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Trans-resveratrol, but not other natural stilbenes occurring in food, carries the risk of drug-food interaction via inhibition of cytochrome P450 enzymes or interaction with xenosensor receptors
L. Hyrsova, A. Vanduchova, J. Dusek, T. Smutny, A. Carazo, V. Maresova, F. Trejtnar, P. Barta, P. Anzenbacher, Z. Dvorak, P. Pavek,
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články
- MeSH
- hepatocyty účinky léků MeSH
- inhibitory cytochromu P450 metabolismus MeSH
- interakce mezi potravou a léky * MeSH
- kultivované buňky MeSH
- lidé MeSH
- resveratrol MeSH
- steroidní receptory metabolismus MeSH
- stilbeny metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Resveratrol (RSV) is a stilbene phytochemical common in food and red wine. RSV inhibits cytochrome P450 CYP3A4 activity and interacts with the pregnane X receptor (PXR), the central regulator of drug/xenobiotic metabolizing enzyme expression. In this work, we comprehensively examined the effects of 13 stilbenes (trans- and cis-resveratrol, trans- and cis-piceatannol, oxyresveratrol, pterostilbene, pinostilbene, a,b-dihydroresveratrol, trans- and cis-trismethoxyresveratrol, trans-3,4,5,4'-tetramethoxystilbene, trans-2,4,3',5'-tetramethoxystilbene, trans-4-methoxystilbene), on CYP3A4 and CYP2B6 mRNA induction, and on CYP3A4/5, CYP2C8/9/19, CYP2D6, CYP2A6, CYP2E1, CYP1A2 and CYP2B6 cytochrome P450 enzyme activities. Expression experiments in five different primary human hepatocyte preparations, reporter gene assays, and ligand binding assays with pregnane X (PXR) and constitutive androstane (CAR) receptors were performed. Inhibition of cytochrome P450 enzymes was examined in human microsomes. We found that only polymethoxylated stilbenes are prone to significantly induce CYP2B6 or CYP3A4 in primary human hepatocytes via pregnane X receptor (PXR) interaction. Natural resveratrol derivatives such as trans- and cis-RSV, oxyresveratrol, pinostilbene and pterostilbene significantly inhibit CYP3A4/5 enzymatic activities; however, only trans-RSV significantly inhibits CYP3A4/5 activity (both testosterone 6β-hydroxylation and midazolam 1´-hydroxylation) in micromolar concentrations by a non-competitive mechanism, suggesting a potential risk of food-drug interactions with CYP3A4/5 substrates.
Citace poskytuje Crossref.org
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- $a Hyrsova, Lucie $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic.
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- $a Resveratrol (RSV) is a stilbene phytochemical common in food and red wine. RSV inhibits cytochrome P450 CYP3A4 activity and interacts with the pregnane X receptor (PXR), the central regulator of drug/xenobiotic metabolizing enzyme expression. In this work, we comprehensively examined the effects of 13 stilbenes (trans- and cis-resveratrol, trans- and cis-piceatannol, oxyresveratrol, pterostilbene, pinostilbene, a,b-dihydroresveratrol, trans- and cis-trismethoxyresveratrol, trans-3,4,5,4'-tetramethoxystilbene, trans-2,4,3',5'-tetramethoxystilbene, trans-4-methoxystilbene), on CYP3A4 and CYP2B6 mRNA induction, and on CYP3A4/5, CYP2C8/9/19, CYP2D6, CYP2A6, CYP2E1, CYP1A2 and CYP2B6 cytochrome P450 enzyme activities. Expression experiments in five different primary human hepatocyte preparations, reporter gene assays, and ligand binding assays with pregnane X (PXR) and constitutive androstane (CAR) receptors were performed. Inhibition of cytochrome P450 enzymes was examined in human microsomes. We found that only polymethoxylated stilbenes are prone to significantly induce CYP2B6 or CYP3A4 in primary human hepatocytes via pregnane X receptor (PXR) interaction. Natural resveratrol derivatives such as trans- and cis-RSV, oxyresveratrol, pinostilbene and pterostilbene significantly inhibit CYP3A4/5 enzymatic activities; however, only trans-RSV significantly inhibits CYP3A4/5 activity (both testosterone 6β-hydroxylation and midazolam 1´-hydroxylation) in micromolar concentrations by a non-competitive mechanism, suggesting a potential risk of food-drug interactions with CYP3A4/5 substrates.
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- $a Vanduchova, Alena $u Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic.
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- $a Dusek, Jan $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic.
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- $a Carazo, Alejandro $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic; Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic.
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- $a Bárta, Pavel, $u Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic. $d 1982- $7 uk20211104475
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- $a Anzenbacher, Pavel $u Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 3, CZ775 15, Olomouc, Czech Republic.
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- $a Dvorak, Zdenek $u Department of Cellular Biology and Genetics, Faculty of Sciences, Palacky University in Olomouc, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
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- $a Pavek, Petr $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, CZ500 05, Czech Republic. Electronic address: petr.pavek@faf.cuni.cz.
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