Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases.

Review pubs.acs.org/crt

Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases Ekaterina A. Korobkova* John Jay College of Criminal Justice, The Department of Sciences, City University of New York, 524 W 59th Street, New York, New York 10019, United States ABSTRACT: Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol−CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP’s activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of polyphenols to the enzymes and (2) the mechanisms of the regulation of CYP gene expression mediated by polyphenols. The structure−activity relationship relevant to the ability of polyphenols to affect the activity of CYP is analyzed. The application of polyphenol−CYP interactions to diseases is discussed.

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CONTENTS

1. Introduction 2. Classification of Polyphenolic Compounds 3. Interactions between Polyphenols and CYP: Direct Binding and Mechanism-Based Inhibition 3.1. Inhibition of CYP by Flavonoids, Stilbenes, and Chalcones 3.2. Inhibition of CYP by Lignans 4. Polyphenol-Mediated Modulation of CYP Gene Expression 4.1. Effect of Polyphenols on Pregnane X Receptor Signaling Pathways 4.2. Influence of Polyphenols on Aryl Hydrocarbon Receptor Signaling Pathways 5. Role of Polyphenol−CYP Interactions in Diseases 5.1. Cancer 5.2. Cardiovascular Diseases (CVD) and Diabetes Conclusions Author Information Corresponding Author Funding Notes © 2015 American Chemical Society

Acknowledgments Abbreviations References

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1. INTRODUCTION Cytochromes P450 (CYPs) are hemeproteins that are critical for the proper physiological functioning of organisms; they are present in all living organisms. Multiple reactions catalyzed by CYP have been described. CYP enzymes participate in the synthesis of various biomolecules essential for cellular growth and division such as fatty acids, lipid-soluble vitamins, and steroid hormones. CYP enzymes metabolize most clinically administered drugs and carcinogenic compounds. Moreover, they participate in cerebral autoregulation.1 In bacteria, CYPs are involved in the synthesis of antibiotics.2 The main reaction catalyzed by CYP is the mono-oxygenation of carbon.3 Peroxidase-like activity resulting in a one-electron oxidation of compounds has been also documented.4,5 The enzymes

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Received: March 27, 2015 Published: June 4, 2015 1359

DOI: 10.1021/acs.chemrestox.5b00121 Chem. Res. Toxicol. 2015, 28, 1359−1390

Chemical Research in Toxicology

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exhibit epoxygenase activity,3 for example, in the epoxidation of arachidonic acid.6 CYPs catalyze N-oxygenation, N-dealkylation,7,8 sulfoxidation,8,9 and the formation of dehalogenated metabolites.10 The introduction of polar groups, such as the hydroxyl group, into the molecules facilitates their excretion. This way, CYP enzymes initiate the detoxification of undesirable xenobiotics. Denitrosation activity exhibited by CYPs also contributes to the detoxification mechanisms.11,12 CYPs have been shown to catalyze multiple unusual reactions3,13 such as reductions,14 rearrangements, and isomerizations. For example, some nonclassical CYP enzymes catalyze the conversion of hydroperoxy fatty acids to their dihydroxy derivatives,15,16 several CYP isoforms catalyze cis−trans isomerization of some estrogen receptor (ER) modulators.17 The formation of a new ring catalyzed by CYP also represents an unusual catalysis, for example, amination reactions with arylsulfonyl azide substrates.18 Recently, it was discovered that a bacterial enzyme, thaxtomin CYP, catalyzes the nitration of Ltryptophan, thus supporting thaxtomin biosynthesis.19 Fifty-seven human genes coding for various CYPs have been identified. These isoenzymes are divided into 18 families. CYP isoforms catalyze primarily reactions associated with the synthesis of endogenous molecules, and only about 15 enzymes belonging to families CYP1, CYP2, and CYP3 participate in the metabolism of foreign chemicals.20,21 Enzymes belonging to the CYP1 family, specifically CYP1A1 and CYP1A2, may be protective for organisms as revealed by animal experiments.22−24 These isoforms are involved in the detoxification of PAHs, N-heterocyclic compounds, and aromatic amines. However, the CYP1-mediated metabolism of smoke components is associated with osteoporosis25 and carcinogenesis.26 The results of the studies performed with human tumors indicate that CYP1B1 may be used as a target in cancer therapy.27 CYP2E1 and CYP2B1 are involved in the oxidation of carcinogenic nitrosamines.28,29 Isoforms that come from the first three CYP families, specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, metabolize about 75% of all drugs.30 CYP3A4 metabolizes over 50% of clinically prescribed medications.31 This isoform is the most abundant CYP enzyme in the adult human liver and small intestine. The contribution of CYP3A4 to the adult hepatic CYP content is about 30%.20 The contribution of CYP3A4 to the intestinal CYP is 80%, while CYP2C9, CYP2C19, and CYP2D6 comprise only 15%, 2%, and less than 1% of the total CYP, respectively.32 Besides the liver and small intestine, CYP enzymes are also present in other organs such as the brain, adrenal cortex, lung, and kidney, where they perform their specified functions.33,34 For example, CYP2D is involved in the synthesis of neurotransmitters35 and catalyzes the convertion of codeine to morphine in the brain.36 CYP11B and CYP21 are involved in the synthesis of steroid hormones in the adrenal cortex.37,38 CYP3A5 is expressed in the human kidney as well as in the liver.39 CYP2S1 is expressed in the skin, lung, spleen, and intestine.40 CYP2F3 and CYP 2F1 are known as lung-selective, and they are involved in the metabolism of pneumotoxicans and carcinogens.41 Besides CYP2F enzymes, other isoforms such as CYP1A1, CYP2A13, and CYP4B1 are expressed in the lung, where they activate 3-methylindole into a reactive intermediate, which damages DNA.42 Mammalian CYP are primarily located in membranes. Microsomal CYPs are associated with the endoplasmic reticulum, being anchored to the ER membrane via an NH2-terminus region. ER is the primary location of CYPs, where these enzymes metabolize

numerous endogenous and exogenous compounds.43 CYPs are also located in mitochondria,44 plasma membranes, and the Golgi apparatus.45 Some CYPs are associated with two subcellular compartments. Thus, they may be bimodally targeted to ER and mitochondria or the plasma membrane and mitochondria.46 The activity of CYP depends on a variety of different factors and may be affected by both endogenous compounds and external agents. Recently, extensive experimental evidence has been collected supporting a significant effect of natural polyphenols on the metabolic reactions catalyzed by CYP enzymes. Polyphenolic compounds are secondary metabolites of higher plants and represent one of the largest and the most abundant class of natural products. The number of polyphenols detected in plants exceeds 8,000.47 Several hundred polyphenols have been identified in edible plants and thus constitute a significant portion of the human diet. The dietary sources of polyphenols include honey, fruits, vegetables, green tea, black tea, chocolate, olive oils, and grains. Polyphenols are recognized for their antioxidant and prooxidant properties and their role in preventing various diseases associated with the production of free radicals. For example, kaempferol and quercetin interact with the components of the respiratory chain in the brain and heart mitochondria inhibiting the production of hydrogen peroxide and thus acting as antioxidants, which can be potentially beneficial in the treatment of neurodegenerative diseases and ischemia.48 Genistein generates ROS via the interactions with the respiratory chain and induces the mitochondrial permeability transition, an essential event in apoptosis.49 A number of studies confirmed a significant effect of berries, a rich source of flavonoids and anthocyanins, on the inflammatory pathways. Thus, the extract of chokeberry fruit reduces ocular inflammation in uveitis50 and decreases endothelial inflammation related to ischemic heart disease;51 the extract also inhibits weight gain and modulates insulin signaling pathways.52 Tart cherry juice reduces inflammation and lipid peroxidation assisting in the recovery of muscle function following active exercise.53 The polyphenols contained in black tea, particularly theaflavin and thearubigins, are also well-known for their health-promoting effects, which are primarily attributed to their antioxidant potency.54 The mechanisms underlying the antioxidant property of black tea polyphenols are based on their standard one-electron reduction potential, their ability to modulate the activity of redox sensitive transcription factors, and their potential to inhibit pro-oxidant enzymes.54 Polyphenolic components of green tea, especially epigallocatechin gallate (EGCG), promote the oxidation of fatty acids and stimulate lipolysis.55 The consumption of green tea lowers the risk of stroke, depression, and diabetes.56 EGCG along with resveratrol have been shown to be protective in aging.57 The antioxidant and pro-oxidant properties of EGCG also have an impact on the development of cancer. 58 Studies with strawberries, a product with high content of polyphenols, revealed the potential to lower the risk of hypertension and to attenuate postprandial oxidative stress, inflammation, and hyperlipidemia.59 The dietary polyphenols can potentially alter the activity of various enzymes and receptors either by modulating the expression level of the proteins or through direct binding to their catalytic centers. Thus, they inhibit the activity of αamylase and α-glucosidase60,61 and have significant affinities to bovine hemoglobin62 and plasma proteins.63 Polyphenols from 1360



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Figure 1. Chemical structures of polyphenolic compounds.

the abundance of phytochemicals in the human diet. For example, it has long been known that CYP plays a significant role in the development of CVD due to its ability to catalyze the oxidation of arachidonic acid.85 Recently, it was discovered that CYP2C supports the death of photoreceptors induced by light and thus contributes to the risk of retinal damage.86 CYP1A1 metabolizes a smoke constituent benzo(a)pyrene (BaP), an immunosuppressor 7,12-dimethylbenz(a)anthracene, and some heterocyclic amines contained in cooked meat to carcinogenic derivatives.87 The metabolic activity of CYP also modulates the bioavailability of some drugs. The induction of CYPs may decrease the toxicity of a drug by lowering its concentration; however, the efficacy of the drug may decrease. A number of studies indicate a significant role of metabolic reactions catalyzed by CYP in the pharmacokinetics of drugs used in the treatment of infectious diseases.88 Phytochemicals affect the activity of CYP enzymes in many ways and thus modulate the pharmacokinetics of drugs and the progression of diseases. The present review focuses on the mechanisms of the polyphenol-mediated regulation of the catalytic activity of CYP. Two types of mechanisms are discussed in detail: (1) the activity-modulatory effects occurring via the direct polyphenol− enzyme binding, which may inhibit or stimulate CYP and (2) processes, in which phytochemicals alter the induction level of CYP genes. The effect of the polyphenols’ chemical structure on their potential to inhibit CYP is discussed. The diseases whose onset, development, and progression are tightly linked to CYP-mediated metabolism are discussed; the recent findings concerning the influence of phytochemicals on these diseases are reviewed.

a mediterranean diet can reduce the induction of cyclooxygenase in endothelial cells and monocytes thus exhibiting vascular protective effects.64,65 However, dietary bioflavonoids can also directly stimulate the activity of cyclooxygenase I and II increasing the level of the arachidonic acid metabolites.66 Green tea polyphenols inhibit DNA methyltransferase (DNMT) mRNA and protein expression.67 EGCG inhibits DNMT directly via the interaction with the catalytic site of the enzyme and thus affects carcinogenesis.68 Flavonoid quercetin inhibits dengue-2 virus NS3 protease via the formation of six hydrogen bonds with amino acid residues in the receptor binding site.69 Derivatives of chalcone and flavonoids from fingerroot also inhibit NS3 protease and thus exhibit antidengue activities.70,71 Enzymatic oxidation of polyphenols or their auto-oxidation in the presence of oxygen, metal ions, H2O2, and other ROS, may result in the formation of active species. For example, resveratrol may form semiquinone radicals,72−74 and polyphenols having a catechol moiety, such as quercetin,75 luteolin,76 and chorogenic acid,77,78 form oquinones. There is also evidence of quercetin forming quinone methide.79 These oxidized polyphenols may react with sulfhydryl or amino groups producing covalent bonds between proteins and phytochemicals.80 Further reactions may also lead to the formation of protein cross-links.81,82 Overall, the interactions between proteins and phytochemicals affect the nutritional, functional, and structural properties of both entities. The binding of a dietary polyphenol to a protein may result in changes of the solubility, thermal stability, and secondary and tertiary structures of the protein.83 For a more comprehensive description of polyphenol−protein interactions, please refer to a review by Ozdal et al.84 The interactions between dietary polyphenols and CYP have received a special interest among scientists due to the extreme importance of CYP in the development of various diseases and 1361



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Table 1. Compounds That Inhibit the CYP1B1 Isoform by Directly Binding to the Enzyme

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*

An EROD assay was employed in all works for the evaluation of the inhibition potential of molecules toward CYP1B1.

gallocatechins, and afzelechin, respectively.89 These compounds contribute astringency to cranberry fruit and wines.90,91 Chalcones are similar in structure to flavonoids except for the open chain in the C ring (Figure 1C). Chalcones are abundantly synthesized in plants constituting medicinal sources and are widely used to produce sweets, juices, and alcoholic beverages. Chalcones are found in leaves and fruits of Campomanesia,92 leaves and flower cones of Humulus lupulus,93 roots of Glycyrrhiza glabra,94 and other plants. Neoflavonoids unlike flavonoids have a backbone structure of 4-phenyl-1,2-benzopyrone (Figure 1C). Even though neoflavonoids are not widely distributed in dietary plants, they are widespread in natural sources. For example, neoflavonoid calophyllolide is found in the seeds of Calophyllum inophyllum.95 Other compounds from the neoflavonoid group were isolated from the perennial tree Dalbergia cochinchinensis.96 N-Containing polyphenols constitute an essential part of some diets as they are present in oats (avenanthramides) and chili peppers (capsaicinoids, Figure 1D). Recently, novel phenolic amides have been isolated from the perrenial herb Paris veriticillata97 and red algae Bostrychia radicans.98

2. CLASSIFICATION OF POLYPHENOLIC COMPOUNDS Polyphenols have been grouped based on chemical structure, the identity of the plant, and the biological role. If classified by the structure, polyphenols can be divided into phenolic acids, flavonoids, chalcones, neoflavonoids, phenolic amides, lignans, and stilbenes (Figure 1). Phenolic acids are primarily found in fruits and vegetables and can be further divided into two major subclasses, the derivatives of benzoic and cinnamic acids (Figure 1A). Flavonoids are a group of over 6,000 polyphenolic compounds. The backbone of most flavonoids consists of chromane or a chromene entity with a benzene ring attached to the C2 carbon atom (Figure 1B). On the basis of their molecular structure, flavonoids can be divided into 6 principal subgroups: flavanones, flavanols, flavonols, flavones, anthocyanidins, and isoflavones. In the core structure of isoflavones, unlike flavonoids, the benzene ring is attached to the C3 atom of chromene-4-one (Figure 1B). An important role in the human diet is also played by proanthocyanidins, oligomeric and polymeric products of biosynthetic pathways involving flavanols. Proanthocyanidin subclasses, procyanidins, prodelphinidins, and propelargonodins are polymers of catechins, 1365



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Table 2. Compounds That Inhibit the CYP2C9 Isoform by Directly Binding to the Enzyme

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3.1. Inhibition of CYP by Flavonoids, Stilbenes, and Chalcones. Shimada et al. studied the inhibition of five different CYP isoforms, CYP1A1, CYP1A2, CYP1B1, CYP2C9, and CYP3A4 by 33 flavonoids.107 Most of these compounds presented flavone derivatives with different positions and numbers of hydroxyl and methoxy groups on the flavone core structure. The authors estimated the inhibition potency of flavone derivatives using 7-ethoxyresorufin O-deethylation (EROD) as a model reaction for the first three enzymes, flurbiprofen 1′-hydroxylation for CYP2C9, and midazolam 4hydroxylation for CYP3A4. The most notable results were observed with the CYP1B1 enzyme. This isoform is located in the endoplasmic reticulum; it oxidizes 17β-estradiol (E2) and PAHs to active procarcinogenic intermediates and thus plays a crucial role in chemical carcinogenesis. The difference spectra appeared as reverse type I binding spectra, whose nature is not completely understood. The UV/vis spectra were used to evaluate the dissociation constants and the efficiencies of binding of the flavone derivatives to the enzyme. Remarkably, the binding strength was correlated with the CYP1B1 inhibition potential. The comparative studies of flavones with different substitution groups revealed structure−activity correlations. The hydroxylation of flavone at the A and C rings, specifically at 3, 5, and 7 positions (galangin) led to a significant decrease in IC50 values from 0.6 μM for flavone to 0.003 μM for galangin. Plasma flavonol concentrations of diabetic patients on a high-flavonol diet was determined to be 0.3 μM (72.1 ng/ mL), while a low-flavonol diet resulted in a plasma flavonol concentration of only 0.02 μM.108 It is thus likely to expect a significant influence of galangin on the activity of CYP1B1 in vivo.

Lignans are polyphenolic compounds widely present in flaxseeds and sesame seeds.99 Small amounts of lignans are also found in fruits.100 Lignan structure is formed by the dimerization of two propylbenzene residues (monolignols). These compounds exhibit antiproliferative activity against breast cancer. For example, a flaxseed component secoisolariciresinol (Figure 1E) reduced human breast tumor growth. The underlying mechanisms involved the suppression of the expression of ERs along with antiapoptotic proteins and some growth factors.101 Mammalian lignans enterolactone and enterodiol reduced the amount of estrone produced via aromatase catalysis in breast cancer cells.102 Studies also indicate that plant lignans and their human metabolites exhibit properties of phytoestrogens as they bind ERs and act as their weak agonists or antagonists.103,104 The backbone structure of stilbenes has two isomeric forms: trans-1,2-diphenylethylene and cis-1,2-diphenyletylene; however, the cis-isomer is unstable because of the steric hindrance. Stilbenes are found in fruits, primarily in grapes, and grape wine.105 Peanuts are also considered to be an essential source of resveratrol (Figure 1E) and other stilbenes.106

3. INTERACTIONS BETWEEN POLYPHENOLS AND CYP: DIRECT BINDING AND MECHANISM-BASED INHIBITION Multiple studies have demonstrated the inhibitory effects of polyphenols, constituents of plant food and herbs, on the activity of CYP enzymes. The modulation by phytochemicals of CYP-catalyzed reactions results in multiple outcomes, including beneficial health effects and undesirable consequences. Polyphenol−CYP interactions may also have a significant impact on the efficiency of drug therapies. 1369



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CYP2C9, flavone derivatives with hydroxyl groups were docked into the protein such that A or C rings interacted with the active site; however, when methoxy groups were introduced into the B ring, the orientation of the molecules changed so that the B ring became closer to the active site. In the case of CYP1A1, CYP1A2, and CYP3A4 enzymes, the B ring of the inhibitors interacted with the active sites of the enzymes. All flavone derivatives interacted with amino acid residues via hydrogen bonds.107 Takemura et al. studied the structure−activity relationship of flavonoids on the inhibition of CYP1A1, CYP1A2, and CYP1B1.112 The authors compared three classes of flavonoids with methoxy and hydroxyl substituents, flavones, flavonols, and flavanones. Remarkably, for all three isoforms, the IC50 values of flavanones were significantly higher than those for flavones and flavonols. A similar phenomenon was observed by Shimada et al.107 for all tested enzymes. Specifically, the flavone and flavanone values of IC50 were 0.6 and 1 μM for CYP1B1 (Table 1) and 14 and 22 μM for CYP2C9 (Table 2), respectively. A double bond in a C ring between the 2 and 3 positions thus plays a significant role in defining the inhibition potential of flavonoids. The presence of the double bond results in a planar geometry of flavones and flavonols as opposed to a tilted geometry of flavanones, which affects the orientation and the binding energy of a molecule in the active site of the enzyme. Interestingly, flavones and flavonols with methoxy groups attached to a B ring, exhibited specificity toward CYP1B1, as the IC50 values of these molecules were significantly lower for CYP1B1 than for CYP1A1 and CYP1A2. The molecular docking studies with chrysoeriol and isorhamnetin (Table 1) revealed that these compounds fit well into the active site of CYP1B1 and do not fit into the active sites of the other two isoforms. This effect is explained by the steric hindrance and the collisions between methoxy substituents of the inhibitors and Ser-122 of CYP1A1 and Thr-124 of CYP1A2.112 Kimura et al. studied the effects of phytochemicals on the activity of two CYP isoforms, CYP3A4 and CYP2C9 using reactions of 6β-hydroxylation of testosterone and 4′-hydroxylation of diclofenac, respectively.111 These two enzymes are known to catalyze the metabolism of many clinically prescribed drugs. Out of 60 tested polyphenols, 12 flavonoids and 3 coumarins significanty inhibited the two enzymes. Amentoflavone (bis-apigenin), a constituent of some medicinal herbs and trees, was identified as the strongest inhibitor of both CYP3A4 and CYP2C9, the IC50 values being 0.07 μM and 0.03 μM, respectively. Remarkably, the concentration of amentoflavone in human blood reaches the level of 0.15 μM (80 ng/ mL) 4.5 h after the oral administration of a perennial herb H. perforatum extract as determined by the LC-MS method.113 The plasma concentration drops to 0.02 μM (10 ng/mL) after 20 h following extract administration. This is comparable with the IC50 values of amentoflavone; therefore, the consumption of this phytochemical may affect significantly the metabolic reactions catalyzed by CYP3A4 and CYP2C9. Apigenin was shown to have the highest inhibition toward the activity of CYP3A4 among flavone monomers with the IC50 values of 0.4 μM and 6.4 μM for CYP3A4 and CYP2C9, respectively. However, in an alternative work, Shimada et al. reported apigenin IC50 values of approximately 4.5 and 2 μM, for CYP3A4 and CYP2C9, respectively.107 The highest apigenin plasma concentration following the consumption of parsley was reported to be 0.3 μM.114 The consumption of celery leaf also

The addition of single hydroxyl groups into the 3, 5, or 7 positions also increased the CYP1B1 inhibition potential of the flavone, however, to a smaller extent, the IC50 values being 0.09 μM, 0.21 μM, and 0.25 μM, respectively (Table 1).107 The hydroxyl group located at the 3-position proved to be the most efficient in the inhibition of CYP1B1. The earlier studies conducted by the same research group showed that while 5,7dihydroxylation of the flavone increased its affinity to CYP1B1, the hydroxyl groups introduced at the 7 and 8 positions weakened the protein−flavone interactions.109 The introduction of methoxy groups into the B ring of 5,7-dihydroxyflavone (57DHF or chrysin) also significantly enhanced the ability to inhibit CYP1B1. The IC50 values decreased from 0.27 μM for chrysin to 0.014 μM and 0.019 μM for 4′M57DHF (acacetin) and 3′4′DM57DHF, respectively (Table 1). A similar trend for a structure−activity relationship was revealed by Androutsopoulos et al., who studied the inhibition potencies of CYP1A1 and CYP1B1 for flavones with multiple hydroxyl and methoxy groups.110 Specifically, the authors showed that it is the 5,7dihydroxy motif of the A ring that plays a crucial role in the inhibitory activity of the molecules. The presence of a methoxy group at the B ring also significantly reduces the value of a reversible inhibition constant Ki. Flavones chrysin, acacetin, and diosmetin exhibited the highest inhibition potential toward both CYP1A1 and CYP1B1 isoforms (Table 1).110 The increase in the inhibition potency of flavones and flavonols upon the addition of a methoxy group to the B ring was also observed for the CYP2C9 isoform by Kimura et al. (Table 2).111 While many of the flavones and flavonols proved to be substrates for CYP1A1, CYP1B1 was found to be a weak metabolizer of flavonoids.110 This suggests that an exceptionally strong inhibition potential toward the CYP1B1 isoform results from favorable interactions of the molecules with the amino acids of the enzyme in the vicinity of the heme group in the case of competitive inhibition or away from the active site in the case of noncompetitive inhibition. The structure−activity correlation studies performed by Shimada et al. with different CYP isoforms revealed differences in the inhibition mechanisms.107 Thus, the activity of CYP1A1 followed the same trend as that of CYP1B1; however, in the case of CYP1A2, the hydroxylation of the A and C rings and the methylation of the B ring of flavone resulted in the reduction of the inhibition potency. Unlike CYP1B1, CYP2C9 exhibited much stronger activity when bound to 3- and 5hydroxyflavones than when in complex with flavone. CYP3A4 appeared the most unaffected by the flavonoids, the IC50 value for 3′4′DM57DHF being 2000-fold higher than that for CYP1B1. For all studied enzymes, isoflavone genistein (4′57THIsoF) exhibited lower inhibition potential than its flavone isomer apigenin (4′57THF). The same trend was observed with methoxy-substituted flavones acaceetin (4′M57DHF) and biochanin A (4′M57DHIsoF). The introduction of a glycoside group also significantly lowered the inhibitory activity of flavonoid as seen with naringenin (4′57THFva) and naringin (4″57THFvaG).107 The molecular docking studies performed with the CYP1B1 isoform revealed that flavone derivatives acting as both strong and weak inhibitors were positioned such that A or C rings were located close to the active site of the enzyme. Remarkably, the inhibitor−enzyme interaction energy estimated with CYP1B1 was essentially higher than that determined for the other enzymes. It was also hypothesized that CYP1B1 enzyme has an expanded pocket for the inhibitors. In the case of 1370



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Figure 2. Interactions between flavonoids and aromatase (CYP19) as revealed by docking analysis. (A) α-NF docked into the active site of aromatase. The flavonoid molecule is shown in orange as a stick model. The iron atom of the heme is represented by a magenta sphere. The selected amino acid residues in the active site of the enzyme are shown as stick models. (B) The mutual orientation of two flavonoids and the heme prosthetic group in the aromatase active site. The flavone is colored orange, the isoflavone is colored blue, and the iron atom is shown as magenta sphere.124 Reprinted with permission from ref 124. Copyright 2009 Elsevier.

results in the elevation of apigenin level in human blood, the maximum concentration being 0.4 μM.115 Thus, the ordinary dietary intake of apigenin may result in flavone plasma levels capable of influencing the activity of CYP3A4 and CYP2C9. Chalcone phloretin and flavonol galangin exhibited moderate inhibition activity toward both isoforms with IC50 values within the range of 3.0−7.5 μM.111 The maximal plasma levels of phloretin metabolite phloretin-2′-O-glucuronide following the consumption of cider or polyphenol-rich juice drink were determined to be 0.073 μM and 0.204 μM, respectively.116,117 However, the plasma level of the original compound as a result of the consumption of 1 kg of apples was only 0.012 μM.118 Thus, it is unlikely that chalcone phloretin would influence the activity of CYP3A4 and CYP2C9 in the human body. The IC50 value of galangin reported for the CYP3A4 enzyme by Kimura et al. (3 μM) is consistent with that determined by Shimada et al. (2.3 μM). However, there is inconsistency in the galangin IC50 values measured for CYP2C9. The method involving the 4′-hydroxylation of diclofenac resulted in the IC50 value of 7.5 μM,111 while the assay involving the 1′-hydroxylation of flurbiprofen led to the IC50 value of 0.2 μM.107 Thus, the effect of galangin in the human body may be significant in regard to the inhibition of CYP1B1 and CYP2C9. The trends of the flavonols’ IC50 values reported by Kimura et al. for CYP3A4 and CYP2C9 indicate that the inhibition potency of the molecules decreases with the number of hydroxyl groups attached to their B ring.111 Thus, the IC50 values increased in the following order among the flavonols: galangin < kaempferol < quercetin < myricetin for both CYP3A4 and CYP2C9 isoforms (Table 2). A similar effect was observed by Shimada et al. (CYP1A2 and CYP2C9 isoforms)107 and Si et al. (CYP2C9 isoform).119 Specifically, the addition of one hydroxyl group to the B ring of chrysin and galangin leading to the formation of apigenin and kaempferol, respectively, resulted in a significant increase of the IC50 value. Androutsopoulos et al. observed a 9-fold increase in the IC50 value upon the addition of a hydroxyl group to the B ring of chrysin for the CYP1A1 isoform and a 4-fold increase in the case of the CYP1B1 isoform (Table 1).110

The most powerful CYP inhibitors identified by Kimura et al., amentoflavone and apigenin (Table 2), exhibited a competitive−noncompetitive mixed type of activity inhibition for both isoforms as revealed by a Lineweaver−Burk analysis.111 A number of natural and synthetic trans-stilbenes inhibit the activity of CYP1B1 via direct binding to the enzyme. Thus, resveratrol found in the skin of berries and grapes and resveratrol metabolite piceatannol found in the roots of Picea abies significantly inhibited the EROD activity of CYP1B1 with the IC50 values of 1.2 μM and 0.82 μM.109 The peak plasma concentration of resveratrol in healthy volunteers who received an oral dose of 5 g of the compound was determined to be 2.4 μM (539 ng/mL).120 A dietary relevant 25 mg dose of resveratrol led to the plasma concentration of 2 μM (491 ng/ mL), which included resveratrol and its metabolites; the plasma level of the unmetabolized resveratrol was below 0.02 μM (5 ng/mL).121 These two compounds also produced a reversed type I spectrum with CYP1B1.87 Synthetic methoxy derivatives of stilbenes trans-2,3′,4,5′-tetramethoxystilbene (23′45′-TMS) and trans-2,2′,4,6′-tetramethoxystilbene (22′46′-TMS) exhibited a selective inhibition toward CYP1B1, the respective IC50 values being 0.023109 and 0.002 μM.122 The IC50 values of 22′46′-TMS for the CYP1A1 and CYP1A2 are only 0.35 μM and 0.17 μM. The IC50 values measured for 22′46′-TMS with the EROD activity assay in MCF-10A and HepG2 cells were 0.22 μM and 0.82 μM, respectively. Interestingly, the hydroxylated derivative of trans-stilbene, oxyresveratrol (trans2,3′,4,5′-tetrahydroxystilbene), a natural compound found in the heartwood of Artocarpus lakoocha, exhibited a much weaker inhibitory activity toward CYP1B1 with an IC50 of 34 μM.122 A series of synthetic trans-stilbene derivatives containing a methoxythio group at the 4′ position has been also studied in regard to the potential inhibition of CYP1A1, CYP1A2, and CY1B1.123 Derivatives with methoxy or chloro groups at the 2 position of the trans-stilbene molecule appeared to be the most selective inhibitors of CYP1B1 with an IC50 value of 0.3 μM. Karkola and Wahala employed docking studies and molecular dynamic simulations to explain the details of flavone binding to CYP19 at the atomic level.124 The CYP19 gene encodes aromatase, which catalyzes the reaction of aromatiza1371



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Table 3. Compounds That Irreversibly Inhibit CYP Enzymes by Mechanism-Based Inactivation

isoflavone this distance was 2.2 Å. There were also differences in Fe−OC angles and tilting angles between the planar carbonyl group of the inhibitor and the heme plane. The angle variations accounted for a weaker coordination of isoflavone in the active center of the aromatase compared to that of flavone (Figure 2B).124 Mo et al. investigated the structural features of inhibitors of CYP2D6, an enzyme chiefly expressed in the liver and responsible for the oxidation of 25% of drugs as well as the metabolism of endogenous molecules, for example, neurotransmitters.125 The authors performed the docking studies with a number of molecules including medicinal agents and flavonoids. Three flavones, baicalin, wogonin, and wogonoside, constituents of a flowering plant S. baicalensis, were found to possess the structural properties required for effective CYP2D6 inhibition, namely, two hydrophobic features and one hydrogen bond acceptor. The binding modes of the three flavones were determined as follows. Baicalin formed five hydrogen bonds with amino acids near the enzyme active center and a π−π

tion converting androgens to estrogens. The results revealed that alpha-naphthoflavone (α-NF) was coordinated to the heme iron via carbonyl oxygen at the C4 position (Figure 2A), while the naphthyl moiety and the B ring were surrounded by two hydrophobic areas in the active site of the protein. The introduction of hydroxyl groups to the B ring of flavone resulted in the weakening of the binding, which was due to the unfavorable interactions with hydrophobic amino acids. The hydroxyl group attached to the C7 position of the flavone core enhanced the inhibition potential of the molecule, as indicated by the significant decrease of the IC50 value. This hydroxyl group was found to interact with Ser478, which strengthens the binding of the flavone derivative to the enzyme. The comparative studies revealed that flavone exhibited stronger affinity toward the aromatase active center than isoflavone. The presence of the benzyl ring (ring B) in the vicinity of the carbonyl group in the molecule of isoflavone results in the steric effects. Thus, the distance between the carbonyl oxygen and the heme iron in flavone was determined to be 2.0 Å, while in 1372



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stacking interaction with Phe120, wogonside also formed five hydrogen bonds and a π−π stacking interaction with Phe120, while wogonin formed only one hydrogen bond with Phe483 and π−π stacking interaction with Phe120.125 Yuan et al. utilized liquid chromatography−tandem mass spectrometry to estimate the inhibition of CYP enzymes by extracts of a flowering plant Humulus lupulus L. (hop).126 Hop is used in brewing beer; it is an estrogenic dietary supplement and a pharmacological agent for sedation, relaxation, and treating insomnia. The CYP inhibition assays were performed with hop extracts and with a mixture of its components prepared at concentrations similar to those present in the standardized extract. The mixture contained prenylated flavanones (8-prenylnaringenin, 6-prenylnaringenin, and isoxanthohumol) and a prenylated chalcone (xanthohumol). The inhibition patterns obtained with the extract and the mixture of polyphenolic compounds were similar, and the contributions of the phytochemicals to the enzyme inhibition were additive as opposed to synergistic. Specifically, the activity of the CYP2C subfamily was effectively inhibited. Isoxanthohumol was found to be the most powerful inhibitor of CYP2C8 with an IC50 value of 0.2 μM, while 8-prenylnaringenin was the most potent inhibitor of CYP2C19 and CYP2C9, IC50 values being 0.4 μM and 1.1 μM, respectively. The latter phytochemical was also a good inhibitor of CYP1A2 with an IC50 value of 1.1 μM.126 A chalcone compound, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC), known to inhibit tumorigenesis, was shown to effectively inhibit the enzymes of the CYP2C subfamily, CYP2C8, CYP2C9, and CYP2C19.127 Since the inhibition potency was negligible when tested with the isoforms belonging to other subfamilies such as CYP1A, CYP2A, CYP3A, CYP2B, CYP2D, and CYP2E, TSAHC may be used as a nonspecific inhibitor of CYP2C enzymes. TSAHC is also known to have antitumor properties and was shown to be active against hepatocarcinoma.128 The IC50 values for the inhibition of CYP2C9 by the hop components as well as chalcone TSAHC are summarized in Table 2. Liu et al. explored various flavone derivatives in order to find selective inhibitors for CYP isoforms 1A1, 1A2, and 1B1.129 The flavone derivatives included pyranoflavones, naphthoflavones, propargyloxyflavones, and 5-hydroxyflavones. Primarily, rigid structures lacking reactive functional groups were used in order to obtain a well-defined picture of pure binding interactions between the inhibitor and the protein. The majority of designed molecules exhibited significant inhibitory effects toward CYP1 family enzymes, while showing negligible inhibition toward enzymes of the CYP2 family. Out of all tested molecules, only 5-hydroxy-4′-propargyloxyflavone (or 5hydroxy-4-flavone propargyl ether, 5H4′FPE) exhibited a high selectivity for CYP1B1 (IC50 = 0.1 μM), the inhibition potential toward CYP1B1 being 120-fold greater than that toward CYP1A1 and about 250-fold greater than that toward CYP1A2. β-Naphthoflavone-like molecules selectively inhibited CYP1A1, while α-NF-like compounds and 5-hydroxyflavones exhibited strong inhibition activity toward a CYP1A2 enzyme. 4′Propargyloxy-β-naphthoflavone was the most powerful inhibitor of CYP1A1, while 5-hydroxy-7,8-pyranoflavone most effectively inhibited CYP1A2, the IC50 values being 0.041 μM and 0.014 μM, respectively. These two molecules were used to obtain information about the shapes of the active site cavities of the enzymes. The surface images generated for the two inhibitors revealed that CYP1A1 has a contracted and elongated cavity, while CYP1A2 has a compact cavity.129

These structural characteristics of the enzymes’ active sites can be utilized for further optimization and the selection of more potent inhibitors. In an alternative work, Sridhar et al. also observed mechanism-based inactivation of CYP1A1 exhibited by propargyloxyflavones.130 The underlying reactions of the mechanism-based inactivation involved (1) the oxidation of the triple bond of the acetylene by CYP1A1 to a reactive ketene intermediate and (2) the interaction of the ketene intermediate with the heme nitrogen resulting in the destruction of the heme. Alternatively, the ketene intermediate may bind covalently to a nucleophilic amino acid side chain in the vicinity of the heme leading to the inactivation of the enzyme. For example, 3′-flavone propargyl ether (3′FPE) inhibited CYP1A1 via direct binding with an IC50 value of 0.02 μM, as well as via the oxidation to the ketene intermediate followed by reactions with the heme. The values of KI and kinact of the mechanism-based inhibition were 0.24 μM and 0.09 min−1 (Table 3). KI represents the concentration of the mechanismbased inactivator (MBI) that gives the half-maximal rate of inactivation, while kinact is the maximal inactivation rate constant that is attained at an infinite concentration of the MBI.131 The docking studies of this propargyl ether showed that the terminal carbon atom of the acetylenic group is in close proximity to the iron atom of the heme. Thus, the ketene intermediate formed under the oxidation of the original molecule could acylate the heme residue. 7-Hydroxyflavone (7HF) also exhibited a mechanism-based inhibition of CYP1A1, the KI and kinact values being 2.34 μM and 0.115 min−1, respectively (Table 3). The direct inhibition potency of 7HF was not very high, the IC50 value being 6.79 μM. A 340-fold difference between the IC50 values for the flavone propargyl ether and the hydroxyl flavone was also explained by docking experiments. Since the flavone propargyl ether is longer than hydroxyflavone, the triple bonds of the propargyl groups can be positioned in a very close proximity to the active center ensuring a higher affinity and inhibition potency in a direct inhibition mechanism. The docking experiments revealed that all of the tested propargyl ether and hydroxyflavones exhibited numerous π−π interactions with phenylalanine amino acids in the vicinity of the heme.130 The docking analysis also showed that the volume of CYP1A1 and CYP1A2 binding cavities is greater than that of CYP2B1 and CYP2A6. This fact along with the presence of phenylalanine amino acids lining the active sites of CYP1 isoforms explains the high affinity of flavone derivatives to these enzymes observed by Sridhar et al.130 and Liu et al.129 Si et al. investigated the effect of a series of flavones and flavonols on CYP2C9.120 All flavonoids were found to reversibly inhibit the enzyme. The Ki values for 6-hydroxyflavone (6HF), 7HF, chrysin, baicalein, apigenin, luteolin, scutellarein, wogonin, galangin, fisetin, kaempferol, morin, and quercetin were less than 2.2 μM. Galangin was the strongest inhibitor with Ki = 0.15 μM. Glucuronidated flavones turned out to be weak inhibitors with Ki values greater than 40 μM. All flavonoids except 6HF acted as competitive inhibitors, indicating the fact that they bound to a substrate binding site. The docking simulation studies revealed that the binding sites of the competitive inhibitors such as luteolin, apigenin, baicalein, quercetin, and morin were close to the heme and that these inhibitors occupied the same position as flurbiprofen, a CYP2C9 specific substrate. The noncompetitive inhibitor 6HF occupied a site far from the heme. The molecule formed a π−π stacking interaction with Phe100 and two hydrogen bonds 1373



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with Leu102 and Phe100.120 This binding site was similar to the allosteric binding site determined for the anticoagulant drug warfarin.132 3.2. Inhibition of CYP by Lignans. A number of lignans inhibit CYP enzymes irreversibly via mechanism-based inactivation. For example, two constituents of herbal medicine Phyllanthus amarus phyllanthin and hypophyllanthin proved to be mechanism-based inhibitors of CYP3A4 with KI values of 1.75 μM and 2.24 μM and kinact values of 0.18 min−1 and 0.15 min−1, respectively (Table 3).133 CYP3A4 is the most important drug metabolizing enzyme, and it is the most abundant enzyme in the liver and gastrointestinal tract. Remarkably, the kinact/KI ratios were higher than those reported for some drugs acting as MBIs such as antidepressant fluoxetine, antibiotic clarithromycin, antiarrhythmic agent amiodarone, and others. The components of Schisandra lignan extract Gomisin C, schizandrin, and deoxyschizandrin also exhibited inhibitory effects on CYP3A enzymes. The underlying inhibitory pathways involved both reversible and irreversible (time-dependent) mechanisms. Gomisin C was identified as the most powerful inhibitor with an IC50 value of 0.30 μM and a Ki value of 0.06 μM.134 The maximum plasma concentration of Gomisin C attainable in rats was reported to be 0.6 μM (∼0.3 μg/mL) following intragastric administration. Five hours after the administration, the concentration decreases down to 0.4 μM. Approximately the same levels of Gomisin C were determined in small intestines.134 Another lignan podophyllotoxin, a component of Podophyllum species, was also shown to inhibit CYP proteins both reversibly and in a time-dependent manner.135 Specifically, it inhibited major drug metabolizing enzymes CYP3A4 and CYP2C9 with IC50 values of 1.1 and 4.6 μM and Ki values of 1.6 and 2.0 μM, respectively.135 The maximum concentration of podophyllotoxin measured in mice plasma was about 11 μM (∼4.5 μg/mL), the concentration dropped down to 2 μM 10 h after lignin injection.136 The timedependent inhibition mechanism of podophyllotoxin was observed for the CYP3A4 with the kinetic parameters KI and kinact of 4.4 μM and 0.06 min−1, respectively (Table 3).135 Lignan honokiol isolated from leaves and seed cones of Magnolia trees exhibits multiple beneficial health properties and has been intensively utilized in eastern medicine. Honokiol exhibited significant inhibition potency toward CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2B6, and CYP2D6 isoforms.137 The IC50 values were 2.1, 8.9, 4.1, 2.2, 13.8, and 14.0, respectively. The Ki values determined from Lineweaver−Burk plots and Dixon plots were 1.2, 4.9, 0.54, 0.57, 17, and 12.5 μM, respectively.137 The plasma concentrations of honokiol measured in mice varied between 750 μM and 18 μM (10 h after i.v. administration).138 The honokiol level in rat plasma ranges between 35 μM and 4 μM (1 h after the i.v. injection).139 While lignan exhibited noncompetitive inhibition toward CYP1A2, it proved to be a competitive inhibitor with respect to the other isoforms.137 In an alternative work, a biophenyl ether lignan obovatol was also shown to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro, the IC50 values being 4.4, 13.9, 11.1, 3.3, and 0.8 μM, respectively.140 The strong potential of lignans to inhibit the catalytic activity of CYP enzymes responsible for drug metabolism suggests the possibility for pharmacokinetic drug interactions. The compounds exhibiting mechanism-based inactivation of CYP enzymes and their respective KI ad kinact values are summarized in Table 3.

The details of lignans’ coordination to the active center of CYP proteins have been investigated by Karkola and Wahala. The authors employed molecular modeling methods to study the complexes of the phytochemicals with aromatase CYP19.125 The results showed that all tested lignans with lactone structure formed a bond between the heme iron and the carbonyl oxygen. Lignan enterolactone also formed hydrogen bonds extended from the hydroxyl groups at the positions C3 and C3′ to the carbonyl groups of Thr310 and Glu302, respectively. Lignans lacking a lactone fragment, for example, lignanodiols also exhibited coordination to the heme of the aromatase. Thus, nordihydroguaiaretic acid was coordinated to the heme iron via a phenolic hydroxyl group. The molecule formed hydrogen bonds with Lys230, Asp309, and Ile305. The hydrocarbon chain of the acid was found to be complementary in shape to the hydrophobic pocket of the active site, which also contributed to the tight binding of the molecule and the inhibition of the enzyme’s activity.125

4. POLYPHENOL-MEDIATED MODULATION OF CYP GENE EXPRESSION A number of studies have revealed that natural polyphenols have the potential to alter the expression level of CYP genes. This may influence the overall activity of metabolic reactions catalyzed by CYP proteins, affect the pharmacokinetics of drugs, and modulate the onset, development, and the progression of diseases. There is evidence of the phytochemical-mediated stimulation of CYP expression. Thus, the mRNA of several CYP isoforms was elevated in pigs treated with beta-naphthoflavone (β-NF) as compared with the control animals. Specifically, the level of CYP1A1 mRNA was increased in the heart regions141 as well as liver, respiratory tissues, and olfactory tissues of pigs.142 The level of mRNA of CYP1A2 and CYP1B1 was only increased in the liver.142 Significant changes in the expression of CYP proteins were observed in male Wistar rats treated with soybean extract containing 37% isoflavones, specifically genistein and daidzein.103 After 10 days of treatment, the expression of CYP1A1 and CYP2D1 was increased by 50% and 32%, respectively, compared with that of the control group of animals. The expression level of some CYP enzymes may be inhibited following the administration of phytochemicals. Thus, the mRNA of CYP3A1 in male Wistar rats was decreased by 35% after 3 and 10 days of treatment with soybean extracts.143 Biflavanone kolaviron was shown to suppress the expression of CYP11A1.144 This isoform initiates steroidogenesis by converting cholesterol to pregnenolone on the inner mitochondrial membrane.145 Kolaviron is contained in the seeds of Garcinia kola, a flowering plant traditionally used in Africa as a medicine against throat infections and chest cold. It was found that kolaviron normalized the expression level of CYP11A1 that was previously increased 3-fold of the control by a chemical toxicant atrazine in rat interstitial Leydig cells.144 A similar effect was observed for quercetin.146 4.1. Effect of Polyphenols on Pregnane X Receptor Signaling Pathways. There is a lot of evidence indicating the ability of dietary polyphenols to influence the signaling pathways of pregnane X receptor (PXR), a member of the nuclear receptor superfamily. The major function of PXR is to recognize the presence of exogenous toxic compounds and to induce the expression of enzymes catalyzing reactions of detoxification. PXR has ligand-binding and DNA-binding 1374



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Table 4. Compounds That Modulate CYP Gene Expression by Interacting with PXR Signaling Pathways

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Table 4. continued

domains located at the C- and N-termini, respectively.147 The ligand-binding pocket of this protein can accommodate molecules of very diverse structure.148,149 The binding of molecular agonists to PXR results in the protein conformational changes that stimulate the dissociation of corepressors from the protein and the association of coactivators with PXR. Upon activation, PXR forms a heterodimer with a retinoid X receptor and binds to the response elements on DNA stimulating the expression of PXR target genes.150 PXR is primarily expressed in the liver, colon, and intestine. Since the gene expression of a major drug metabolizing enzyme CYP3A4 is regulated by PXR, the interactions of polyphenols with PXR may affect the pharmacokinetics of drugs. A polymethoxylated flavone tangeretin, found in the peels of tangerine and other citrus fruits, was found to enhance the PXR-dependent transcriptional activity of CYP3A4 in human inestinal LS180 cells (Table 4).151 A flavone baicalein also induced the expression of CYP3A4 mRNA by activating PXR in HepG2 (human liver hepatocellular carcinoma) and LS174T (human colon adenocarcinoma epithelial) cells (Table 4).152 Li et al. showed that there may be a species-specific difference in the activation of PXR between polyphenols of different structure.153 The authors investigated the potential of genistein, daidzein, and diadzein metabolite equol to stimulate human and mouse PXR (Table 4). It was found that genistein was the most effective activator of mouse PXR, while in the case of human PXR, equol was a stronger activator than genistein. The

treatment of human hepatocytes with equol enhanced the level of CYP3A4 mRNA, while the treatment of mouse hepatocytes with this compound had no effect on gene expression. Isoflavones genistein and daidzein stimulated the expression of CYP3A11 (human CYP3A4 orthologue in mouse) in mouse hepatocytes. Moreover, isoflavones promoted the interaction of PXR with the steroid receptor coactivator 1.153 Yu et al. used a reporter gene assay to evaluate the ability of major bioactive compounds of traditional Chinese medicines to activate the PXR signaling pathway. Out of the 34 tested molecules, 8 were found to trans-activate PXR and induce CYP3A4 reporter gene. Five of them represent a class of polyphenols; these include schisantherin A, schisandrin A, schisandrin B, schisandrol A, and resveratrol (Table 4).154 There is also evidence of PXR antagonistic effects exhibited by phytochemicals. Thus, silybin and isosilybin, flavonolignans extracted from the seeds of a Sillybun marianum (milk thistle) plant, strongly inhibited PXR-mediated CYP3A4 induction in LS180 colon adenocarcinoma cells, as revealed by a reporter gene assay and a real-time polymerase chain reaction.155 Molecular docking studies and TR-FRET PXR competitive binding assays showed that both flavonoids bound directly to PXR and exhibited strong interactions with the protein.155 Besides the direct binding mechanism, polyphenols may affect the PXR-mediated CYP3A4 gene expression by modulating other biochemical processes. Dong et al. found that flavonoids luteolin and apigenin enhanced the PXR1376



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caused by dioxin. A similar effect was observed with the green tea extract whose major constituents are catechins. Recently, it was shown that the major components of black soybean seed coat procyanidins and cyanidin 3-glucoside suppressed the transformation of AhR and downregulated CYP1A1 expression in HepG2 cells and ICR mice. The phytochemicals also reduced the DNA damage induced by BaP.170 Flavanone naringenin, a constituent of oranges, grapefruits, and tomatoes, selectively inhibited the expression of CYP1B1 induced by 7,12-dimethylbenz(a)anthracene (DMBA) in MCF-7 cells.171 While CYP1B1 has eight XREs in its promoter region, DMBA induces the XRE transactivation only at −940 bp and −1675 (bp upstream). As revealed by the luciferase reporter gene assay, naringenin suppressed the induction of CYP1B1 mRNA by antagonizing XRE binding at −1675. Since naringenin was not a ligand of AhR, it was hypothesized that the flavonone could interact with the protein in the area different from the ligand-binding site and could induce the conformational changes in the ligand-binding domain or in the area of AhR−Arnt interactions. These changes in AhR conformation apparently prevented the transcription factor from performing its normal function.171 Luteolin, a flavone found in parsley, thyme, carrots, oranges, and other products inhibited AhR transformation in hepatic cells by competing with its ligand 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), which is the most potent activator of AhR. The expression of CYP1A1 induced by TCDD was suppressed.172 Murray et al. performed AhR-dependent reporter-based screen of methoxylated flavonoids to test their agonist/ antagonist activity.173 Methoxyflavones had been shown to be more resistant to CYP-catalyzed oxidation than the hydroxylated flavones, which made them promising candidates for potential AhR inhibition. The screen identified two flavonoids, 5-methoxyflavone and 7,4′-dimethoxyisoflavone, as powerful AhR agonists. 6,2′,4′-Trimethoxyflavone (TMF) was characterized as a strong antagonist. TMF was able to compete with agonists such as TCDD and BaP, and it showed no partial AhR agonist activity, in contrast to, for instance, an antagonist α-NF. TMF did not have a species or promoter dependence and exhibited limited cytotoxicity.173 Multiple reports document the agonistic activity of polyphenolic compounds toward AhR. Thus, β-NF is known as a strong AhR agonist, which exhibits strong affinity to this transcription factor.174 This property of β-NF mediates its antitumor activity in breast cancer.175 An anticancer drug aminoflavone (AF) that suppresses the growth of MCF-7 breast cancer cells promotes the induction of CYP1A1 via the activation of AhR.176 The treatment of human renal cancer sensitive cells with AF resulted in time-dependent AhR translocation to the nucleus and the induction of AhR transcriptional activity. The formation of covalent adducts on DNA increased leading the cells to apoptosis. The treatment of the cells with the AhR antagonist α-NF prior to the exposure to AF resulted in the decrease of apoptosis indicating that the antiproliferative effect of AF is mediated by the stimulation of AhR.176 Polyphenolic cocoa extract (PCE) was shown to stimulate the expression of CYP1A1 in MCF-7 cells.177 The major components of PCE derived from cocoa leaves and stems are anthocyanins, epicatechin, catechin, leucocyanidins, chlorogenic acid, and p-coumaryl-quinic acid.178 The increased level of CYP1A1 mRNA was associated with the activation of AhR

mediated gene expression of CYP3A4 in HepG2 cells via the inhibition of cyclin-dependent kinases (Cdks).156 The sitespecific phosphorylation of nuclear receptors by kinases plays an important role in their activities.157 For example, Cdk2 directly phosphorylates human PXR presumably at Ser350. The activation of this kinase leads to the inhibition of PXR, while the suppression of Cdk2 activity results in the activation of the nuclear receptor.158 The activation of PXR by apigenin proceeded via the inhibition of multiple Cdks.156 The structures of the compounds interacting with PXR signaling pathways are summarized in Table 4. 4.2. Influence of Polyphenols on Aryl Hydrocarbon Receptor Signaling Pathways. A number of studies demonstrated the ability of dietary polyphenols to affect the expression levels of CYP proteins by interacting with the pathways involving an aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that controls responses to PAHs and dioxins.159 There are also natural activators that function as high affinity ligands, for example, formylindolo[3,2b]carbazols derived from the amino acid tryptophan.160 A ligand-free, cytosolic AhR exists as a heterotetrameric complex composed of a ligand binding subunit, two isoforms of a heat shock protein HSP90, and an immunophilin-like X-associated protein 2.161 Recently, amino acid residues on AhR involved in its binding to HSP90 were identified; these residues overlapped with those located at the ligand-binding site.162 When a PAH or another ligand binds to AhR, a transformation occurs which involves a conformational change in the protein. A ligandbinding subunit detaches from the complex and migrates to the nucleus, where it forms a heterodimer with an AhR nuclear translocator (Arnt). An alternative theory suggests that upon ligand binding the entire complex translocates to the nucleus where it dissociates into separate subunits; the AhR subunit then dimerizes with Arnt.161 The AhR−Arnt heterodimerdimer binds the xenobiotic response element (XRE) and activates the expression of genes coding for the enzymes belonging to the CYP1 family. CYP1A1 and CYP1B1 catalyze the oxidation of PAHs to reactive species that damage DNA, which may ultimately result in the initiation of cancer.163 However, CYP1A1 and CYP1A2 also play an important role in the detoxification of PAHs, N-heterocyclic amines, and aromatic amines.22−24 Dietary phytochemicals may inhibit the activity of CYP1 via direct binding107,110,111,113,130 and at the same time alter their expression by modulating AhR signaling pathways.164 Phytochemicals thus affect the expression and the activity profiles of CYP1 enzymes in a very complex way. Studies indicate that chemicals of a very diverse structure have the potential to bind AhR and to activate its target genes, specifically CYP1 enzymes.165 These observations suggest a high level of promiscuity of the AhR ligand-binding site. Recently, Soshilov and Denison investigated the structural basis of such promiscuity and identified amino acid residues responsible for the selectivity of ligand binding and the agonist/antagonist character of the ligands inside the binding domain of AhR.166 Numerous dietary polyphenols exhibit their anticancer effects via the inhibition of AhR. Earlier works have shown the ability of flavonoids167 and resveratrol168 to antagonize AhR. The extracts of black tea, which consist of polyphenols catechins, thearubigins, and theaflavin, are capable of inhibiting the transformation of AhR, which occurs upon dioxin binding to the AhR ligand binding site.169 The dietary polyphenols contained in black tea thus suppress the toxicity that may be 1377



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Table 5. Compounds That Modulate CYP Gene Expression by Interacting with AhR Signaling Pathways

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Table 5. continued

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Table 5. continued

pathway as the level of AhR/DNA complexes in nuclear extracts increased following the PCE treatment. Remarkably, a protein complex including AhR and estrogen receptor-α (ERα) was detected suggesting that both proteins and possibly the interactions between them contribute to the activation of CYP1A1 expression as a result of the cells exposure to PCE.177 In an alternative study, flavonols quercetin and kaempferol also activated AhR and induced its target genes in HepG2 cells.179 Anthocyanidin pelargonidin increased the AhR-dependent expression of CYP1A1 mRNA in human hepatic and intestinal cells.180 CYP1A2 was also induced to a lesser extent in human hepatocytes. Peralgonidin was shown to be a weak ligand/ agonist of the AhR. The anthocyanidin competitively inhibited TCDD binding to the receptor, and its interaction with the AhR-CYP1A signaling pathway proceeded via a ligand-dependent mechanism. The effect on the transcriptional activity of AhR was also studied for the four other anthocianidins, specifically, cyanidin, delphinidin, peonidin, petunidin, and malvidin. None of these compounds exhibited significant potential to activate AhR.180 The specific structural difference of pelargonidin from the rest of the compounds is that the B ring of the molecule is monosubstituted. Peonidin and cyanidin are disubstituted, while malvidin, petunidin, and delphinium are trisubstituted at the B rings. Some anthocyanins, glucosides of anthocyanidins, also have potential to influence AhR-CYP1A pathway. Thus, pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) activated AhR and induced CYP1A1 mRNA in human hepatic and intestinal cells. The receptor activation involved a ligand-dependent mechanism in the case of PEL-2 and a ligand-independent mechanism in the case of CYA-3.181

Amakura et al. investigated the effect of 37 plants on the AhR using a luciferase assay.182 Rosemary and cassia seeds were found to have a noticeable activation effect on AhR. The authors also examined the effect of the individual polyphenolic constituents on AhR. Nine polyphenols were isolated from rosemary. This is a perennial herb whose leaves are used in flavoring foods and as herbal tea. At the concentration of 1000 μM, a noticeable activation effect was observed with caffeic acid and two flavone glucosides nepitrin and homoplantagenin. At the concentration of 100 μM, two flavones, cirsimaritin and ladanein, and two flavone glucosides, nepitrin and homoplantagenin, exhibited significant AhR activation. The luciferase activity affected by the tested compounds diminished in the following order: cirsimaritin > ladanein > nepitrin > homoplantagenin. This trend shows that the addition of hydroxyl groups to the B ring of flavones increases its AhR activation potency, while glycosidation decreases the ability of flavones to stimulate the receptor. At the concentrations of 10 μM, the luciferase activity was at approximately the same level for the four flavones. Both nepitrin and homoplantagenin exhibited significant affinity toward AhR.182 By using immunofluorescence microscopy, Hiura et al. showed that flavone baicalein induced the nuclear translocation of AhR.183 The direct binding of the flavone to the receptor was revealed by a quartz crystal microbalance method.183 Mohammadi-Bardbori et al. showed that polyphenolic compounds have a potential to activate AhR-mediated CYP expression indirectly, by affecting the metabolic turnover of AhR ligands.184 The authors demonstrated that the flavonol quercetin and stilben resveratrol, which have low binding affinity to the AhR, activated the receptor and induced the activity of CYP1A1 in HaCaT cells. The underlying mechanism 1380



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Chocolate and cacao powder known to be rich in polyphenols significantly reduced the number of revertant colonies induced by BaP in an Ames test. The crude cacao powder caused the decrease of EROD activity down to 17.4% compared with the control value indicating the suppression of CYP1A activity.193 A dietary methoxyflavonoid chrysoeriol found in a perennial herb Digitalis purpurea194 inhibited the expression of CYP1A1, CYP1A2, and CYP1B1 genes in MCF-7 breast cancer cells.195 The compound prevented the binding of BaP to AhR and inhibited the formation of BPDE-dG adducts (Table 5). Chrysoeriol thus exhibited a chemopreventive role against a pro-carcinogen, BaP.195 1,2-Dimethylhydrazine (DMH) is also a potential carcinogen that acts as a DNA alkylating agent. The administration of DMH induced colon cancer in rats with the increase in the activity of CYP2E1 as well as the reduction of the activities of phase II enzymes.195 These rats were then treated with troxerutin, a flavonol that can be isolated from the Japanese pagoda tree and is found in various food products such as grains, coffee, tea, fruits, and vegetables. The supplementation of rats with troxerutin caused the alteration in the activities of metabolic enzymes and the reversal of the pathological changes.196 Diethylnitrosamine (DEN) is well-known for its carcinogenic properties. The CYP catalysis of DEN results in the formation of DNA adducts such as O6-ethyl-dG, O4-ethyldT, and O6-ethyl-dT and ethyl radicals, which initiate processes leading to carcinogenesis.197 A propolis component caffeic acid phenethyl ester (CAPE) inhibited the activities of CYP1B1 and CYP1B2 in male Fischer-344 rats. This inhibition slowed down DEN activation and prevented the generation of preneoplastic lesions. The administration of CAPE before DEN markedly reduced tumor incidence.198 In an alternative study, the NEDstimulated hepatocarcinogenesis in rats was blocked by naringenin. The underlying processes included the suppression of the activity of CYP enzymes as well as free radical scavenging and enhancement of the antioxidant protection.199 It was demonstrated that ellagic acid and its metabolites urolithin-A (Uro-A) and urolithin-B (Uro-B) have the potential to induce the expression and activity of CYP1 enzymes in Caco-2 colon cancer cells.200 A few CYP genes exhibited profound changes as a result of the treatment with these compounds. CYP1A1 and CYP1B1 enzymes were upregulated, the induction of CYP1A1 being 25-fold greater than the control. CYP1B1 participates in the activation of PAH, thus contributing to the initiation of tumor.26 CYP1A1, while being associated with carcinogenesis,27 has also been reported to be involved in the detoxification of harmful agents.23,24 Uro-A and Uro-B also slightly upregulated the CYP27B1 gene. This enzyme catalyzes the conversion of 25-hydroxyvitamin D3 (calcidiol) to the hormone 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol exhibits antiproliferative effects against prostate epithelial cells and inhibits the growth of colon tumor. Uro-B also significantly suppressed the expression of CYP3A5, an isoform involved in the metabolism of some anticancer drugs.200 Polyphenol−CYP interactions may have a significant impact on estrogen carcinogenesis. One of the pathways of estrogenmediated cancer involves metabolic oxidation of estrogen catalyzed by CYP enzymes. For example, the CYP1B1 isoform catalyzes the hydroxylation of estrogen, E2, at the 4-positions producing 4-OHE2.201 A resulting catechol is then easily oxidized by molecular oxygen to o-quinone, which then converts to the semiquinone radical through the acceptance

involved the inhibition of the metabolic clearance of endogenous AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Since FICZ is an exceptionally good substrate for CYP1A1,160 the inhibition of this enzyme by quercetin and resveratrol prolonged the presence of FICZ in the cells thus activating the transcriptional activity of AhR and inducing the activity of CYP1A1. Thus, the phytochemicals affected the feedback control of FICZ operated by CYP1A1. Interestingly, while quercetin was a more effective inhibitor of CYP1A1 than resveratrol, the IC50 values being 1.2 μM and 11.8 μM, respectively, it was also a more powerful activator of the AhR.184 Quercetin can potentially inhibit CYP1A1 via the direct binding with the IC50 value of approximately 2 μM, as was shown earlier by Shimada et al.107 The inhibition of CYP1A1 by the polyphenols may also occur at the transcriptional level and involve the generation of ROS. The pro-oxidant properties of these compounds have been observed in the presence of hemeproteins (quercetin)185,186 and Cu ions (quercetin and resveratrol).187,188 It was hypothesized that the suppression of CYP1A1 gene expression stimulated by the polyphenol-induced oxidative stress is mediated by nuclear factor 1, as had been shown previously.184,189 The structures of the compounds interacting with AhR signaling pathways are summarized in Table 5.

5. ROLE OF POLYPHENOL−CYP INTERACTIONS IN DISEASES Polyphenol−CYP interactions have a significant impact on human health, specifically on the onset, progression, and development of diseases as well as in the therapeutic treatment of multiple disorders. The following chapter highlights recent findings concerning the involvement of dietary polyphenols in CYP-mediated processes with a special focus on cancer, CVD, and diabetes. 5.1. Cancer. A number of studies have revealed the ability of products rich in polyphenols to suppress the metabolism of PAHs whose oxidized products are known to cause DNA damage and initiate cancer. For example, BaP and its derivatives represent one of the main classes of environmental procarcinogenes. The active carcinogenic form, BaP-7,8-diol-9,10epoxide (BPDE), whose production is catalyzed by CYP1, covalently binds DNA. The inhibition by dietary polyphenols of CYP enzymes catalyzing PAH oxidation may result in the suppression of cancer development. For example, DMBA is known to induce hamster buccal pouch (HBP) tumors. The administration of quercetin, a flavonol often used as an ingredient in foods and beverages, resulted in the suppression of the development of HBP carcinomas.190 The underlying mechanism involves the quercetin-mediated downregulation of the expression of CYP1A1 and CYP1B1 isoforms. The inhibition of ROS generation resulted from the suppression of CYP activities led to the prevention of ROS-induced DNA damage and the inhibition of the NF-κB signaling circuit.191 A similar effect on HBP carcinomas was observed with black tea polyphenols polyphenon-B and BTF-35. Administration of these compounds resulted in the reduction of the level of CYP1A1 and CYP1B1 enzymes and the inhibition of oxidative DNA damage. The activities of phase I enzymes were decreased as a result of the polyphenol treatment, while the activities of phase II enzymes were augmented. Collectively, these effects formed the basis for the chemoprevention of HBP carcinomas by black tea polyphenols.192 An antimutagenic effect was reported for cacao extracts in Salmonella typhimurium. 1381



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coadministration of resveratrol also enhanced apoptosis. The observed effects are thought to involve the resveratrol-mediated suppression of the expression of CYP1B1 gene.213 5.2. Cardiovascular Diseases (CVD) and Diabetes. It was discovered that the administration of some dietary polyphenols results in the upregulation of specific CYP genes, ultimately leading to the reduction of the risk of obesity and CVD. For example, the treatment of mice with a high-fat diet resulted in the downregulation of multiple genes responsible for lipid metabolism, liver function, and immunity including two CYP isoforms cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1).214 CYP7A1 is a microsomal enzyme that catalyzes the first step in the synthesis of bile acid from cholesterol.215 CYP8B1 is a hepatic enzyme that regulates the solubility of cholesterol by modulating the ratio of cholic and chenodeoxycholic acids.216 Remarkably, when mice were treated with quercetin and resveratrol the inhibition in the gene expression caused by the high-fat diet was restored as indicated by the integrated transcriptomic and metabolonomic analysis. The simultaneous supplementation of the two phytochemicals resulted in a more pronounced gene restoration effect compared to either treatment alone suggesting a synergistic activity in enhancing fatty acid oxidation in the liver and protecting against fatty liver disorder.214 The enhancement of CYP7A1 mRNA was also observed in type 2 diabetic mice treated with buckwheat sprouts (BS), a product known to be rich in flavonoids and anthocyanin.217 The concentration of cholesterol in the plasma and liver tissues was determined to be lower in diabetic mice treated with BS compared with the control level as a result of the upregulation of CYP7A1 gene. The administration of BS also led to the increase in the concentration of bile acid in feces. Interestingly, the experiments with nondiabetic mice revealed no BS effect on the metabolism, suggesting that BS could be used as an effective agent for blood-glucose control.217 In an alternative study, mice were treated with a mild-high-fat diet supplemented with quercetin. A higher level of gene expression was observed for CYP4A subfamily isoforms compared with the control level (mild-high-fat diet only). Specifically, the expression of CYP4A10, CYP4A14, and CYP4A31 genes was increased suggesting an enhancement of the ω-oxidation of fatty acids.218 The main metabolic pathway of fatty acids is β-oxidation. During a high-fat diet or in obesity, the flow of fatty acids into the liver increases, which results in a higher rate of ω-oxidation. This type of oxidation occurs in the endoplasmic reticulum and is catalyzed by CYP4A enzymes. ωHydroxy fatty acids are then converted to short chain dicarboxylic acids in cytosol. These metabolic products can then be excreted in the urine. The ω-oxidation of fatty acids supported by quercetin reduces the level of circulating lipids lowering the risk of the development of CVD.218 The microvascular and macrovascular pathology in diabetes219 is initiated by intramitochondrial ROS, which may be produced during CYP2E1 catalysis. The studies with the extract of a perennial plant Solanum torvum (ST) performed in human liver microsomes revealed the inhibition potential of ST toward CYP2E1.220 The evaluation of the free-radical scavenging properties was performed in the pooled plasma of diabetic patients revealing the antioxidant activity of ST.220 The antidiabetic potential of ST fruit extracts was also demonstrated with diabetic rats. 221,222 The polyphenolic compounds constitute a significant portion of the extract and include rutin, caffeic acid, gallic acid, and catechin.222 Thus, ST could

of one electron. The radicals produce damage on DNA and proteins initiating carcinogenesis.202 The covalent DNA adducts 4-OHE2-N7-Gua and 4-OHE2-N3-Ade were detected after reactions of recombinant CYP1B1 with NADPH-P450 reductase, E2, and 2′-dG or 2′-dA proving the importance of estrogen metabolism in the generation of DNA lesions and carcinogenesis.203 An alternative and most well studied mechanism of estrogen-mediated cancer involves ER-mediated signaling pathways stimulated by estrogen.204,205 Chrysoeriol selectively suppressed the activity of CYP1B1 thus preventing the oxidation of E2 and the generation of carcinogenic 4-OHE2. The flavonoid was tested at the physiological concentrations, and the result was confirmed in vitro and in MCF-7 cells.206 A soybean component isoflavone genistein also inhibited the adverse properties of E2 and suppressed prostate cancer. This phytochemical together with 3,3′-diindolylmethane (DIM) increased the level of 2-OHE2 in both the E2-sensitive LNCaP cells and the E2-insensitive PC-3 cells.207 However, since 2-OHE2 is quickly O-methylated, its estrogenic activity is negligible. Both genistein and DIM decreased the amount of 16α-OHE1,207 which is formed via the catalysis by CYP3A4 and CYP3A5.208 These effects combined together diminished the proliferation of prostate cancer cells and increased apoptosis.207 The ability of polyphenolic compounds to reduce estrogenmediated cancer growth is also associated with their ability to inhibit aromatase (CYP19), as it catalyzes the rate-limiting reaction in the synthesis of estrogen. Thus, the flavonoid isoliquiritigenin (ILN) isolated from rhizomes of a bean plant inhibited aromatase in an in vitro enzyme system and in MCF-7 cells transfected with CYP19. The growth of the cells was blocked as a result of the exposure to the compound. ILN also suppressed the level of aromatase mRNA in wild-type MCF-7 cells.209 A phytochemical icariin whose active metabolite is icaritin is the major constituent of Epimedium. Extracts from these plants are traditionally used in Chinese herbal medicine. Icaritin is an estrogenic ligand; at low concentrations, it induced the growth of breast cancer cells. However, at higher concentrations of the compound, the suppression of cell growth was observed.210 Icaritin was an AhR agonist that increased the expression of AhR-regulated CYP1A1 gene (Table 5). AhR signaling pathways are known to intersect with ER activity. Icaritinmediated stimulation of AhR signaling led to the acceleration of ERα proteasome degradation ultimately resulting in the inhibition of breast cancer cells proliferation.210 The modulation of the activity of CYP enzymes by dietary polyphenols affects the pharmacokinetics and bioavailability of drugs and thus influences the efficacy of chemical therapies. For example, flavonoids myricetin and quercetin significantly affected the metabolism of an anticancer drug doxorubicin. These phytochemicals inhibited the activity of CYP3A4 in rats with IC50 values of 7.8 μM for myricetin and 1.97 μM for quercetin. The peak plasma concentration of the drug increased, and the relative bioavailability of oral doxorubicin was amplified approximately 2-fold when coadministered with myricetin or quercetin. Thus, both phytochemicals could improve the effectiveness of orally administered doxorubicin.211,212 Resveratrol treatment was proposed to be used as an adjunct therapy to improve chemosensitivity in cholangiocarcinoma. The proliferation of cancer cells pretreated with resveratrol was inhibited to a greater extent than when treated with 5-fluorouracil, gemcitabine, or mitomycin C alone. The 1382



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For example, quercetin downregulates CYP1B1, CYP3A4, and CYP3A5. The same flavonoid upregulates CYP7A1, CYP8B1, CYP4A10, CYP4A14, and CYP4A31. Resveratrol downregulates CYP1B1 and upregulates CYP7A1 and CYP8B1. Multiple flavones and flavonols, while being agonists of PXR and AhR and thus stimulating the expression of the respective CYP genes, inhibit CYP enzymes via the direct binding. A system-level study of the effect of natural polyphenols on the activity of multiple CYP enzymes is required to predict therapy outcomes and to design effective diets.

be used as a natural source of health-protective phytochemicals for the inhibition of lipid peroxidation and against the generation of superoxide in diabetes.

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CONCLUSIONS A significant amount of work conducted in the past decade focused on characterizing the biochemical processes linking the consumption of polyphenol-rich products with the improvement of human health. Recently, evidence has been collected pointing toward the importance of CYP enzymes as mediators in the development of multiple disorders. The expanded active site pocket of some CYP enzymes, the promiscuous nature of the PXR ligand-binding pocket, as well as a marked affinity of some phytochemicals toward AhR make CYP enzymes especially receptive to natural polyphenols, which possess multiple structures and are highly abundant in food. In this review, we summarized the data collected over the last five to six years on the direct binding of natural polyphenols to CYP enzymes. The analysis of the IC50 and Ki values obtained by different researchers for flavonoids with various structures resulted in the following conclusions in regard to the structure−activity relationships. (1) Flavanones are weaker CYP inhibitors than flavones and flavonols. (2) The introduction of hydroxyl groups to the B ring of flavones and flavonols decreases the inhibition potential of the molecules. (3) The introduction of methoxy groups into the B ring of flavones increases the potential of flavones to inhibit CYP1A1 and CYP1B1 enzymes. (4) The introduction of hydroxyl groups at the A ring of flavones, specifically, 5 and 7 positions, increases the inhibition potential of flavones toward CYP1A1 and CYP1B1. (5) Isoflavones exhibit a lower inhibition potential toward CYP enzymes than their respective flavone isomers. (6) The introduction of a glycoside group reduces the CYP inhibitory potential of flavonoids. Besides flavonoids, stilbenes were found to be exclusively powerful inhibitors of the CYP1B1 enzyme, specifically resveratrol and picetannol. The plasma concentrations of many dietary polyphenols are comparable with their values of IC50 and Ki, which emphasizes their role in the metabolic activity of CYP. A number of lignans, components of herbal medicines, fruits, and perennial plants, inhibit CYP enzymes via a mechanism-based inactivation. The expression of CYP enzymes is regulated by multiple processes including conformational modifications in transcription factors, their translocation to the nucleus, and their binding to the response elements in the promotor region of the gene. Natural polyphenols were shown to influence CYP expression by affecting all of these processes. Multiple flavonoids act as agonists of PXR and AhR. Several flavonoids proved to be antagonists of AhR. A trans-stilbene resveratrol exhibits agonistic property toward both PXR and AhR. Several lignans proved to be agonists of PXR. Flavanolignans exhibit inhibitory potential toward PXR, while procyanidins antagonize AhR. The modulation of the metabolic activity of CYP by natural polyphenols may directly affect the development of various diseases such as cancer, CVD, and diabetes, as well as the effectiveness of their treatment. However, multiple mechanisms underlying these processes remain unknown. For example, the kinetics of the processes associated with mechanism-based inactivation of CYP observed for different flavonoids and lignans have not been described, and the structure of the polyphenol metabolites is not known. Moreover, some polyphenols influence the activity of multiple CYP isoforms.

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AUTHOR INFORMATION

Corresponding Author

*Tel: 212-237-8064. Fax: 212-237-8318. E-mail: ekorobkova@ jjay.cuny.edu. Funding

I thank the PSC-CUNY Research Award Program and the PRISM Program at John Jay College of Criminal Justice at the City University of New York. Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS I thank Jenny Fong, Alicia Williams, Baibhav Rawal, Tasheda Kelly, Veena Mehta, and Michael Muyalde for their help with the literature search and figures. I also thank the three anonymous referees for valuable comments and suggestions.

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ABBREVIATIONS AF, aminoflavone; AhR, aryl hydrocarbon receptor; Arnt, AhR nuclear translocator; BaP, benzo(a)pyrene; BPDE, BaP-7,8diol-9,10-epoxide; BS, buckwheat sprouts; CAPE, caffeic acid phenethyl ester; CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; CVD, cardiovascular diseases; Cdks, cyclin-dependent kinases; CYP, cytochrome P450; DEN, diethylnitrosamine; DMBA, 7,12-dimethylbenz(a)anthracene; DMH, 1,2-dimethylhydrazine; EGCG, epigallocatechin gallate; EROD, 7-ethoxyresorufin O-deethylation; E2, 17β-estradiol; ER, estrogen receptor; ERα, estrogen receptor-α; E1, estrone; ILN, isoliquiritigenin; MBI, mechanism-based inactivator; αNF, alpha-naphthoflavone; β-NF, beta-naphthoflavone; PAH, polycyclic aromatic hydrocarbons; PCE, polyphenolic cocoa extract; PXR, pregnane X receptor; ST, Solanum torvum; tBPA, tert-butylphenylacetylene; TMS, 2,4,3′,5′-tetramethoxystilbene; TSAHC, 4′-(p-toluenesulfonylamido-4-hydroxychalcone); TMF, 6,2′,4′-trimethoxyflavone; Uro-A, urolithin-A; Uro-B, urolithin-B; XRE, xenobiotic response element

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REFERENCES

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Natural polyphenols: Influence on membrane transporters.

Natural polyphenols binding to amyloid: a broad class of compounds to treat different human amyloid diseases.

Resources and biological activities of natural polyphenols.

Natural Polyphenols for Prevention and Treatment of Cancer.

Photoprotective characteristics of natural antioxidant polyphenols.

Natural polyphenols and spinal cord injury.

Natural Products for Infectious Diseases.

In Vitro Evaluation of the Effects of Eurycoma longifolia Extract on CYP-Mediated Drug Metabolism.

Complex disruption effect of natural polyphenols on Bcl-2-Bax: molecular dynamics simulation and essential dynamics study.

Molecular mechanisms underlying the potential antiobesity-related diseases effect of cocoa polyphenols.

Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds.

Improvement of endurance of DMD animal model using natural polyphenols.

Probiotic actions on diseases: implications for therapeutic treatments.

The Chemistry of Gut Microbial Metabolism of Polyphenols.

Overview of metabolism and bioavailability enhancement of polyphenols.

Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties.

Regulation of galactose metabolism: implications for therapy.

The effect of temperature and humidity on adhesion of a gecko-inspired adhesive: implications for the natural system.

Unraveling the performance of dispersion-corrected functionals for the accurate description of weakly bound natural polyphenols.

Diseases of phenylalanine metabolism.

Sex steroid signaling: implications for lung diseases.

Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols.

Retraction. Updated Knowledge about Polyphenols: Functions, Bioavailability, Metabolism, and Health.

Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz.