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
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
30394306
DOI
10.1016/j.toxlet.2018.10.028
PII: S0378-4274(18)31988-X
Knihovny.cz E-zdroje
- Klíčová slova
- Cytochrome P450, Drug metabolism, Food-drug interactions, Pregnane X receptor, Resveratrol, Stilbenes,
- 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
- Názvy látek
- inhibitory cytochromu P450 MeSH
- resveratrol MeSH
- steroidní receptory MeSH
- stilbeny 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.
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