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

Mohos, Violetta; Fliszár-Nyúl, Eszter; Ungvári, Orsolya; Kuffa, Katalin; Needs, Paul W.; Kroon, Paul A.; Telbisz, Ágnes; Özvegy‐Laczka, Csilla; Poór, Miklós

doi:10.3390/nu12082306

Cited by 52 publications

(37 citation statements)

References 78 publications

(137 reference statements)

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“…Functional BCRP has been detected in bEnd3 cerebral endothelial cells and reported to regulate the paracellular tightness [ 8 ]. According to literature data, quercetin and isorhamnetin also exert inhibitory effects on BCRP efflux function and may be candidates for potentiating drug delivery in the brain [ 57 , 58 ]. The detection of isorhamnetin, known to originate from the methylation of quercetin [ 29 ], shows the capacity of cerebral endothelial cells to metabolize quercetin in normoglycemic or hyperglycemic condition, and suggests the possible contribution of isorhamnetin to the biological effects of quercetin.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect

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Veeren

et al. 2021

IJMS

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Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.

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Section: Discussionmentioning

confidence: 99%

Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect

Taïlé

Patché

Veeren

et al. 2021

IJMS

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“…It was shown that sulfated derivatives of quercetin and chrysin can inhibit several CYPs in vitro. In particular, quercetin 3′-sulfate has a selective concentration-dependent inhibition activity to CYP2C19 and CYP3A4 up to 30 μM, but the inhibition effect did not exceed 50% and overall was less than that of ticlopidine and ketoconazole (used as positive controls) [ 49 ]. Chrysin 7-sulfate has an IC50 value of 2.7 μM to CYP2C9, which is comparable to that of the positive control sulfaphenazole [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

et al. 2021

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Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The Kd values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.

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“…These proteins transport the flavonoid conjugates from the proximal tubular cells to the urine, finally excreting them [46]. The BCRP transporter is not a specific transporter, and quercetin, isorhamnetin, and quercetin 3'-sulfate can also cross the apical membrane via tubular secretion through this transporter [47].…”

Section: Quercetin Metabolites' Luminal Efflux By Tubular Cellsmentioning

confidence: 99%

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

2021

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Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

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

Cited by 52 publications

References 78 publications

Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect

Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

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