Paradoxically, inhibitory effects of green tea catechins on several P450 enzymes have been reported in in vivo trials [125, 126]. The latter observation suggests that this enzyme is not activated by the flavonols, but by their sulfated or glucorunidated products [150, 151]. Their model is based on GALAS methodology, which involves QSAR (quantitative structure-activity relationship) and local similarity-based corrections. Further metabolism leads to the formation of the glucuronide and the sulfate metabolites of -resveratrol [128, 129]. The catalytic mechanisms of P450 enzymes are thoroughly investigated in the literature, as demonstrated in a scheme based on previous publications (Figure 1) [1, 40–42]. Conflicting data have been presented in several works describing in vitro and in vivo studies. Flavonoids are hydroxylated and/or o-demethylated by various hepatic P450 enzymes prior to their elimination . The biochemical mechanisms underlying metabolic herb-drug interaction were well described in a recent review . Moreover, medicinal herbs are not inspected by regulatory authorities such as the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) . Cyp3a4 Inhibitors List Of Drugs Cyp3a4 Inducers Foods Cyp3a4 Substrates List Of Cyp3a4 Inducers. A. These herbal sources of polyphenols deserve special attention when the activity of P450s is discussed, due to the dramatic increase in the use of herbal medicines and supplements [65, 66]. The involvement of microbiota in the metabolism of these compounds generally starts with the hydrolysis of polymeric, glycosylated and/or esterified polyphenols by brush border and/or microbial enzymes, which is a prerequisite for the absorption and bioactivity of most compounds [134–136]. The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a The flavonols kaempferol, quercetin, and galangin inhibit CYP3A4-mediated metabolism of xenobiotics in vitro [87, 148, 149]. Note this is not a exhaustive list of all CYP inhibitors and only the genes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 are considered. Mnemonic: S. ome C ertain S illy C ompounds A nnoyingly I nhibit E nzymes, G rrrrrrr S odium valporate C iprofloxacin . Amentoflavone (a dimer of apigenin) has even a stronger inhibitory effect, with an IC50 value of 0.07 μM . Tannic acid, a type of hydrolysable tannin commonly found in plant foods, inhibited testosterone 6-β-hydroxylation (CYP3A4) in human- and rat-liver microsomes with IC50 values of 20.2 μM and 16.8 μM, respectively . For example, total polyphenol intake in the Finnish diet is 817–919 mg/individual/day . Continuous exposure to these compounds, especially those that activate the xenobiotic nuclear receptor PXR (pregnane X receptor), may lead, in a feedback fashion, to increased expression of CYP3A4 in the intestine, making the food-drug interaction even more complex during extended periods of use [84–87]. A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. C. imetidine/omeprazole . Sign up here as a reviewer to help fast-track new submissions. The interaction of phenolic acids with CYP3A4 and their potential metabolism by the enzyme would be of high relevance as the research of the more multi-member interactions of CYP3A4, polyphenols and gut microbiota advances, due to the high antimicrobial activity of phenolic acids. CYP3A4; Le métabolisme des médicaments, essentiellement hépatique, fait intervenir : Le plus souvent plusieurs CYP ; Plus rarement un seul CYP ou un CYP préférentiel : c'est dans ces circonstances que le risque d'interaction est le plus élevé. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. If unavoidable, reduce the dose by approximately one third (rounded to the nearest 150 mg dosage strength) After discontinuation of a strong CYP3A4 inhibitor resume the dose that was taken prior to initiating the strong CYP3A4 inhibitor Avoid concurrent use of strong CYP3A inducers A recent study conducted on rats found that oral administration of morin, a flavonol found in many fruits and herbal medicines, increased the plasma half-life () of febuxostat, a drug used to treat gout 2.5-fold as compared with the control group, leading to significantly higher bioavailability. CYP3A4 should be a major point of focus in studies of the undesirable clinical consequences of the timed use of prescribed drugs and herbs . However, naringin appears to be a weak inhibitor of CYP3A4, while its aglycone, naringenin, may be a more potent inhibitor. The coadministration of active constituents derived from food or herbs and prescribed drugs may lead to undesirable clinical effects, which may include increased toxicity and/or treatment failure [67–69]. The inhibitory effects of -resveratrol on CYP3A4 in vitro and in vivo are well established, and it has been suggested that resveratrol might act as an irreversible, mechanism-based inactivator of this enzyme [38, 175–179]. Considering the water soluble green tea catechins, which should be very poor substrates for CYPs, their biotransformation by human gut microbiota could lead to the formation of better CYP substrates, as was demonstrated in vitro by Stoupi et al. Both actions are known to be mediated by CYP3A4 . Cytochrome P450 enzymes (P450s) are responsible for the metabolism of a wide range of endogenous compounds (steroid hormones, lipids, and bile acids), as well as xenobiotics including drugs, environmental pollutants, and dietary products [1–4]. ketoconazole) and nefazodone, Rifampicin, Carbamaze-pine, Phenytoin, Rifampicin, St John’s Wort, Recommendations on how DDIs can be managedAvoid concurrent use of strong CYP3A4 inhibitors. Bergamottin is a component of grapefruit juice and a known CYP3A4 inhibitor at the enzymatic level; however, its effects on the CYP1A2, 2D6, and CYP3A4 at the transcriptional level are currently unknown. CAS number iv CYP2C19 503612-47-3 319460-85-0 0.49 (total radioactiv 0.03 179324-69-7 <0.01 0.9 22316-47-8 Compound Compound properties Max DDI Observed People taking medications which are metabolized by CYP3A4 have to be careful with grapefruit juice, as this juice increases blood levels of the medication. A recent review concluded that the CYP3A4 active site is considerably larger than the active site of any other P450 isoform . May be more of a concern for higher u0003doses of Gleevec. Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart CYP3A4 and CYP3A5 Substrates Hence, potential interactions between promising new drugs and CYP3A4 are assessed starting at the early stages of their development [9–11]. It may be reasonable to avoid concurrent use with other enzyme inducers (e.g., St. John’s wart, primidone) for all DOAC medications. interactions between dietary polyphenols and CYP3A4. ... Ads related to: CYP3A4 Inhibitors And Inducers List PDF Results from Microsoft . A. Fahmi, T. S. Maurer, M. Kish, E. Cardenas, S. Boldt, and D. Nettleton, “A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3a4 inhibition, inactivation, and induction determined, Y.-H. Wang, D. R. Jones, and S. D. Hall, “Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites,”, J. 3. Last edited: Mar 31, 2008. I. This is consistent with findings that have demonstrated the importance of ligand hydrophobicity for interactions with these enzymes [38, 123, 124]. Download PDF format. Curcumin is a well‐known dietary component derived from Curcuma longa L., a widely used spice. In addition, ester and amide analogues of caffeic acid have been found to act as competitive inhibitors, with IC50 values ranging from 0.31 μM to 0.82 μM . Another intensively studied polyphenol is the stilbene -resveratrol (trans-3,4′,5-trihydroxystilbene), a polyphenol found in grape skins and red wine, peanuts, and a limited number of other plants, and its effects on CYP3A4 will be discussed later (Section 5.2.1). ConsumerLab.com's answer explains. The remarkably lower blood flow to the intestinal mucosa as compared to the liver allows for prolonged exposure to the intestinal metabolizing enzymes and lead to relatively high enterocytic drug concentrations. Selective: CYP3A4, IC50: 30 nM: S2900: Cobicistat (GS-9350) Cobicistat (GS-9350) is a potent and selective inhibitor of CYP3A … Epigallocatechin gallate, the most abundant catechin in green tee, is also a potent inhibitor of CYP3A in human liver and intestinal microsomes [ 5 ]. Several herbal products have been known to modulate cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) which are recognized as representative drug metabolizing enzymes and drug transporter, respectively. There is accumulating evidence to suggest that gut microbiota play a significant role in the metabolism, bioavailability, and bioactivity of dietary polyphenols [132–134]. Choi et al. Interactions between polyphenols and CYP3A4 are important due to their potential implications for drug metabolism. Recent studies have Up to date, the protein data bank (PDB) contains 18 crystal structure of human CYP3A4. In that study, they showed that pre-incubation of human liver microsomes with 100 μM gallic acid before the assay of androstenedione 6-β-hydroxylase activity significantly increased the inhibitory effects of the gallic acid. If we consider that CYP3A4 is responsible for the metabolism of more than 50% of clinical pharmaceuticals, all nutrient–drug interactions should be considered clinically relevant, in which case all clinical studies of drugs should include a food–drug interaction screening (Kimura and others 2010). Medicinal herbs such as St. John’s wort (Hypericum perforatum), ginseng (Panax ginseng), black cohosh (Actaea racemosa), echinacea (Echinacea purpurea), cranberry (Vaccinium macrocarpon), and ginger (Zingiber officinale) are rich sources of a vast array of polyphenolic compounds [74, 110–115]. Via Ginevra 4, 6900 Lugano - CH© Copyright 2021 European Society for Medical Oncology All rights reserved worldwide. Drug-drug, food-drug, and herb-drug interactions in the liver have been well documented in the literature [72, 88–90]. The predominance of CYP3A4 in human intestine and its high capacity enable it to can act several-fold more efficiently in the intestine than in the liver [20, 27, 28]. CYP3A4 Inhibitors Drugs that inhibit CYP3A4 activity will … A CYP3A inhibitor used to increase the systemic exposure of atazanavir or darunavir in combination with other antiretroviral agents in the treatment of HIV-1 infection. This evidence indicates that the use of flavonoid-containing dietary supplements concurrent with conventional pharmacotherapeutic regimens should be considered in order to avoid drug-flavonoid interactions [54, 72, 143–146]. Antivira, antibacterial, anti-inflammatory, neuroprotective, and anticarcinogenic effects have also been attributed to polyphenols [106–109]. In a study designed to reveal structure-activity relationships, flavones possessing more than two hydroxyl groups (e.g., luteolin and diosmetin) were shown to inhibit the biotransformation of midazolam in vitro, whereas flavones that do not have hydroxyl groups in their A and B rings (e.g., flavone and tangeretin) stimulated midazolam metabolism . Here, we focus on the interactions of polyphenols with CYP3A4, the major enzyme in the gut and liver metabolism of drugs and xenobiotics. The Panel recommends against the use of JAK inhibitors for the treatment of COVID-19, except in a clinical trial (AIII). Meanwhile it has been reported that flavonoids rich with hydroxyl group such as green tea catechins are fairly water soluble and are not likely to be good substrates for P450 enzymes [121, 122]. However, this estimate varies depending on the type of diet. Hence, their interactions with CYP3A4 are studied in more systems than most other polyphenols and provide evidence for various interactions of polyphenols with this enzyme. Below is a short list of some other medications that are processed through the CYP3A4 enzyme. For example, Koe and coworkers recently developed a novel multiplex RT-qPCR in vitro assay to examine the P450 enzyme-induction properties of herb-derived compounds . In addition, they reported that the removal of gallic acid-derived products from the incubation mixture completely restored CYP3A activity . enzymes that eliminate most of the drugs and toxins from our body Substrates or inhibitors can bind to CYP3A4 at multiple sites due to the flexible structure of this enzyme’s active site [195–197]. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Grapefruit juice, in large quantities (32 oz. Necessary cookies enable core functionality. The latter include UDP-glucuronosyl transferases and sulfotransferases that add to the increased water solubility of the hydroxylated polyphenols, producing glucuronides and sulfates, which are then eliminated from the body [29, 47, 48]. • Anastrozole. In general, the total intake of polyphenols is approximated at 1 g/individual/day and polyphenols are considered by many to be the major source of antioxidants in our diet [51, 95–97]. These biotransformations affect the structural characteristics of polyphenols and may generate metabolites with altered bioactivity profiles [30, 134]. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. showed that the traditional QSAR model applied to one data set does not lead to predictive models that would be useful for in silico filtering of chemical libraries and presents a multiple pharmacophore hypothesis (MPH) that is a conceptual extension of the conventional QSAR approach. The role of intestinal microbiota in the metabolism and bioavailability of dietary polyphenols has been examined [30, 132–136], but, unfortunately, data on the three-way interactions between polyphenols, microbiota and P450s are scarce. Traditionally, the liver was considered the prime site The metabolic fate of polyphenols is largely dictated by their chemical structure and depends on several parameters, including their functional groups (i.e., benzene or flavone derivatives), molecular weight, stereostructure, glycosylation, polymerization, and conjugation with other phenolics [97, 116, 117]. For instance, soy isoflavones have been found to inhibit CYP3A4 metabolism [169–171], whereas the administration of genistein resulted in a modest induction of CYP3A enzymes among healthy participants [172, 173]. Indeed, medical doctors as well as pharma professionals should be aware of the many interactions of polyphenolics with drugs and tools should be developed to assess the potential of individual polyphenolics to enter the active sites of P450 enzymes and become substrates, competitive inhibitors, or other types of inhibitors of these enzymes in the intestine and the liver. ketoconazole) and nefazodone. Also note that if a drug inhibits CYP3A4 it is expected to induce CYP3A5 although literature proving this for each drug is not available. For example, carbamazepine is a potent inducer of CYP3A4, ketoconazole is potent inhibitor of CYP3A4, and midazolam is a substrate of CYP3A4. B. Delucchi, “Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4,”, B. Piver, F. Berthou, Y. Dreano, and D. Lucas, “Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components,”, S.-P. Hong, D.-H. Choi, and J.-S. Choi, “Effects of resveratrol on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem, in rats,”, Y. C. Chi, S. P. Lin, and Y. C. Hou, “A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats,”, P. Detampel, M. Beck, S. Krähenbühl, and J. Huwyler, “Drug interaction potential of resveratrol,”, M. A. Correia and P. R. O. de Montellano, “Inhibition of cytochrome P450 enzymes,” in, Y. Sahali-Sahly, S. K. Balani, J. H. Lin, and T. A. Baillie, “, H. Iwata, Y. Tezuka, S. Kadota, A. Hiratsuka, and T. Watabe, “Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract,”, R. Venkataramanan, V. Ramachandran, B. J. Komoroski, S. Zhang, P. L. Schiff, and S. C. Strom, “Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures,”, R. Zuber, M. Modrianský, Z. Dvořák et al., “Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities,”, H.-T. Yao, Y.-W. Chang, S.-J. It is also possible that the larger stereodimensions of the dimer may lead to irreversible binding of the hydroxylation product to the enzyme, thereby achieving inhibition via a suicidal mode of action [12, 155]. Recently, Singh and Pai reported the success of a systematically optimized nanoparticulate drug delivery system to increase the oral bioavailability of -resveratrol in rats . However, recent studies demonstrate a very complex allosteric mechanism of P450’s including overlay of a multiple substrate-binding space-filling mechanism, enzyme conformational changes induced by ligands and modulation of protein-protein interactions in the enzyme oligomers [158, 202]. critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. It exhibits a high level of membrane permeability and is categorized as a class-II compound in the Biopharmaceutical Classification System (BCS) . A recent study in rats suggests that the coadministration of apigenin would be very useful for improving the bioavailability of paclitaxel in chemotherapeutic applications, due to the inhibitory effects of apigenin on CYP3A and P-glycoprotein, leading to higher concentration of paclitaxel in the plasma . The concurrent use of drugs and herbal products is becoming increasingly prevalent over the last decade. A. ntifungals, amiodarone . CYP3A4 inhibitors. A three-dimensional pharmacophore based on 38 substrates of CYP3A4 possessed two hydrogen bond acceptors, one hydrogen bond donor, and one hydrophobic region . While members of this family share many structural and functional features, existing reports do not provide sufficient information to allow us to fully understand the rules that determine the nature of these interactions. Inhibitory effects of catechins on CYP3A4 have been reported in several additional in vitro and in vivo studies, but no specific mode of action has been suggested [73, 121, 125, 126, 162]. B. Aggarwal and S. Shishodia, “Molecular targets of dietary agents for prevention and therapy of cancer,”, G. Garrido, D. González, Y. Lemus et al., “, S. N. Nichenametla, T. G. Taruscio, D. L. Barney, and J. H. Exon, “A review of the effects and mechanisms of polyphenolics in cancer,”, N. T. Zaveri, “Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications,”, N. Kalogeropoulos, K. Yannakopoulou, A. Gioxari, A. Chiou, and D. P. Makris, “Polyphenol characterization and encapsulation in, H. J. Lee, H.-S. Lee, H. J. Cho, S. Y. Kim, and H. J. The substrates were then characterized according to the proximal and distal binding relative. telithromycin), antifungals (e.g. Table of Substrates, Inhibitors and Inducers (including: CYP Enzymes, Clinical index drugs, transporters, and examples of clinical substrates, inhibitors, and inducers). The lignans gomisins B and C, components of Schisandra fruit (Schisandra chinensis) extract, have been identified as potent inhibitors of CYP3A4 in vitro . Allosteric behavior includes homotropic and heterotropic activation and inhibition effects depending on thermodynamic factors as demonstrated by Denisov and Sligar. Various foods (& supplements) can inhibit or stimulate CYP3A4 production - including black pepper, which is 5-9% piperine. In 1998, various researchers showed that grapefruit juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their bioavailability. Increase Gleevec levels. Thus, a summary of knowledge on the modulation of CYP and P-gp by commonly used herbs can provide robust fundamentals for optimizing CYP and/or P-gp substrate drug-… Furthermore, the intestine receives not only dietary compounds, but also phase I and II metabolites that have been excreted back into the intestine through the enterohepatic cycle [29, 30]. In the Vietnamese diet, it is 595 mg/individual/day , and in the Mediterranean diet, polyphenol intake ranges between 1800 and 3000 mg/individual/day . Interestingly, prolonged exposure to quercetin leads to a significant increase in CYP3A4 mRNA expression levels in cell cultures [87, 153]. telithromycin), antifungals (e.g. That's a great tip Hip! The assumption of independence of IRs from the substrate was evaluated on a set of eight victim drugs and eight inhibitors. Also note that if a drug inhibits CYP3A4 it is expected to induce CYP3A5 although literature proving this for each drug is not available. It is important to note that not all drugs within a class of medications are known to be inhibitors of CYP3A4. How significant is the interaction?”, U. Fuhr and A. L. Kummert, “The fata of naringin in humans: a key to grapefruit juice-drug interactions?”, P.-C. Ho, D. J. Saville, and S. Wanwimolruk, “Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds,”, K. Iwanaga, M. Hayashi, Y. Hamahata et al., “Furanocoumarin derivatives in Kampo extract medicines inhibit cytochrome P450 3A4 and P-glycoprotein,”, K. M. VanderMolen, G. R. Ainslie, M. F. Paine, and N. H. Oberlies, “Labeled content of two furanocoumarins in dietary supplements correlates with neither actual content nor CYP3A inhibitory activity,”, Y.-F. Ueng, C.-C. Chen, H. Yamazaki et al., “Mechanism-based inhibition of CYP1A1 and CYP3A4 by the furanocoumarin chalepensin,”, B. C. Foster, S. Vandenhoek, J. Hana et al., “, E. S. Roberts-Kirchhoff, J. R. Crowley, P. F. Hollenberg, and H. Kim, “Metabolism of genistein by rat and human cytochrome P450s,”, L. M. Scott, P. Durant, S. Leone-Kabler et al., “Effects of prior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymes,”, C.-Q. A. Izzo, “Herb-drug interactions: an overview of the clinical evidence,”, T. L. Poulos, “Cytochrome P450 dynamics,” in, A. R. Topletz, J. A selected list of such interactions appears in the Table. CYP3A4 is an important CYP enzyme, responsible for clearing approximately 45 – 60% of currently prescribed drugs. However, to the best of our knowledge the research in this area is limited and additional data are needed. This review focuses on Box 12, 76100 Rehovot, Israel, Oxidative Medicine and Cellular Longevity, Activation (modest activation in clinical trials), Anthocyanins (and anthocyanins aglycones), Resveratrol (and resveratrol derivatives), Inhibition (with slight activation at low concentrations), I. G. Denisov, T. M. Makris, S. G. Sligar, and I. Schlichting, “Structure and chemistry of cytochrome P450,”, T. L. Domanski, Y. These structures represent two distinct open conformations of CYP3A4 because ketoconazole and erythromycin induce different types of coordinate shifts . Box 12, 76100 Rehovot, Israel. The number of hydroxyl groups, stereostructure, molecular weight and lipophilicity all seem to have some sort of effect on individual results. Drug-metabolizing P450s such as CYP3A4 have relaxed selectivity and are able to bind and metabolize a large array of substrates of different size, shapes, and chemical properties, for example, many dietary polyphenols. St John's Wort is an inducer of CYP3A4. Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly. CYP3A4 is mainly involved in the metabolism of ART drugs, including NNRTIs, PIs, and integrase inhibitors. Several herbal products have been known to modulate cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) which are recognized as representative drug metabolizing enzymes and drug transporter, respectively. • Azithromzcin. Loai Basheer, Zohar Kerem, "Interactions between CYP3A4 and Dietary Polyphenols", Oxidative Medicine and Cellular Longevity, vol. B. Houston, and A. Galetin, “Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations,”, S. D. Hall, K. E. Thummel, P. B. Watkins et al., “Molecular and physical mechanisms of first-pass extraction,”, D. G. Bailey, G. Dresser, and J. M. O. Arnold, “Grapefruit-medication interactions: forbidden fruit or avoidable consequences?”, M. Gertz, A. Harrison, J. In large, flavonoids account for about two-thirds of the total intake of dietary polyphenols and phenolic acids account for the remaining one-third . way. The IC50 values of anthocyanin derivatives ranged from 12.2 to 7,842 μM; whereas ketoconazole, a synthetic CYP3A4 inhibitor that is often used as a reference, has an IC50 value of 18.4 nM. A direct impact on humans is mediated especially through our own set of 57 P450s . Strong inhibitors of CYP3A4 include: Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir. and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This inhibition occurs when a CYP3A4 substrate/inhibitor forms a reactive intermediate at the CYP3A4 active site, leading to enzyme inactivation by modification to the heme or the apoprotein [180, 181]. Silymarin (0.1 mM and 0.25 mM) significantly reduced the activity of CYP3A4 in human hepatocyte cultures by 50 and 100%, respectively, as determined by the formation of 6-β-hydroxy testosterone . B. Blumberg, “Flavonoid basics: chemistry, sources, mechanisms of action, and safety,”, G. F. Ferrazzano, I. Amato, A. Ingenito, A. Zarrelli, G. Pinto, and A. Pollio, “Plant polyphenols and their anti-cariogenic properties: a review,”, A. Scalbert and G. Williamson, “Dietary intake and bioavailability of polyphenols,”, J. D. Lambert, S. Sang, and C. S. Yang, “Biotransformation of green tea polyphenols and the biological activities of those metabolites,”, J. D. Lambert, S. Sang, and C. S. Yang, “Possible controversy over dietary polyphenols: benefits vs risks,”, S. Wanwimolruk and V. Prachayasittikul, “Cytochrome P450 enzyme mediated herbal drug interactions (part 1),”, K. E. Heim, A. R. Tagliaferro, and D. J. Bobilya, “Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships,”, I. Rodeiro, M. T. Donato, A. Lahoz, G. Garrido, R. Delgado, and M. J. Gómez-Lechón, “Interactions of polyphenols with the P450 system: possible implications on human therapeutics,”, L. M. Blanco-Colio, M. Valderrama, L. A. Alvarez-Sala et al., “Red wine intake prevents nuclear factor-, L. Hooper, P. A. Kroon, E. B. Rimm et al., “Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials,”, J. P. E. Spencer, “Flavonoids and brain health: multiple effects underpinned by common mechanisms,”, Y. J. Surh, “Cancer chemoprevention with dietary phytochemicals,”, L. Rodríguez-Fragoso, J. L. Martínez-Arismendi, D. Orozco-Bustos, J. Reyes-Esparza, E. Torres, and S. W. Burchiel, “Potential risks resulting from fruit/vegetable-drug interactions: effects on drug-metabolizing enzymes and drug transporters,”, L. Korkina, C. De Luca, and S. Pastore, “Plant polyphenols and human skin: friends or foes,”, Y. D. Muthiah, C. E. Ong, S. A. Sulaiman, S. C. Tan, and R. Ismail, “In-vitro inhibitory effect of Tualang honey on cytochrome P450 2C8 activity,”, D. Schwarz, P. Kisselev, W.-H. Schunck, and I.
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