert effect of the immune defense system against a possible infectious agent. The less evident effect of GA in comparison to CSE could have been attributable to the synergistic and/or additive effects of polyphenols in the latter. The immune-stimulating activity of CSE reported here could be useful for future practical applications in fish health.

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“…Results not solely present a new insight in interactions between phenols and several membrane transporters, but can help also in assessment of their potential absorption and disposition properties, yet gain also valuable information for understanding possible interference of phenols with the transport activity of drugs. Since ingestion of extra dietary phenolic supplements as support to chemotherapy was proposed as promising therapeutic approach [ 7 , 10 ], but such diet could consequently influence drugs absorption and disposition [ 58 ]. For proper drug application this is for sure of high importance.…”

Section: Discussionmentioning

confidence: 99%

“…BTL does not transport only bilirubin into hepatocytes [ 51 , 52 ], but can transport a wide variety of poly-aromatic compounds among vitally important endogenous substrates and drugs [ 35 , 53 , 54 ]. Its tissue expression is broad from vascular endothelium to stomach, intestine, kidney and liver epithelia ( Figure 2 ) [ 55 , 56 , 57 , 58 ]. These peculiarities make BTL a hot spot for future investigation as potential important endogenous drug delivery system to the intracellular targets, especially for its ability of cancer drugs uptake [ 59 ] and also as tumor biomarker [ 60 ].…”

Section: Introductionmentioning

confidence: 99%

An In Silico Approach for Assessment of the Membrane Transporter Activities of Phenols: A Case Study Based on Computational Models of Transport Activity for the Transporter Bilitranslocase

Venko

Novič

2019

Molecules

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Phenols are the most abundant naturally accessible antioxidants present in a human normal diet. Since numerous beneficial applications of phenols as preventive agents in various diseases were revealed, the evaluation of phenols bioavailability is of high interest of researchers, consumers and drug manufacturers. The hydrophilic nature of phenols makes a cell membrane penetration difficult, which imply an alternative way of uptake via membrane transporters. However, the structural and functional data of membrane transporters are limited, thus the in silico modelling is really challenging and urgent tool in elucidation of transporter ligands. Focus of this research was a particular transporter bilitranslocase (BTL). BTL has a broad tissue expression (vascular endothelium, absorptive and excretory epithelia) and can transport wide variety of poly-aromatic compounds. With available BTL data (pKi [mmol/L] for 120 organic compounds) a robust and reliable QSAR models for BTL transport activity were developed and extrapolated on 300 phenolic compounds. For all compounds the transporter profiles were assessed and results show that dietary phenols and some drug candidates are likely to interact with BTL. Moreover, synopsis of predictions from BTL models and hits/predictions of 20 transporters from Metrabase and Chembench platforms were revealed. With such joint transporter analyses a new insights for elucidation of BTL functional role were acquired. Regarding limitation of models for virtual profiling of transporter interactions the computational approach reported in this study could be applied for further development of reliable in silico models for any transporter, if in vitro experimental data are available.

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Bioavailability of Flavonoids: The Role of Cell Membrane Transporters

Cited by 20 publications

References 254 publications

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

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

Chestnut Shell Extract Modulates Immune Parameters in the Rainbow Trout Oncorhynchus mykiss

An In Silico Approach for Assessment of the Membrane Transporter Activities of Phenols: A Case Study Based on Computational Models of Transport Activity for the Transporter Bilitranslocase

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