Review Article Interactions between CYP3A4 and Dietary ...

Review ArticleInteractions between CYP3A4 and Dietary Polyphenols

Loai Basheer and Zohar Kerem

Institute of Biochemistry Food Science and Nutrition The Robert H Smith Faculty of Agriculture Food and EnvironmentThe Hebrew University of Jerusalem PO Box 12 76100 Rehovot Israel

Correspondence should be addressed to Zohar Kerem zoharkeremmailhujiacil

Received 14 October 2014 Revised 15 December 2014 Accepted 19 December 2014

Academic Editor Cristina Angeloni

Copyright copy 2015 L Basheer and Z Kerem This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a criticalrole in the metabolism of xenobiotics such as drugs and dietary compounds CYP3A4 is known to be the main enzyme involvedin the metabolism of drugs and most other xenobiotics Dietary compounds of which polyphenolics are the most studied havebeen shown to interact with CYP3A4 and alter its expression and activity Traditionally the liver was considered the prime siteof CYP3A-mediated first-pass metabolic extraction but in vitro and in vivo studies now suggest that the small intestine can be ofequal or even greater importance for the metabolism of polyphenolics and drugs Recent studies have pointed to the role of gutmicrobiota in the metabolic fate of polyphenolics in human suggesting their involvement in the complex interactions betweendietary polyphenols and CYP3A4 Last but not least all the above suggests that coadministration of drugs and foods that are richin polyphenols is expected to stimulate undesirable clinical consequences This review focuses on interactions between dietarypolyphenols and CYP3A4 as they relate to structural considerations food-drug interactions and potential negative consequencesof interactions between CYP3A4 and polyphenols

1 Introduction

Cytochrome P450 enzymes (P450s) are responsible for themetabolism of a wide range of endogenous compounds (ster-oid hormones lipids and bile acids) as well as xenobioticsincluding drugs environmental pollutants and dietary prod-ucts [1ndash4] P450 enzymes are widely distributed among thephylogenetic trees [5] and considered as a significant playerin the world around us where life and the earth itself wouldbe visibly different and diminished without cytochromeP450s [6] A direct impact on humans is mediated especiallythrough our own set of 57 P450s [7] CYP is an abbreviationfor cytochrome P450 the gene family is then indicated by anumber following the letters ldquoCYPrdquo Subfamilies are repre-sented by a letter that is followed by yet another numberto indicate the specific gene For example for the enzymeCYP3A4 ldquo3rdquo stands for the gene family ldquoArdquo for the subfamilyand ldquo4rdquo defines the gene that encodes a specific polypeptide[8]

Among this large family of oxidizing enzymes CYP3A4 isrecognized as themain enzyme involved in themetabolism of

drugs in the liver and no less importantly in the gut Hencepotential interactions between promising new drugs andCYP3A4 are assessed starting at the early stages of their devel-opment [9ndash11] CYP3A4 ismost abundant P450 in the humanliver accounting for 30 of the total P450 protein contentbut is also expressed in the prostate breast gut colon smallintestine and brain [12ndash17] In the small intestine CYP3Aenzymes represent the principle drug-metabolizing systemand account for approximately 80 of total P450 content [18ndash20] Although the total amount of CYP3A expressed in thehuman small intestine represents approximately 1 of theamount expressed in the liver [21 22] substantial drug extrac-tion takes place during the absorption of orally administereddrugs [23ndash26] Orally administered substrates must passthrough enterocytes while they can bypass hepatocytes byremaining in the sinusoidal blood before reaching the sys-temic circulation The remarkably lower blood flow to theintestinal mucosa as compared to the liver allows for pro-longed exposure to the intestinal metabolizing enzymes andlead to relatively high enterocytic drug concentrations Thepredominance of CYP3A4 in human intestine and its high

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 854015 15 pageshttpdxdoiorg1011552015854015

2 Oxidative Medicine and Cellular Longevity

capacity enable it to can act several-fold more efficiently inthe intestine than in the liver [20 27 28] Furthermore theintestine receives not only dietary compounds but also phaseI and II metabolites that have been excreted back into theintestine through the enterohepatic cycle [29 30] All thesefacts indicate the importance of intestinal CYP3A4 activityin the metabolism of dietary constituents In rodents theisofrom CYP3A is expressed predominantly in the liver withonly scant expression observed in the intestine [31ndash33] Thedifferent isoforms and distinct expression levels and patternsfor P450s in the intestine between humans and rodentslimit the suitability of rodents as a model to predict drugmetabolism or oral bioavailability in human [34]This pointsthe importance of studying the effects of ingested polyphenolsand other dietary substrates on the metabolism of intesti-nal CYP3A4 in humans or in models other than rodentsrsquointestine The latter include cell cultures microsomes andmicroorganisms that express the specific P450 of interest or awhole array of P450s [35ndash39]

The active site of a substrate-free cytochrome P450 con-tains one-heme iron center anchored by the four bonds of theheme group fifth proximal ligand of the conserved cysteineand water molecule as the sixth distal ligand [1]The catalyticmechanisms of P450 enzymes are thoroughly investigatedin the literature as demonstrated in a scheme based onprevious publications (Figure 1) [1 40ndash42] Like most otherP450 enzymes CYP3A4 acts as a monooxygenase (eg itcatalyzes the insertion of one atom of oxygen into an organicsubstrate while another oxygen atom is reduced to water)[43]The substrate chemical characteristics and the preferredposition of hydroxyl insertion change from one family ofP450 to another [3 44ndash46] P450 enzymes play a majorrole in phase I metabolism of dietary xenobiotics includingpolyphenols whereby a hydroxyl group is introduced to themolecule These metabolic products are more water-solubleand become available to phase II enzymes The latter includeUDP-glucuronosyl transferases and sulfotransferases thatadd to the increased water solubility of the hydroxylatedpolyphenols producing glucuronides and sulfates which arethen eliminated from the body [29 47 48]

In recent studies evidence has accumulated to indicatepotent interactions between CYP3A4 and edible phytochem-icals These compounds some of which are abundant in ourdiet belong to the large and diverse family of polypheno-lics including flavonoids phenolic acids phenolic alcoholstilbenoids and lignans [49ndash53] It is commonly acceptedthat the powerful antioxidant activity of polyphenolic com-pounds is due to their free-radical scavenging capacity andtheir iron-chelating activity [54ndash56] Reviews of the healthbenefits of polyphenols demonstrate that these compoundshave numerous therapeutic effects against several diseases(eg atherosclerosis certain forms of carcinogenic processesand cardiovascular and neurodegenerative diseases) [57ndash60] Among the therapeutic implications of polyphenols onhuman health the interactions between polyphenols andcytochrome P450 have been recently reviewed [56 61ndash64]These interactions were highlighted following the increaseduse of herbal medicines and supplements As many of theherbs used in these preparations are known to be rich in

polyphenolics their interaction with the major enzyme ofpresystemic metabolism has attracted significant researchattention [56 65ndash67] Since cytochrome P450 enzymes areresponsible for the metabolism of a wide range of drugs andpolyphenols which might also change their antimicrobialpotential and human toxicity the simultaneous consumptionof drugs herbals and plant foods raises concerns The coad-ministration of active constituents derived from food or herbsand prescribed drugs may lead to undesirable clinical effectswhichmay include increased toxicity andor treatment failure[67ndash69]

Here we focus on the interactions of polyphenols withCYP3A4 the major enzyme in the gut and liver metabolismof drugs and xenobiotics The effects of several subcategoriesof polyphenols on the expression and activity of CYP3A4(inhibition or induction) are reviewed (Table 1) Structuraland physicochemical considerations that define these inter-actions are also reviewed

2 CYP3A4 and Food-Drug Interactions

Drug-metabolizing P450s such as CYP3A4 have relaxedselectivity and are able to bind and metabolize a large arrayof substrates of different size shapes and chemical propertiesfor example many dietary polyphenols Crystal structuresbiophysical studies and molecular dynamics have providedimportant insights into how drug-metabolizing P450s espe-cially CYP3A4 structurally adapt to a variety of inhibitorsand substrates [70] Indeed CYP3A4 is involved in themetabolism of over 50 of marketed drugs that undergometabolic elimination [71]The high level of CYP3A4 expres-sion in the intestine as well as its broad substrate specificitymay explain the accumulating data regarding its suscepti-bility to modulation by food constituents [38 61 72ndash75]Examples of metabolic food-drug interactions involving themodulation of CYP3A4 activity by components from dietaryand herbal sources are accumulating including those ofgrapefruit with over 85 drugs for example cyclosporine andfelodipine [27 76ndash78] and those of St Johnrsquos wort [54 79 80]and red wine [38 75 81] with cyclosporine In most of thesecases components in foods drinks food additives and orallyadministered medicines were shown to inhibit CYP3A4activity and as a result increase the actual dose of the drugthat reaches the blood circulation in its active form whichoften causes unfavorable and long-lasting interactions andprobably fatal toxicity [82 83] Continuous exposure to thesecompounds especially those that activate the xenobioticnuclear receptor PXR (pregnane X receptor) may lead ina feedback fashion to increased expression of CYP3A4 inthe intestine making the food-drug interaction even morecomplex during extended periods of use [84ndash87] Drug-drugfood-drug and herb-drug interactions in the liver have beenwell documented in the literature [72 88ndash90] An intensiveCYP3A4-dependent intestinal metabolism of low-absorbedcompounds such as most polyphenols might be expected[29 54 91ndash93] However to the best of our knowledge theresearch in this area is limited and additional data are needed

Oxidative Medicine and Cellular Longevity 3

O

O

O

O

O

O

O

O

O

O O

O O

O

O

O

O

O

O

O

O

O

OH

OH

H2O

H2O

H2O

Fe3+

Fe3+

Fe3+

Fe4+

Fe3+

Fe3+

Fe3+

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Fe2+

2eminus

H++

H+

H+

Oxidaseshunt

shunt

shunt

Peroxide

AutoxidationOHminus

Ominus

H2O2

O2

eminus

eminus

O2minus

∙

O2

minus

2H+

Figure 1 The catalytic cycle of P450s a flavonoid structure was selected to represent dietary polyphenols

3 Polyphenols

As reviewed in other works in this issue polyphenols con-stitute a large and diverse family of compounds that is com-monly divided into subfamilies that share similar chemistryflavonoids flavonols phenolic acids phenolic alcohols stil-benoids tannins and lignans (Figure 2) Polyphenols arefound in several foods fruits vegetables and herbs [52 9495] In general the total intake of polyphenols is approxi-mated at 1 gindividualday and polyphenols are consideredby many to be the major source of antioxidants in our diet[51 95ndash97] However this estimate varies depending on thetype of diet For example total polyphenol intake in theFinnish diet is 817ndash919mgindividualday [98] In the Viet-namese diet it is 595mgindividualday [99] and in theMediterranean diet polyphenol intake ranges between 1800and 3000mgindividualday [100] Still and due to their low

absorption it has been suggested that their major sites ofantioxidant activity are the stomach [101] and the intestine[102] Whether acting in the gastrointestinal tract or inthe liver the potent antioxidant effects of polyphenols arewidely accepted as health promoting [103ndash105] Antiviraantibacterial anti-inflammatory neuroprotective and anti-carcinogenic effects have also been attributed to polyphenols[106ndash109]Medicinal herbs such as St Johnrsquos wort (Hypericumperforatum) ginseng (Panax ginseng) black cohosh (Actaearacemosa) echinacea (Echinacea purpurea) cranberry (Vac-cinium macrocarpon) and ginger (Zingiber officinale) arerich sources of a vast array of polyphenolic compounds [74110ndash115] The biochemical mechanisms underlying metabolicherb-drug interaction were well described in a recent review[72] These herbal sources of polyphenols deserve specialattention when the activity of P450s is discussed due tothe dramatic increase in the use of herbal medicines and


Table 1 Potential interactions of polyphenols with CYP3A4

Category ofpolyphenols

Subcategory ofpolyphenols Polyphenols in category Interaction with CYP3A4 References

Flavonoids

Flavonols

Kaempferol galangin Inhibition [87 148 149]

Quercetin

Inhibition [87 148ndash150]Induction of CYP3A4 mRNAexpression in vivo and inprolonged-exposure assays

[87 151 153]

Flavones

Apigenin chrysinamentoflavone Inhibition [73]

Luteolin diosmetin Inhibition [156]Flavone tangeretin Activation [156]120572-Naphthoflavone Activation [11]

Flavonols EGCG ECG Inhibition [73 121 139 162]Flavanones Naringin naringenin Inhibition [73 165]

Isoflavones GenesteinInhibition [169ndash171]Activation (modest activationin clinical trials) [172 173]

Anthocyanins Anthocyanins (andanthocyanins aglycones) Inhibition [174]

Nonflavonoids

Stilbenes Resveratrol (andresveratrol derivatives) Inhibition [38 175ndash179]

Lignans

Gomisins (B and C) Inhibition [182]

Silymarin mixtureInhibition (with slightactivation at lowconcentrations)

[183 184]

Tannins Tannic acid Inhibition [185]

Phenolic acids Hydroxycinnamic acid Caffeic acid Inhibition [186]Hydroxybenzoic acid Gallic acid Inhibition [187 188]

Polyphenols

Phenolicacids

Hydroxycinnamicacids

Examples caffeic acidMain food sources strawberries coffee

Hydroxybenzoicacids

Examples gallic acid Main food sources areca nut vinegar

Non flavonoids

StilbenesExamples resveratrol viniferin

Main food sources grapes red wine

LignansExamples pinoresinol

Main food sources flax seed sesame seed

TanninsExamples tannic acid

Main food sources pomegranate legumes

Flavonoids

FlavonesExamples flavone luteolin

Main food sources celery parsley

FlavonolsExamples quercitin kaempferol

Main food sources apple broccoli

FlavanonesExamples naringin butin

Main food sources citrus fruits

FlavanolsExamples catechins EGCG

Main food sources tea chocolate

IsoflavonesExamples genistein

Main food sources soybean fava bean

AnthocyaninsExamples cyanidin

Main food sources onion berries

Figure 2 Classification of polyphenols


supplements [65 66] Recent surveys suggest that one in threeAmericans use dietary supplements daily and among cancerpatients the rate is much higher [54] Moreover medicinalherbs are not inspected by regulatory authorities such as theFood and Drug Administration (FDA) and the EuropeanAgency for the Evaluation of Medicinal Products (EMEA)[72] Indeed medical doctors as well as pharma professionalsshould be aware of the many interactions of polyphenolicswith drugs and tools should be developed to assess the poten-tial of individual polyphenolics to enter the active sites ofP450 enzymes and become substrates competitive inhibitorsor other types of inhibitors of these enzymes in the intestineand the liver CYP3A4 should be a major point of focus instudies of the undesirable clinical consequences of the timeduse of prescribed drugs and herbs [74]

4 Metabolism of Polyphenols by P450s

41 Metabolism of Polyphenols by P450 Enzymes The meta-bolic fate of polyphenols is largely dictated by their chemicalstructure and depends on several parameters includingtheir functional groups (ie benzene or flavone derivatives)molecular weight stereostructure glycosylation polymer-ization and conjugation with other phenolics [97 116 117]Flavonoids which are the largest subgroup of polyphenolshave been identified as substrates of P450 enzymes [118 119]Flavonoids are hydroxylated andor o-demethylated by var-ious hepatic P450 enzymes prior to their elimination [67]Jancova and coworkers showed that silybin a flavono-lignanfound in silymarin ismetabolized to o-demethylated productbyCYP2C8 andCYP3A4 in vitro [120]Meanwhile it has beenreported that flavonoids rich with hydroxyl group such asgreen tea catechins are fairly water soluble and are not likelyto be good substrates for P450 enzymes [121 122]This is con-sistent with findings that have demonstrated the importanceof ligand hydrophobicity for interactions with these enzymes[38 123 124] Paradoxically inhibitory effects of green tea cat-echins on several P450 enzymes have been reported in in vivotrials [125 126] Another intensively studied polyphenol isthe stilbene 119905-resveratrol (trans-3410158405-trihydroxystilbene) apolyphenol found in grape skins and red wine peanuts anda limited number of other plants and its effects on CYP3A4will be discussed later (Section 521) It exhibits a high level ofmembrane permeability and is categorized as a class-II com-pound in the Biopharmaceutical Classification System (BCS)[127] 119905-Resveratrol has a lowbioavailability (less than 1) dueto the low water solubility (a log119875 of 31) and the extensivefirst-pass metabolism by CYP3A4 in the intestine and inthe liver which extended by the enterohepatic recircula-tion Further metabolism leads to the formation of theglucuronide and the sulfate metabolites of 119905-resveratrol [128129] Recently Singh and Pai reported the success of a sys-tematically optimized nanoparticulate drug delivery systemto increase the oral bioavailability of 119905-resveratrol in rats [130]In a similar context in in vitro study Seljak et al developeda mixed lipidndashmixed surfactant self-microemulsifying drugdelivery system (SMEDDS) to improve the biopharmaceu-tical pharmacokinetic and toxicological characteristics ofresveratrol suggesting a way to lower the applied dose of

resveratrol to reduce toxicity while maintaining a sufficientpharmacological response [131]

42 Involvement of Microbiota in the Metabolism of Polyphe-nols There is accumulating evidence to suggest that gutmicrobiota play a significant role in themetabolism bioavail-ability and bioactivity of dietary polyphenols [132ndash134]The involvement of microbiota in the metabolism of thesecompounds generally starts with the hydrolysis of polymericglycosylated andor esterified polyphenols by brush borderandor microbial enzymes which is a prerequisite for theabsorption and bioactivity of most compounds [134ndash136]These biotransformations affect the structural characteristicsof polyphenols and may generate metabolites with alteredbioactivity profiles [30 134] Considering the water solublegreen tea catechins which should be very poor substratesfor CYPs their biotransformation by human gut microbiotacould lead to the formation of better CYP substrates as wasdemonstrated in vitro by Stoupi et al [137] Taken together wesuggest that gut microbiota may play a role in the formationof polyphenol-derived metabolites that are more likely tointeract with P450 enzymesThe role of intestinal microbiotain the metabolism and bioavailability of dietary polyphenolshas been examined [30 132ndash136] but unfortunately data onthe three-way interactions between polyphenols microbiotaand P450s are scarce

5 Modulation of CYP3A4 Activityby Polyphenols

Interactions between polyphenols and CYP3A4 are impor-tant due to their potential implications for drug metabolismThese interactions can modulate the activity or expression ofthe enzyme Kimura et al demonstrated inhibitory effects ofpolyphenols on humanCYP3A4 andCYP2C9 activity in vitro[73] These inhibitory effects generally involve the formationof a covalent bond between the polyphenol and the CYP3A4molecule which leads to the inactivation of the enzyme orreversible binding that causes reversible inhibition [138] Insome cases the inhibition of P450 enzymes by polyphenolsmay have a chemopreventative effect due to the potentialactivation of carcinogens by P450 enzymes within the courseof their natural metabolic activity [81 139ndash142] The inhibi-tion of xenobiotic-metabolizing phase I enzymes (ie P450enzymes) could be one target of the chemopreventive effectsof naturally occurring polyphenols Alternatively it couldbe the induction of phase II conjugation enzymes such asUDP-glucuronosyl transferase and glutathione S-transferasewhich are responsible for the detoxification of carcinogens[54]

51 Interactions between Flavonoids and CYP3A4 In largeflavonoids account for about two-thirds of the total intakeof dietary polyphenols and phenolic acids account for theremaining one-third [33] Flavonoids which are found pri-marily in fruits vegetables and beverages such as tea andwine are bioactive compounds that carry several benefits forhuman health [142ndash144] Flavonoids are known to modulateseveral P450 enzymes including CYP1A1 CYP1A2 CYP1B1


CYP2C9 CYP3A4 and CYP3A5 [145 146] Hence theirinteractions with CYP3A4 are studied in more systems thanmost other polyphenols and provide evidence for variousinteractions of polyphenols with this enzyme There is accu-mulated evidence that within the family of polyphenolsflavonoids especially can modulate drug metabolism andin several modes by altering the expression andor activityof P450 enzymes by affecting the P-glycoprotein-mediatedcellular efflux of drugs andor by inhibiting the intestinalglucuronidation of the drug This evidence indicates that theuse of flavonoid-containing dietary supplements concurrentwith conventional pharmacotherapeutic regimens should beconsidered in order to avoid drug-flavonoid interactions [5472 143ndash146] In this direction studies are being conducted todevelop methods for evaluating food-drug interactions Forexample Koe and coworkers recently developed a novel mul-tiplex RT-qPCR in vitro assay to examine the P450 enzyme-induction properties of herb-derived compounds [147]

511 Flavonols The flavonols kaempferol quercetin andgalangin inhibit CYP3A4-mediated metabolism of xeno-biotics in vitro [87 148 149] Studies performed in vivohave shown conflicting modulation of CYP3A activity byquercetin Choi et al reported that oral administration ofquercetin to rats led to inhibition of CYP3A which caused asignificant enhancement in the doxorubicin concentration inthe plasma On the contrary Yu et al reported an activationof the enzyme that resulted in a reduction in the plasmaconcentration of cyclosporine in a similar model The latterobservation suggests that this enzyme is not activated bythe flavonols but by their sulfated or glucorunidated prod-ucts [150 151] No in vivo inhibition of CYP3A4-mediatedmetabolism of nifedipine was observed following the inges-tion of a high dose of quercetin by others [152] Interest-ingly prolonged exposure to quercetin leads to a significantincrease in CYP3A4 mRNA expression levels in cell cultures[87 153] We suggest that these findings might be relatedto the well-established induction of CYP3A4 in response toconsumption of St Johnrsquos wort extract which is a rich sourceof quercetin in addition to another recognized inducerthe nonphenolic hyperforin [54 85 86 154] Kaempferoland quercetin have been found to inhibit intestinal UDP-glucuronyl transferase in vitro at clinically achievable concen-trations which may lead to an increase in the bioavailabilityof several drugs [146] A recent study conducted on rats foundthat oral administration of morin a flavonol found in manyfruits and herbal medicines increased the plasma half-life(11990512

) of febuxostat a drug used to treat gout 25-fold as com-pared with the control group leading to significantly higherbioavailability One suggested mode of action was that morincould be effective in inhibiting CYP1A1 CYP1A2 and CYP3Amediated metabolism of febuxostat [143]

512 Flavones The flavones apigenin and chrysin have amarked inhibitory effect on CYP3A4 activity in vitro withIC50

values of 04 120583M and 09 120583M respectively Amento-flavone (a dimer of apigenin) has even a stronger inhibitoryeffect with an IC

50value of 007120583M [73] Calculations of

the lipophilicity of the two compounds provide support for

previous suggestions that higher lipophilicity may contributeto stronger binding of the substrate It is also possible that thelarger stereodimensions of the dimer may lead to irreversiblebinding of the hydroxylation product to the enzyme therebyachieving inhibition via a suicidal mode of action [12 155]A recent study in rats suggests that the coadministration ofapigenin would be very useful for improving the bioavailabil-ity of paclitaxel in chemotherapeutic applications due to theinhibitory effects of apigenin on CYP3A and P-glycoproteinleading to higher concentration of paclitaxel in the plasma[144]The ability of apigenin to inhibit intestinal UGT activityhas also been investigated in vitro [146] In a study designedto reveal structure-activity relationships flavones possessingmore than two hydroxyl groups (eg luteolin and diosmetin)were shown to inhibit the biotransformation of midazolam invitro whereas flavones that do not have hydroxyl groups intheir A and B rings (eg flavone and tangeretin) stimulatedmidazolam metabolism [156] These results may supportthe activation effect of 120572-naphthoflavone (a flavone withno hydroxyl groups) on CYP3A4 and two other CYP3Aenzymes CYP3A5 and CYP3A7 [11] In addition 120572-naph-thoflavone represents an interesting case of heterotropiccooperativity in CYP3A4 as it interacts with a peripheralligand binding site located at the distal surface of the enzymeand surrounded by the FF9 and GG9 loops resulting inallosteric mechanism [157ndash161]

513 Flavonols Green tea flavonols epigallocatechingallate(EGCG) and epicatechingallate (ECG) inhibit the mutagenicaction of aflatoxin B

1(AFB1) and 11015840-hydroxylation of mida-

zolam in vitro Both actions are known to be mediated byCYP3A4 [139] Inhibitory effects of catechins on CYP3A4have been reported in several additional in vitro and in vivostudies but no specific mode of action has been suggested[73 121 125 126 162]

514 Flavanones The inhibition of CYP3A4 by grapefruitjuice is probably the most well-known example of food-drug inhibition [76 163] It was suggested that the flavanonenaringin the predominant flavanone in grapefruit mightbe responsible for the observed interaction effect [164]However naringin appears to be a weak inhibitor of CYP3A4while its aglycone naringenin may be a more potentinhibitor The IC

50value of naringin is 10-fold greater than

that of naringenin in vitro and this difference is attributedto the lack of a hydroxyl group on ring A of naringin [73165] This is in agreement with the finding of Shimada andcoauthors regarding the importance of the hydroxylation ofring A flavones for the inhibition of CYP3A4 [148] Howeverthe most potent inhibitor of CYP3A4 in grapefruit has beensuggested to be bergapten a furanocoumarin derivative [165]that does not belong to the polyphenol family but has arelatively similar structure The inhibitory effects of otherfuranocoumarins on CYP3A4 activity in vitro are also wellestablished [166ndash168]

515 Isoflavones Isoflavones such as genistein and daidzeinare found in soybean and hence are very abundant in manyprocessed food products Isoflavones differ from flavones in


the location of their phenyl group It has been suggested thatisoflavonesmay act as phytoestrogens and they appear poten-tial substrates or inhibitors of P450 enzymes Conflictingdata have been presented in several works describing in vitroand in vivo studies For instance soy isoflavones have beenfound to inhibit CYP3A4 metabolism [169ndash171] whereas theadministration of genistein resulted in a modest induction ofCYP3A enzymes among healthy participants [172 173]

516 Anthocyanins Dreiseitel et al found that anthocyaninsand their aglycones are weak inhibitors of CYP3A4 in vitro[174] The IC

50values of anthocyanin derivatives ranged

from 122 to 7842120583M whereas ketoconazole a syntheticCYP3A4 inhibitor that is often used as a reference has anIC50value of 184 nM Measurement of the IC

50values of the

different aglycones revealed an inverse relationship betweenthe number of sugarmoieties per compound and the ability ofanthocyanins to inhibit CYP3A4 [174] This provides furthersupport for the accumulating data pointing to the importanceof lipophilicity for interactionwithCYP3A4 [38 123 124]Werecently reached a similar conclusion using software to studydocking of polyphenols in which we observed a correlationbetween the log119875 values of ligands and their docking energieswith CYP3A4 (CDOCKER energy expressed in KcalmoleBasheer and Kerem unpublished data)

52 Interaction between Nonflavonoids and CYP3A4

521 Stilbenoids The inhibitory effects of 119905-resveratrol onCYP3A4 in vitro and in vivo are well established and it hasbeen suggested that resveratrol might act as an irreversiblemechanism-based inactivator of this enzyme [38 175ndash179]This inhibition occurs when a CYP3A4 substrateinhibitorforms a reactive intermediate at the CYP3A4 active site lead-ing to enzyme inactivation bymodification to the heme or theapoprotein [180 181] Chan and Delucchi suggested that anelectron-rich unsaturatedmolecule like resveratrol could be asubstrate for CYP3A4 andmight in turn inactivate CYP3A4during the course of catalysis [175] Clinical and rat trialshave found that the administration of resveratrol increasesthe area under the plasma concentration-time curve (AUC)for several drugs [81 177]Thus consuming large amounts ofresveratrol could theoretically increase the bioavailability ofand risk of toxicity from drugs that undergo extensive first-pass metabolism by CYP3A4 [179] In vitro study of the effectof lipophilicity on the interactions of resveratrol derivativeswith CYP3A4 revealed that methoxy-stilbenes have lowerIC50

values and greater affinity for CYP3A4 as comparedto the parent resveratrol and its glucosides [38] CYP3A-mediated aromatic hydroxylation and epoxidation of resver-atrol is possible and results in a reactive p-benzoquinonemethide metabolite that is capable of binding covalently toCYP3A4 leading to inactivation and potential drug interac-tions [175]

522 Lignans The lignans gomisins B and C componentsof Schisandra fruit (Schisandra chinensis) extract have beenidentified as potent inhibitors of CYP3A4 in vitro [182]Other evidence for the inhibitory effects of plant lignans on

CYP3A4 is provided by silymarin a mixture of flavonolig-nans extracted from milk thistle (Silybum marianum) Sily-marin (01mM and 025mM) significantly reduced the activ-ity of CYP3A4 in human hepatocyte cultures by 50 and 100respectively as determined by the formation of 6-120573-hydroxytestosterone [183] Studying the effects of selected lignansfrom silymarin (silybin dehydrosilybin silydianin and sily-cristin) onCYP3A4 activity as determined in vitro by nifedip-ine oxidation revealed that CYP3A4 activity is inhibited asthe concentration of each flavonolignan increases Howevera slight increase in activity was also observed in the presenceof low flavonolignan concentrations (01ndash1 120583M) [184]

523 Tannins Tannic acid a type of hydrolysable tannincommonly found in plant foods inhibited testosterone 6-120573-hydroxylation (CYP3A4) in human- and rat-liver micro-somes with IC

50values of 202120583M and 168 120583M respectively

[185]

53 Interactions between Phenolic Acids and CYP3A4 Phe-nolic acids do not all belong to the polyphenols but are com-monly discussed together The interaction of phenolic acidswith CYP3A4 and their potential metabolism by the enzymewould be of high relevance as the research of the moremulti-member interactions of CYP3A4 polyphenols and gutmicrobiota advances due to the high antimicrobial activity ofphenolic acids

531 Hydroxycinnamic Acids Caffeic acid (34-dihydrocin-namic acid) which do belong to the polyphenols is oneof the most common phenolic acids found in fruits coffeeolive oil and dietary supplements Caffeic acid has beenshown to inhibit CYP3A4 activity in human livermicrosomesby noncompetitive inhibition with an IC

50of 072 120583M In

addition ester and amide analogues of caffeic acid have beenfound to act as competitive inhibitors with IC

50values

ranging from 031 120583M to 082 120583M [186]

532 Hydroxybenzoic Acids Gallic acid (345-trihydrox-ybenzoic acid) also a member of the polyphenols andis abundant in many beverages for example wine teapomegranate juice and olive oil has an inhibitory effect onandrostenedione 6-120573-hydroxylase activity in vitro (apparent119870119894value 70 120583M) which is regarded as a marker for CYP3A

enzyme activity [187] In another study Stupans and cowork-ers provided additional evidence for the inhibition of CYP3Aactivity by gallic acid In that study they showed that pre-incubation of human liver microsomes with 100 120583M gallicacid before the assay of androstenedione 6-120573-hydroxylaseactivity significantly increased the inhibitory effects of thegallic acid In addition they reported that the removal ofgallic acid-derived products from the incubation mixturecompletely restored CYP3A activity [188]

6 Structure-Activity Relationships

Various interactions have been demonstrated between com-pounds belonging to the large family of polyphenols andP450 enzymes While members of this family share many


structural and functional features existing reports do notprovide sufficient information to allow us to fully understandthe rules that determine the nature of these interactionsThe number of hydroxyl groups stereostructure molecularweight and lipophilicity all seem to have some sort of effecton individual results Up to date the protein data bank (PDB)contains 18 crystal structure of human CYP3A4 One of themost prominent characteristics reported was the large highlyordered hydrophobic core of phenylalanine residues abovethe active site [189 190] A recent review concluded that theCYP3A4 active site is considerably larger than the active siteof any other P450 isoform [191]

CYP3A4 substrates form hydrogen bonds with the Asn74residue of CYP3A4 Structural requirements of CYP3A4substrates have been suggested to include a hydrogen-bondacceptor atom located 55ndash78 A from the site of metabolismand 3 A from the oxygen molecule associated with the heme[192] A three-dimensional pharmacophore based on 38 sub-strates of CYP3A4 possessed two hydrogen bond acceptorsone hydrogen bond donor and one hydrophobic region [193]Inhibitor pharmacophores include three hydrophobes atdistances of 52 to 88 A fromahydrogen-bond acceptor threehydrophobes at distances of 42 to 71 A from a hydrogen-bond acceptor and at an additional 52 A from anotherhydrogen-bond acceptor or one hydrophobe at a distance of81 to 163 A from the two furthest of three hydrogen-bondacceptors [194]

Substrates or inhibitors can bind to CYP3A4 at multiplesites due to the flexible structure of this enzymersquos activesite [195ndash197] For example a study of the crystal structuresof human CYP3A4 in complex with two well characterizeddrugs ketoconazole and erythromycin revealed that theenzyme undergoes dramatic conformational changes uponligand binding with an increase in the volume of the activesite ofmore than 80These structures represent two distinctopen conformations of CYP3A4 because ketoconazole anderythromycin induce different types of coordinate shifts[198] CYP3A4 like many of P450 enzymes have large andflexible substrate binding pockets capable of accommodat-ing large substrates or alternatively two or three smallermolecules [199] Examples on CYP3A4 cooperativity and itsnon-Mechaelis-Menten kinetics are found in several studies[195 200 201] However recent studies demonstrate a verycomplex allostericmechanismof P450rsquos including overlay of amultiple substrate-binding space-filling mechanism enzymeconformational changes induced by ligands and modulationof protein-protein interactions in the enzyme oligomers[158 202] Allosteric behavior includes homotropic andheterotropic activation and inhibition effects depending onthermodynamic factors as demonstrated by Denisov andSligar The latter suggest that ldquofunctional cooperativityrdquo bestdescribes P450s fold that includes remote binding sites whichmay serve for the allosteric regulation of equilibrium andorkinetic functional properties including substrate binding andproduct dissociation stability of oxy-complex and autoxida-tion [203]

61 Quantitative Structure-Activity Relationship (QSAR)Didziapetris and coworkers developed a structure-activity

relationship model to predict the probability that a com-pound can inhibit human CYP3A4 based on data for morethan 800 compounds from various literature sources Theirmodel is based on GALAS methodology which involvesQSAR (quantitative structure-activity relationship) and localsimilarity-based corrections The findings of the GALASmodel revealed that increasing the size of themolecule via theincorporation of hydrophobic aliphatic or aromatic residuesenhances the ability of the compound to inhibit CYP3A4while a strong acidic or basic group in the molecule reducesits inhibition potential This model emphasizes the impor-tance of lipophilicity and the presence of hydrophobic groupson the inhibition potency of compounds which is consistentwith the phenylalanine residues already seen at the active site[123] An additional QSAR study based on five statistical toolsidentified a strong correlation between the n-octanolwaterpartition coefficient (log119875) and the binding affinity of com-pounds for CYP3A4 [124] In line with these findings a studyon the influence of lipophilicity on the interactions of hydrox-ystilbenes with CYP3A4 revealed that methoxy-stilbeneshad lower IC

50values and greater affinity for CYP3A4 as

compared to the parent resveratrol and its glucosides Theseresults support the hypothesized role of lipophilicity in theinteraction of polyphenols with CYP3A4 [38] Other QSARanalyses conducted by Lewis and coworkers rationalizedthe lipophilicity relationships in CYP3A4 inhibitors in termsof typical active-site interactions such as hydrogen bondingand 120587ndash120587 stacking whereas the multiple binding sites in theheme environment could lead to variation in gradients [204205]

Mao et al showed that the traditional QSAR modelapplied to one data set does not lead to predictive modelsthat would be useful for in silico filtering of chemical librariesand presents a multiple pharmacophore hypothesis (MPH)that is a conceptual extension of the conventional QSARapproach Their study was based on 2400 marketed drugsandmade use of pair-wise comparisons of IC

50activity values

for different substrates of CYP3A4 The substrates were thencharacterized according to the proximal and distal bindingrelative MPH provides us with structural insight into howmultiple substrates of CYP3A4may interact with the enzyme(eg the extent to which their binding sites may lie in closeproximity to one another or even overlap) [206]

7 Concluding Remarks

A number of studies in recent years have highlighted thepotential risk inherent in the uncontrolled use of herbalmedicines concurrent with conventional therapeutic regi-mens and emphasized the need for regulation in this fieldbased on a set of evaluation criteria [207ndash211] We proposehere that it is the polyphenols in the herbal preparations thatinteract with CYP3A4 modify the metabolism of xenobi-otics and drugs and consequently change the active dosesof prescribed medicines and the nature of the prescribedcompounds The abundance of polyphenols in many foodproducts the abundance of CYP3A4 in the intestine its broadranges of substratesinhibitors and cooperativity the poten-tial involvement of gut microbiota in polyphenol-CYP3A4


interactions and vice versa the extended exposure of theintestinal enzyme to polyphenol metabolites through theenterohepatic cycle and the short-term inhibition and long-term induction of CYP3A4 by some phenolic compounds allcontribute to the interest in the polyphenol-CYP3A4 inter-actions and their outcomes and underscore the need forfurther research in this area

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] I G Denisov T M Makris S G Sligar and I SchlichtingldquoStructure and chemistry of cytochrome P450rdquo ChemicalReviews vol 105 no 6 pp 2253ndash2277 2005

[2] T L Domanski Y A He K K Khan F Roussel Q Wang andJ R Halpert ldquoPhenylalanine and tryptophan scanning mutage-nesis of CYP3A4 substrate recognition site residues and effecton substrate oxidation and cooperativityrdquo Biochemistry vol 40no 34 pp 10150ndash10160 2001

[3] D W Nebert and D W Russell ldquoClinical importance of thecytochromes P450rdquoTheLancet vol 360 no 9340 pp 1155ndash11622002

[4] P RO deMontellanoCytochrome P450 StructureMechanismand Biochemistry Springer 3rd edition 2005

[5] D R Nelson ldquoThe cytochrome P450 homepagerdquo HumanGenomics vol 4 no 1 pp 59ndash65 2009

[6] D R Nelson ldquoA world of cytochrome P450srdquo Philosophicaltransactions of the Royal Society of London Series B BiologicalSciences vol 368 no 1612 Article ID 20120430 2013

[7] D W Nebert K Wikvall and W L Miller ldquoHuman cyto-chromes P450 in health and diseaserdquo Philosophical transactionsof the Royal Society of London Series B Biological sciences vol368 no 1612 Article ID 20120431 2013

[8] D W Nebert D R Nelson M J Coon et al ldquoThe P450superfamily update on new sequences gene mapping andrecommended nomenclaturerdquoDNAandCell Biology vol 10 no1 pp 1ndash14 1991

[9] U M Zanger and M Schwab ldquoCytochrome P450 enzymesin drug metabolism regulation of gene expression enzymeactivities and impact of genetic variationrdquo Pharmacology ampTherapeutics vol 138 no 1 pp 103ndash141 2013

[10] F P Guengerich ldquoCytochrome P450 and chemical toxicologyrdquoChemical Research in Toxicology vol 21 no 1 pp 70ndash83 2008

[11] S Ekins D M Stresser and J A Williams ldquoIn vitro andpharmacophore insights into CYP3A enzymesrdquo Trends in Phar-macological Sciences vol 24 no 4 pp 161ndash166 2003

[12] K S Lown D G Bailey R J Fontana et al ldquoGrapefruit juiceincreases felodipine oral availability in humans by decreasingintestinal CYP3A protein expressionrdquo The Journal of ClinicalInvestigation vol 99 no 10 pp 2545ndash2553 1997

[13] J C Kolars K S Lown P Schmiedlin-Ren et al ldquoCYP3A geneexpression in human gut epitheliumrdquo Pharmacogenetics andGenomics vol 4 no 5 pp 247ndash259 1994

[14] C S Ferguson andR F Tyndale ldquoCytochromeP450 enzymes inthe brain emerging evidence of biological significancerdquo Trendsin Pharmacological Sciences vol 32 no 12 pp 708ndash714 2011

[15] C Ghosh N Marchi N K Desai et al ldquoCellular localizationand functional significance of CYP3A4 in the human epilepticbrainrdquo Epilepsia vol 52 no 3 pp 562ndash571 2011

[16] F P Guengerich ldquoCytochrome P-450 3A4 regulation and rolein drug metabolismrdquo Annual Review of Pharmacology andToxicology vol 39 pp 1ndash17 1999

[17] Z Huang M J Fasco H L Figge K Keyomarsi and L SKaminsky ldquoExpression of cytochromes P450 in human breasttissue and tumorsrdquo Drug Metabolism and Disposition vol 24no 8 pp 899ndash905 1996

[18] J H Lin M Chiba and T A Baillie ldquoIs the role of the smallintestine in first-pass metabolism overemphasizedrdquo Pharma-cological Reviews vol 51 no 2 pp 135ndash158 1999

[19] M F Paine H L Hart S S Ludington R L Haining A ERettie and D C Zeldin ldquoThe human intestinal cytochromeP450 lsquopiersquordquo Drug Metabolism amp Disposition vol 34 no 5 pp880ndash886 2006

[20] A Galetin M Gertz and J B Houston ldquoContribution ofintestinal cytochrome P450-mediated metabolism to drug-drug inhibition and induction interactionsrdquo Drug Metabolismand Pharmacokinetics vol 25 no 1 pp 28ndash47 2010

[21] J Yang G T Tucker and A Rostami-Hodjegan ldquoCytochromeP450 3A expression and activity in the human small intestinerdquoClinical Pharmacology and Therapeutics vol 76 no 4 article391 2004

[22] M F Paine M Khalighi J M Fisher et al ldquoCharacterization ofinterintestinal and intraintestinal variations in human CYP3A-dependent metabolismrdquo Journal of Pharmacology and Experi-mental Therapeutics vol 283 no 3 pp 1552ndash1562 1997

[23] F H Karlsson S Bouchene C Hilgendorf H Dolgos and SA Peters ldquoUtility of in vitro systems and preclinical data forthe prediction of human intestinal first-passmetabolism duringdrug discovery and preclinical developmentrdquo Drug Metabolismand Disposition vol 41 no 12 pp 2033ndash2046 2013

[24] S Siissalo and A T Heikkinen ldquoIn vitro methods to studythe interplay of drug metabolism and efflux in the intestinerdquoCurrent Drug Metabolism vol 14 no 1 pp 102ndash111 2013

[25] M Gertz J D Davis A Harrison J B Houston andA GaletinldquoGrapefruit juice-drug interaction studies as a method to assessthe extent of intestinal availability utility and limitationsrdquoCurrent Drug Metabolism vol 9 no 8 pp 785ndash795 2008

[26] S D Hall K E Thummel P B Watkins et al ldquoMolecular andphysical mechanisms of first-pass extractionrdquoDrugMetabolismand Disposition vol 27 no 2 pp 161ndash166 1999

[27] D G Bailey G Dresser and J M O Arnold ldquoGrapefruit-medication interactions forbidden fruit or avoidable conse-quencesrdquo Canadian Medical Association Journal vol 185 no4 pp 309ndash316 2013

[28] M Gertz A Harrison J B Houston and A Galetin ldquoPredic-tion of human intestinal first-pass metabolism of 25 CYP3Asubstrates from in vitro clearance and permeability datardquo DrugMetabolism and Disposition vol 38 no 7 pp 1147ndash1158 2010

[29] J vanDuynhoven E E Vaughan DM Jacobs et al ldquoMetabolicfate of polyphenols in the human superorganismrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 108 no 1 pp 4531ndash4538 2011

[30] GWilliamson andMNClifford ldquoColonicmetabolites of berrypolyphenols the missing link to biological activityrdquo BritishJournal of Nutrition vol 104 supplement 3 pp S48ndashS66 2010

[31] L S Kaminsky and Q-Y Zhang ldquoThe small intestine as axenobiotic-metabolizing organrdquo Drug Metabolism and Disposi-tion vol 31 no 12 pp 1520ndash1525 2003


[32] MMartignoni G Groothuis andR deKanter ldquoComparison ofmouse and rat cytochrome P450-mediated metabolism in liverand intestinerdquo Drug Metabolism and Disposition vol 34 no 6pp 1047ndash1054 2006

[33] M Lindell M Lang and H Lennernas ldquoExpression of genesencoding for drugmetabolising cytochrome P450 enzymes andP-glycoprotein in the rat small intestine comparison to theliverrdquo European Journal of Drug Metabolism and Pharmacoki-netics vol 28 no 1 pp 41ndash48 2003

[34] X Cao S T Gibbs L Fang et al ldquoWhy is it challenging topredict intestinal drug absorption and oral bioavailability inhuman using rat modelrdquo Pharmaceutical Research vol 23 no8 pp 1675ndash1686 2006

[35] C Awortwe P S Fasinu and B Rosenkranz ldquoApplicationof Caco-2 cell line in herb-drug interaction studies currentapproaches and challengesrdquo Journal of Pharmacy and Pharma-ceutical Sciences vol 17 no 1 pp 1ndash19 2014

[36] N Holmstock F J Gonzalez M Baes P Annaert and PAugustijns ldquoPXRCYP3A4-humanizedmice for studying drug-drug interactions involving intestinal P-glycoproteinrdquo Molecu-lar Pharmaceutics vol 10 no 3 pp 1056ndash1062 2013

[37] K Schroer M Kittelmann and S Lutz ldquoRecombinant humancytochrome P450monooxygenases for drugmetabolite synthe-sisrdquo Biotechnology and Bioengineering vol 106 no 5 pp 699ndash706 2010

[38] G Regev-Shoshani O Shoseyov and Z Kerem ldquoInfluenceof lipophilicity on the interactions of hydroxy stilbenes withcytochrome P450 3A4rdquo Biochemical and Biophysical ResearchCommunications vol 323 no 2 pp 668ndash673 2004

[39] L Tang L Ye C Lv Z Zheng Y Gong and Z Liu ldquoInvolve-ment of CYP3A45 andCYP2D6 in themetabolism of aconitineusing human liver microsomes and recombinant CYP450enzymesrdquo Toxicology Letters vol 202 no 1 pp 47ndash54 2011

[40] Y V Grinkova I G Denisov M A McLean and S GSligar ldquoOxidase uncoupling in heme monooxygenases humancytochrome P450 CYP3A4 in Nanodiscsrdquo Biochemical andBiophysical Research Communications vol 430 no 4 pp 1223ndash1227 2013

[41] D Hamdane H Zhang and P Hollenberg ldquoOxygen activationby cytochrome P450monooxygenaserdquo Photosynthesis Researchvol 98 no 1ndash3 pp 657ndash666 2008

[42] B Meunier S P de Visser and S Shaik ldquoMechanism ofoxidation reactions catalyzed by cytochrome P450 enzymesrdquoChemical Reviews vol 104 no 9 pp 3947ndash3980 2004

[43] P R O de Montellano and J J de Voss ldquoSubstrate oxidation bycytochrome P450 enzymesrdquo in Cytochrome P450 pp 183ndash245Springer New York NY USA 3rd edition 2005

[44] S-F Zhou J-P Liu and B Chowbay ldquoPolymorphism ofhuman cytochrome P450 enzymes and its clinical impactrdquoDrugMetabolism Reviews vol 41 no 2 pp 89ndash295 2009

[45] M H Choi P L Skipper J S Wishnok and S R Tan-nenbaum ldquoCharacterization of testosterone 11120573-hydroxylationcatalyzed by human liver microsomal cytochromes P450rdquoDrugMetabolism and Disposition vol 33 no 6 pp 714ndash718 2005

[46] N Yasui-Furukori M Hidestrand E Spina G Facciola M GScordo and G Tybring ldquoDifferent enantioselective 9-hydrox-ylation of risperidone by the two human CYP2D6 and CYP3A4enzymesrdquo Drug Metabolism amp Disposition vol 29 no 10 pp1263ndash1268 2001

[47] Z Liu and M Hu ldquoNatural polyphenol disposition via coupledmetabolic pathwaysrdquo Expert Opinion on Drug Metabolism andToxicology vol 3 no 3 pp 389ndash406 2007

[48] C Manach J Hubert R Llorach and A Scalbert ldquoThe com-plex links between dietary phytochemicals and human healthdeciphered by metabolomicsrdquo Molecular Nutrition and FoodResearch vol 53 no 10 pp 1303ndash1315 2009

[49] M P Corcoran D L McKay and J B Blumberg ldquoFlavonoidbasics chemistry sources mechanisms of action and safetyrdquoJournal of Nutrition in Gerontology and Geriatrics vol 31 no 3pp 176ndash189 2012

[50] G F Ferrazzano I Amato A Ingenito A Zarrelli G Pinto andA Pollio ldquoPlant polyphenols and their anti-cariogenic proper-ties a reviewrdquoMolecules vol 16 no 2 pp 1486ndash1507 2011

[51] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000

[52] J D Lambert S Sang and C S Yang ldquoBiotransformationof green tea polyphenols and the biological activities of thosemetabolitesrdquo Molecular Pharmaceutics vol 4 no 6 pp 819ndash825 2007

[53] J D Lambert S Sang and C S Yang ldquoPossible controversyover dietary polyphenols benefits vs risksrdquo Chemical Researchin Toxicology vol 20 no 4 pp 583ndash585 2007

[54] S Wanwimolruk and V Prachayasittikul ldquoCytochrome P450enzyme mediated herbal drug interactions (part 1)rdquo EXCLIJournal vol 13 pp 347ndash391 2014

[55] K E Heim A R Tagliaferro and D J Bobilya ldquoFlavonoidantioxidants chemistry metabolism and structure-activityrelationshipsrdquo Journal of Nutritional Biochemistry vol 13 no10 pp 572ndash584 2002

[56] I Rodeiro M T Donato A Lahoz G Garrido R Delgadoand M J Gomez-Lechon ldquoInteractions of polyphenols withthe P450 system possible implications on human therapeuticsrdquoMini-Reviews in Medicinal Chemistry vol 8 no 2 pp 97ndash1062008

[57] L M Blanco-Colio M Valderrama L A Alvarez-Sala et alldquoRed wine intake prevents nuclear factor-120581B activation inperipheral blood mononuclear cells of healthy volunteers dur-ing postprandial lipemiardquo Circulation vol 102 no 9 pp 1020ndash1026 2000

[58] L Hooper P A Kroon E B Rimm et al ldquoFlavonoids flavon-oid-rich foods and cardiovascular risk a meta-analysis ofrandomized controlled trialsrdquoThe American Journal of ClinicalNutrition vol 88 no 1 pp 38ndash50 2008

[59] J P E Spencer ldquoFlavonoids and brain health multiple effectsunderpinned by common mechanismsrdquo Genes and Nutritionvol 4 no 4 pp 243ndash250 2009

[60] Y J Surh ldquoCancer chemoprevention with dietary phytochemi-calsrdquo Nature Reviews Cancer vol 3 no 10 pp 768ndash780 2003

[61] L Rodrıguez-Fragoso J L Martınez-Arismendi D Orozco-Bustos J Reyes-Esparza E Torres and S W Burchiel ldquoPoten-tial risks resulting from fruitvegetable-drug interactionseffects on drug-metabolizing enzymes and drug transportersrdquoJournal of Food Science vol 76 no 4 pp R112ndashR124 2011

[62] L Korkina C De Luca and S Pastore ldquoPlant polyphenols andhuman skin friends or foesrdquo Annals of the New York Academyof Sciences vol 1259 no 1 pp 77ndash86 2012

[63] Y D Muthiah C E Ong S A Sulaiman S C Tan and RIsmail ldquoIn-vitro inhibitory effect of Tualang honey on cyto-chrome P450 2C8 activityrdquo Journal of Pharmacy and Pharma-cology vol 64 no 12 pp 1761ndash1769 2012


[64] D Schwarz P KisselevW-H Schunck and I Roots ldquoInhibitionof 17120573-estradiol activation by CYP1A1 genotype- and regiose-lective inhibition by St JohnrsquosWort and several natural polyphe-nolsrdquo Biochimica et Biophysica ActamdashProteins and Proteomicsvol 1814 no 1 pp 168ndash174 2011

[65] J M Lillywhite J E Simonsen and V Wilson ldquoGrowingChinese medicinal herbs in the United States understandingpractitioner preferencesrdquo Agriculture and Human Values vol29 no 2 pp 151ndash159 2012

[66] A Jain R Sharma N Gahalain J Chaudary and G K GuptaldquoHerbal plants used in diabetic complications an overviewrdquoJournal of Pharmacy Research vol 4 no 4 pp 986ndash988 2011

[67] S Zhou Y Gao W Jiang M Huang A Xu and J W PaxtonldquoInteractions of herbs with cytochrome P450rdquoDrugMetabolismReviews vol 35 no 1 pp 35ndash98 2003

[68] A A Izzo ldquoHerb-drug interactions an overview of the clinicalevidencerdquo Fundamental and Clinical Pharmacology vol 19 no1 pp 1ndash16 2005

[69] P H Marathe and A D Rodrigues ldquoIn vivo animal models forinvestigating potential CYP3A- and Pgp-mediated drug-druginteractionsrdquo Current Drug Metabolism vol 7 no 7 pp 687ndash704 2006

[70] T L Poulos ldquoCytochrome P450 dynamicsrdquo in Fifty Years ofCytochrome P450 Research pp 75ndash94 Springer Tokyo Japan2014

[71] A R Topletz J B Dennison R J Barbuch C E HaddenS D Hall and J L Renbarger ldquoThe relative contributions ofCYP3A4 and CYP3A5 to the metabolism of vinorelbinerdquo DrugMetabolism amp Disposition vol 41 no 9 pp 1651ndash1661 2013

[72] S J Brantley A A Argikar Y S Lin S Nagar and M FPaine ldquoHerb-drug interactions challenges and opportunitiesfor improved predictionsrdquo Drug Metabolism and Dispositionvol 42 no 3 pp 301ndash317 2014

[73] Y Kimura H Ito R Ohnishi and T Hatano ldquoInhibitory effectsof polyphenols on human cytochrome P450 3A4 and 2C9activityrdquo Food and Chemical Toxicology vol 48 no 1 pp 429ndash435 2010

[74] I RodeiroM TDonato N Jimenez et al ldquoInhibition of humanP450 enzymes by natural extracts used in traditional medicinerdquoPhytotherapy Research vol 23 no 2 pp 279ndash282 2009

[75] R ZHarris G R Jang and S Tsunoda ldquoDietary effects on drugmetabolism and transportrdquo Clinical Pharmacokinetics vol 42no 13 pp 1071ndash1088 2003

[76] D G Bailey J Malcolm O Arnold and J D Spence ldquoGrape-fruit juice-drug interactionsrdquoBritish Journal of Clinical Pharma-cology vol 46 no 2 pp 101ndash110 1998

[77] Y-M Ku D I Min and M Flanigan ldquoEffect of grapefruitjuice on the pharmacokinetics of microemulsion cyclosporineand its metabolite in healthy volunteers does the formulationdifferencematterrdquo Journal of Clinical Pharmacology vol 38 no10 pp 959ndash965 1998

[78] D IMin Y-M Ku P J Perry et al ldquoEffect of grapefruit juice oncyclosporine pharmacokinetics in renal transplant patients1rdquoTransplantation vol 62 no 1 pp 123ndash125 1996

[79] J S Markowitz J L Donovan C L deVane et al ldquoEffect of StJohnrsquos Wort on drug metabolism by induction of cytochromeP450 3A4 enzymerdquo Journal of the AmericanMedical Associationvol 290 no 11 pp 1500ndash1504 2003

[80] G W Barone B J Gurley B L Ketel M L Lightfoot andS R Abul-Ezz ldquoDrug interaction between St Johnrsquos wort andcyclosporinerdquo Annals of Pharmacotherapy vol 34 no 9 pp1013ndash1016 2000

[81] H-H S Chow L L Garland C-H Hsu et al ldquoResveratrolmodulates drug- and carcinogen-metabolizing enzymes in ahealthy volunteer studyrdquo Cancer Prevention Research vol 3 no9 pp 1168ndash1175 2010

[82] S F Zhou C C Xue X Q Yu C Li and G Wang ldquoClinicallyimportant drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role oftherapeutic drug monitoringrdquo Therapeutic Drug Monitoringvol 29 no 6 pp 687ndash710 2007

[83] X-W Chen K B Sneed S-Y Pan et al ldquoHerb-drug inter-actions and mechanistic and clinical considerationsrdquo CurrentDrug Metabolism vol 13 no 5 pp 640ndash651 2012

[84] F Qiu J Jiang Y Ma et al ldquoOpposite effects of single-dose andmultidose administration of the ethanol extract of danshen onCYP3A in healthy volunteersrdquo Evidence-Based Complementaryand Alternative Medicine vol 2013 Article ID 730734 8 pages2013

[85] R Rahimi and M Abdollahi ldquoAn update on the ability of StJohnrsquos wort to affect the metabolism of other drugsrdquo ExpertOpinion on Drug Metabolism and Toxicology vol 8 no 6 pp691ndash708 2012

[86] H G Xie and R B Kim ldquoSt Johnrsquos wort-associated druginteractions Short-term inhibition and long-term inductionrdquoClinical Pharmacology amp Therapeutics vol 78 no 1 pp 19ndash242005

[87] J Patel B Buddha S Dey D Pal and A K Mitra ldquoIn vitrointeraction of the HIV protease inhibitor ritonavir with herbalconstituents changes in P-gp and CYP3A4 activityrdquoThe Amer-ican Journal of Therapeutics vol 11 no 4 pp 262ndash277 2004

[88] T M Vijayakumar R M Kumar A Agrawal G P Dubey andK Ilango ldquoComparative inhibitory potential of selected dietarybioactive polyphenols phytosterols on CYP3A4 and CYP2D6with fluorometric high-throughput screeningrdquo Journal of FoodScience and Technology 2014

[89] S J Brantley T N Graf N H Oberlies and M F Paine ldquoAsystematic approach to evaluate herb-drug interaction mecha-nisms investigation of milk thistle extracts and eight isolatedconstituents as CYP3A inhibitorsrdquo Drug Metabolism and Dis-position vol 41 no 9 pp 1662ndash1670 2013

[90] I Rodeiro M J Gomez-Lechon G Perez et al ldquoMangiferaindica L extract and mangiferin modulate cytochrome P450andUDP-glucuronosyltransferase enzymes in primary culturesof human hepatocytesrdquo Phytotherapy Research vol 27 no 5 pp745ndash752 2013

[91] J I Boullata ldquoDrug and nutrition interactions not just food forthoughtrdquo Journal of Clinical Pharmacy andTherapeutics vol 38no 4 pp 269ndash271 2013

[92] O A Fahmi T SMaurerM Kish E Cardenas S Boldt andDNettleton ldquoA combined model for predicting CYP3A4 clinicalnet drug-drug interaction based on CYP3a4 inhibition inac-tivation and induction determined in vitrordquo Drug Metabolismand Disposition vol 36 no 8 pp 1698ndash1708 2008

[93] Y-H Wang D R Jones and S D Hall ldquoPrediction of cyto-chrome P450 3A inhibition by verapamil enantiomers and theirmetabolitesrdquoDrugMetabolism andDisposition vol 32 no 2 pp259ndash266 2004

[94] J A Ross and CM Kasum ldquoDietary flavonoids bioavailabilitymetabolic effects and safetyrdquo Annual Review of Nutrition vol22 pp 19ndash34 2002

[95] A Scalbert I T Johnson and M Saltmarsh ldquoPolyphenolsantioxidants and beyondrdquo The American Journal of ClinicalNutrition vol 81 no 1 pp 215Sndash217S 2005


[96] P Chabert C Auger J Pincemail and V B Schini-KerthldquoOverview of plant-derived antioxidantsrdquo in Systems Biology ofFree Radicals andAntioxidants pp 4005ndash4022 Springer BerlinGermany 2014

[97] J Perez-JimenezM E Dıaz-Rubio and F Saura-Calixto ldquoNon-extractable polyphenols a major dietary antioxidant occur-rence metabolic fate and health effectsrdquo Nutrition ResearchReviews vol 26 no 2 pp 118ndash129 2013

[98] M-L Ovaskainen R Torronen J M Koponen et al ldquoDietaryintake andmajor food sources of polyphenols in Finnish adultsrdquoJournal of Nutrition vol 138 no 3 pp 562ndash566 2008

[99] NNThuC SakuraiHUto et al ldquoThepolyphenol content andantioxidant activities of the main edible vegetables in NorthernVietnamrdquo Journal of Nutritional Science and Vitaminology vol50 no 3 pp 203ndash210 2004

[100] F Saura-Calixto J Serrano and I Goni ldquoIntake and bioaccessi-bility of total polyphenols in a whole dietrdquo Food Chemistry vol101 no 2 pp 492ndash501 2007

[101] J Kanner and T Lapidot ldquoThe stomach as a bioreactor dietarylipid peroxidation in the gastric fluid and the effects of plant-derived antioxidantsrdquo Free Radical Biology amp Medicine vol 31no 11 pp 1388ndash1395 2001

[102] Z Kerem D Chetrit O Shoseyov and G Regev-ShoshanildquoProtection of lipids from oxidation by epicatechin trans-resveratrol and gallic and caffeic acids in intestinal modelsystemsrdquo Journal of Agricultural and Food Chemistry vol 54no 26 pp 10288ndash10293 2006

[103] C J Dufresne and E R Farnworth ldquoA review of latest researchfindings on the health promotion properties of teardquo Journal ofNutritional Biochemistry vol 12 no 7 pp 404ndash421 2001

[104] F Shahidi and Y Zhong ldquoNovel antioxidants in food qualitypreservation and health promotionrdquo European Journal of LipidScience and Technology vol 112 no 9 pp 930ndash940 2010

[105] N Khan and H Mukhtar ldquoCancer and metastasis preventionand treatment by green teardquoCancer andMetastasis Reviews vol29 no 3 pp 435ndash445 2010

[106] B B Aggarwal and S Shishodia ldquoMolecular targets of dietaryagents for prevention and therapy of cancerrdquo BiochemicalPharmacology vol 71 no 10 pp 1397ndash1421 2006

[107] G Garrido D Gonzalez Y Lemus et al ldquoIn vivo and invitro anti-inflammatory activity of Mangifera indica L extract(VIMANG)rdquo Pharmacological Research vol 50 no 2 pp 143ndash149 2004

[108] S N Nichenametla T G Taruscio D L Barney and J H ExonldquoA review of the effects and mechanisms of polyphenolics incancerrdquo Critical Reviews in Food Science and Nutrition vol 46no 2 pp 161ndash183 2006

[109] N T Zaveri ldquoGreen tea and its polyphenolic catechins medic-inal uses in cancer and noncancer applicationsrdquo Life Sciencesvol 78 no 18 pp 2073ndash2080 2006

[110] N Kalogeropoulos K Yannakopoulou A Gioxari A Chiouand D P Makris ldquoPolyphenol characterization and encap-sulation in 120573-cyclodextrin of a flavonoid-rich Hypericumperforatum (St Johnrsquos wort) extractrdquo LWTmdashFood Science andTechnology vol 43 no 6 pp 882ndash889 2010

[111] H J Lee H-S Lee H J Cho S Y Kim and H J Suh ldquoUtiliza-tion of hydrolytic enzymes for the extraction of ginsenosidesfrom Korean ginseng leavesrdquo Process Biochemistry vol 47 no3 pp 538ndash543 2012

[112] M Maizura A Aminah and W M W Aida ldquoTotal phenoliccontent and antioxidant activity of kesum (Polygonum minus)

ginger (Zingiber officinale) and turmeric (Curcuma longa)extractrdquo International Food Research Journal vol 18 no 2 pp529ndash534 2011

[113] B Jiang F KronenbergM J Balick andE J Kennelly ldquoStabilityof black cohosh triterpene glycosides and polyphenols poten-tial clinical relevancerdquo Phytomedicine vol 20 no 6 pp 564ndash569 2013

[114] S S Georgieva V L Christova-Bagdassarian and M SAtanassova ldquoComparative evaluation of the polyphenol com-position and antioxidant capacity of propolis and Echinaceapurpureardquo Journal of Experimental and IntegrativeMedicine vol4 no 1 pp 51ndash56 2014

[115] F F Anhe D Roy G Pilon et al ldquoA polyphenol-rich cranberryextract protects from diet-induced obesity insulin resistanceand intestinal inflammation in association with increasedAkkermansia spp population in the gut microbiota of micerdquoGut 2014

[116] A R Rechner G Kuhnle P Bremner G P Hubbard K PMoore and C A Rice-Evans ldquoThe metabolic fate of dietarypolyphenols in humansrdquo Free Radical Biology andMedicine vol33 no 2 pp 220ndash235 2002

[117] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998

[118] H Doostdar M D Burke and R T Mayer ldquoBioflavonoidsselective substrates and inhibitors for cytochrome P450 CYP1Aand CYP1B1rdquo Toxicology vol 144 no 1ndash3 pp 31ndash38 2000

[119] C Rice-Evans ldquoFlavonoid antioxidantsrdquo Current MedicinalChemistry vol 8 no 7 pp 797ndash807 2001

[120] P Jancova E Anzenbacherova B Papouskova et al ldquoSily-bin is metabolized by cytochrome P450 2C8 in vitrordquo DrugMetabolism amp Disposition vol 35 no 11 pp 2035ndash2039 2007

[121] C S Yang and E Pan ldquoThe effects of green tea polyphenolson drug metabolismrdquo Expert Opinion on Drug Metabolism andToxicology vol 8 no 6 pp 677ndash689 2012

[122] S Sang J D Lambert C-T Ho and C S Yang ldquoThe chemistryand biotransformation of tea constituentsrdquo PharmacologicalResearch vol 64 no 2 pp 87ndash99 2011

[123] R Didziapetris J Dapkunas A Sazonovas and P JapertasldquoTrainable structure-activity relationship model for virtualscreening of CYP3A4 inhibitionrdquo Journal of Computer-AidedMolecular Design vol 24 no 11 pp 891ndash906 2010

[124] K Roy and P P Roy ldquoQSAR of cytochrome inhibitorsrdquo ExpertOpinion on Drug Metabolism and Toxicology vol 5 no 10 pp1245ndash1266 2009

[125] S Misaka K Kawabe S Onoue et al ldquoGreen tea extractaffects the cytochrome P450 3A activity and pharmacokineticsof simvastatin in ratsrdquo Drug Metabolism and Pharmacokineticsvol 28 no 6 pp 514ndash518 2013

[126] M Nishikawa N Ariyoshi A Kotani et al ldquoEffects of con-tinuous ingestion of green tea or grape seed extracts on thepharmacokinetics of midazolamrdquo Drug Metabolism and Phar-macokinetics vol 19 no 4 pp 280ndash289 2004

[127] A Amri J C Chaumeil S Sfar andC Charrueau ldquoAdministra-tion of resveratrol what formulation solutions to bioavailabilitylimitationsrdquo Journal of Controlled Release vol 158 no 2 pp182ndash193 2012

[128] T Walle ldquoBioavailability of resveratrolrdquo Annals of the New YorkAcademy of Sciences vol 1215 no 1 pp 9ndash15 2011

[129] J-F Marier P Vachon A Gritsas J Zhang J-P Moreau andM P Ducharme ldquoMetabolism and disposition of resveratrol in


rats extent of absorption glucuronidation and enterohepaticrecirculation evidenced by a linked-rat modelrdquo Journal ofPharmacology and ExperimentalTherapeutics vol 302 no 1 pp369ndash373 2002

[130] G Singh and R S Pai ldquoIn-vitroin-vivo characterization oftrans-resveratrol-loaded nanoparticulate drug delivery systemfor oral administrationrdquo Journal of Pharmacy and Pharmacol-ogy vol 66 no 8 pp 1062ndash1076 2014

[131] K B Seljak K Berginc J Trontelj A Zvonar A Kristl andM Gasperlin ldquoA self-microemulsifying drug delivery systemto overcome intestinal resveratrol toxicity and presystemicmetabolismrdquo Journal of Pharmaceutical Sciences vol 103 no 11pp 3491ndash3500 2014

[132] S G Parkar TM Trower andD E Stevenson ldquoFecalmicrobialmetabolism of polyphenols and its effects on human gutmicrobiotardquo Anaerobe vol 23 pp 12ndash19 2013

[133] S G Parkar D E Stevenson andM A Skinner ldquoThe potentialinfluence of fruit polyphenols on colonicmicroflora and humangut healthrdquo International Journal of Food Microbiology vol 124no 3 pp 295ndash298 2008

[134] S Bolca T van de Wiele and S Possemiers ldquoGut metabotypesgovern health effects of dietary polyphenolsrdquo Current Opinionin Biotechnology vol 24 no 2 pp 220ndash225 2013

[135] C Morand C Dubray D Milenkovic et al ldquoHesperidincontributes to the vascular protective effects of orange juice arandomized crossover study in healthy volunteersrdquoThe Ameri-can Journal of Clinical Nutrition vol 93 no 1 pp 73ndash80 2011

[136] J W Lampe ldquoInterindividual differences in response to plant-based diets implications for cancer riskrdquoThe American Journalof Clinical Nutrition vol 89 no 5 pp 1553Sndash1557S 2009

[137] S Stoupi G Williamson J W Drynan D Barron and M NClifford ldquoA comparison of the in vitro biotransformation of(-)-epicatechin and procyanidin B2 by human faecal micro-biotardquoMolecular Nutrition and Food Research vol 54 no 6 pp747ndash759 2010

[138] G K Dresser J D Spence and D G Bailey ldquoPharmacokinetic-pharmacodynamic consequences and clinical relevance ofcytochrome P450 3A4 inhibitionrdquo Clinical Pharmacokineticsvol 38 no 1 pp 41ndash57 2000

[139] S Muto K-I Fujita Y Yamazaki and T Kamataki ldquoInhibitionby green tea catechins of metabolic activation of procar-cinogens by human cytochrome P450rdquo Mutation ResearchmdashFundamental and Molecular Mechanisms of Mutagenesis vol479 no 1-2 pp 197ndash206 2001

[140] C R Wolf ldquoChemoprevention increased potential to bearfruitrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 6 pp 2941ndash2943 2001

[141] S Parys S Kehraus A Krick et al ldquoIn vitro chemopreven-tive potential of fucophlorethols from the brown alga Fucusvesiculosus L by anti-oxidant activity and inhibition of selectedcytochrome P450 enzymesrdquo Phytochemistry vol 71 no 2-3 pp221ndash229 2010

[142] M Athar J H Back X Tang et al ldquoResveratrol a review ofpreclinical studies for human cancer preventionrdquo Toxicologyand Applied Pharmacology vol 224 no 3 pp 274ndash283 2007

[143] K Sahu A A Siddiqui M Shaharyar and S Malik ldquoPhar-macokinetic interaction between febuxostat and morin in ratsrdquoExpert Opinion on Drug Metabolism and Toxicology vol 10 no3 pp 307ndash312 2014

[144] K K Kumar L Priyanka K Gnananath P R Babu and SSujatha ldquoPharmacokinetic drug interactions between apigenin

rutin and paclitaxel mediated by P-glycoprotein in ratsrdquo Euro-pean Journal of Drug Metabolism and Pharmacokinetics 2014

[145] A Ferreira S Pousinho A Fortuna A Falcao and G AlvesldquoFlavonoid compounds as reversal agents of the P-glycoprotein-mediatedmultidrug resistance biology chemistry and pharma-cologyrdquo Phytochemistry Reviews 2014

[146] B T Gufford G Chen P Lazarus T N Graf N H Oberliesand M F Paine ldquoIdentification of diet-derived constituentsas potent inhibitors of intestinal glucuronidationrdquo DrugMetabolism amp Disposition vol 42 no 10 pp 1675ndash1683 2014

[147] X F Koe T S TMuhammad A S C Chong H AbdulWahaband M L Tan ldquoCytochrome P450 induction properties of foodand herbal-derived compounds using a novel multiplex RT-qPCR in vitro assay a drug-food interaction prediction toolrdquoFood Science amp Nutrition vol 2 no 5 pp 500ndash520 2014

[148] T Shimada K Tanaka S Takenaka et al ldquoStructure-functionrelationships of inhibition of human cytochromes P450 1A11A2 1B1 2C9 and 3A4 by 33 flavonoid derivativesrdquo ChemicalResearch in Toxicology vol 23 no 12 pp 1921ndash1935 2010

[149] M A Sarkar G Scambia F O Ranelletti et al ldquoQuercetinnot only inhibits P-glycoprotein efflux activity but also inhibitsCYP3A isozymesrdquo Cancer Chemotherapy and Pharmacologyvol 36 no 5 pp 448ndash449 1995

[150] J-S Choi Y-J Piao and K W Kang ldquoEffects of quercetin onthe bioavailability of doxorubicin in rats role of CYP3A4 andP-gp inhibition by quercetinrdquo Archives of Pharmacal Researchvol 34 no 4 pp 607ndash613 2011

[151] C-P Yu P-P Wu Y-C Hou et al ldquoQuercetin and rutinreduced the bioavailability of cyclosporine from Neoral animmunosuppressant through activating P-glycoprotein andCYP 3A4rdquo Journal of Agricultural and Food Chemistry vol 59no 9 pp 4644ndash4648 2011

[152] J Rashid C McKinstry A G Renwick M Dirnhuber D GWaller and C F George ldquoQuercetin an in vitro inhibitorof CYP3A does not contribute to the interaction betweennifedipine and grapefruit juicerdquo British Journal of ClinicalPharmacology vol 36 no 5 pp 460ndash463 1993

[153] J L Raucy ldquoRegulation of CYP3A4 expression in humanhepatocytes by pharmaceuticals and natural productsrdquo DrugMetabolism and Disposition vol 31 no 5 pp 533ndash539 2003

[154] W C Lau T D Welch T Shields M Rubenfire U S Tantryand P A Gurbel ldquoThe effect of St JohnrsquosWort on the pharmaco-dynamic response of clopidogrel in hyporesponsive volunteersand patients increased platelet inhibition by enhancement ofCYP3A4metabolic activityrdquo Journal of Cardiovascular Pharma-cology vol 57 no 1 pp 86ndash93 2011

[155] A Kamel and S Harriman ldquoInhibition of cytochrome P450enzymes and biochemical aspects of mechanism-based inacti-vation (MBI)rdquo Drug Discovery Today Technologies vol 10 no1 pp e177ndashe189 2013

[156] L Quintieri P Palatini A Nassi P Ruzza and M Flore-ani ldquoFlavonoids diosmetin and luteolin inhibit midazolammetabolism by human liver microsomes and recombinant CYP3A4 and CYP3A5 enzymesrdquo Biochemical Pharmacology vol 75no 6 pp 1426ndash1437 2008

[157] E V Sineva J A O Rumfeldt J R Halpert and D R DavydovldquoA large-scale allosteric transition in cytochrome P450 3A4revealed by luminescence resonance energy transfer (LRET)rdquoPLoS ONE vol 8 no 12 Article ID e83898 2013

[158] D R Davydov N Y Davydova E V Sineva I Kufareva and JR Halpert ldquoPivotal role of P450-P450 interactions in CYP3A4


allostery the case of 120572-naphthoflavonerdquo Biochemical Journalvol 453 no 2 pp 219ndash230 2013

[159] D R Davydov J A O Rumfeldt E V Sineva H Fernando NY Davydova and J R Halpert ldquoPeripheral ligand-binding sitein cytochrome P450 3A4 located with fluorescence resonanceenergy transfer (FRET)rdquo Journal of Biological Chemistry vol287 no 9 pp 6797ndash6809 2012

[160] D J Frank I G Denisov and S G Sligar ldquoAnalysis ofheterotropic cooperativity in cytochrome P450 3A4 using 120572-naphthoflavone and testosteronerdquo Journal of Biological Chem-istry vol 286 no 7 pp 5540ndash5545 2011

[161] A G Roberts and W M Atkins ldquoEnergetics of heterotropiccooperativity between120572-naphthoflavone and testosterone bind-ing to CYP3A4rdquo Archives of Biochemistry and Biophysics vol463 no 1 pp 89ndash101 2007

[162] M I Netsch H Gutmann C B Schmidlin C Aydogan andJ Drewe ldquoInduction of CYP1A by green tea extract in humanintestinal cell linesrdquo Planta Medica vol 72 no 6 pp 514ndash5202006

[163] D G Bailey J M O Arnold and J D Spence ldquoGrapefruit juiceand drugs How significant is the interactionrdquoClinical Pharma-cokinetics vol 26 no 2 pp 91ndash98 1994

[164] U Fuhr and A L Kummert ldquoThe fata of naringin in humans akey to grapefruit juice-drug interactionsrdquo Clinical Pharmacol-ogy andTherapeutics vol 58 no 4 pp 365ndash373 1995

[165] P-C Ho D J Saville and S Wanwimolruk ldquoInhibitionof human CYP3A4 activity by grapefruit flavonoids fura-nocoumarins and related compoundsrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 4 no 3 pp 217ndash227 2001

[166] K Iwanaga M Hayashi Y Hamahata et al ldquoFuranocoumarinderivatives in Kampo extract medicines inhibit cytochromeP450 3A4 and P-glycoproteinrdquo Drug Metabolism and Disposi-tion vol 38 no 8 pp 1286ndash1294 2010

[167] K M VanderMolen G R Ainslie M F Paine and N HOberlies ldquoLabeled content of two furanocoumarins in dietarysupplements correlates with neither actual content nor CYP3Ainhibitory activityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 98 pp 260ndash265 2014

[168] Y-F Ueng C-C Chen H Yamazaki et al ldquoMechanism-basedinhibition of CYP1A1 and CYP3A4 by the furanocoumarinchalepensinrdquo Drug Metabolism and Pharmacokinetics vol 28no 3 pp 229ndash238 2013

[169] B C Foster S Vandenhoek J Hana et al ldquoIn vitro inhibitionof human cytochrome P450-mediated metabolism of markersubstrates by natural productsrdquo Phytomedicine vol 10 no 4 pp334ndash342 2003

[170] E S Roberts-Kirchhoff J R Crowley P F Hollenberg and HKim ldquoMetabolism of genistein by rat and human cytochromeP450srdquo Chemical Research in Toxicology vol 12 no 7 pp 610ndash616 1999

[171] L M Scott P Durant S Leone-Kabler et al ldquoEffects ofprior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymesrdquo Journal of SteroidBiochemistry and Molecular Biology vol 112 no 4-5 pp 179ndash185 2008

[172] C-Q Xiao R Chen J Lin et al ldquoEffect of genistein on theactivities of cytochrome P450 3A and P-glycoprotein inChinesehealthy participantsrdquo Xenobiotica vol 42 no 2 pp 173ndash1782012

[173] Y Chen C-Q Xiao Y-J He et al ldquoGenistein alters caffeineexposure in healthy female volunteersrdquo European Journal ofClinical Pharmacology vol 67 no 4 pp 347ndash353 2011

[174] A Dreiseitel P Schreier A Oehme S Locher G Hajak andP G Sand ldquoAnthocyanins and their metabolites are weakinhibitors of cytochrome P450 3A4rdquo Molecular Nutrition andFood Research vol 52 no 12 pp 1428ndash1433 2008

[175] W K Chan and A B Delucchi ldquoResveratrol a red wineconstituent is a mechanism-based inactivator of cytochromeP450 3A4rdquo Life Sciences vol 67 no 25 pp 3103ndash3112 2000

[176] B Piver F Berthou Y Dreano and D Lucas ldquoInhibition ofCYP3A CYP1A and CYP2E1 activities by resveratrol and othernon volatile red wine componentsrdquo Toxicology Letters vol 125no 1ndash3 pp 83ndash91 2001

[177] S-P Hong D-H Choi and J-S Choi ldquoEffects of resveratrolon the pharmacokinetics of diltiazem and its major metabolitedesacetyldiltiazem in ratsrdquo Cardiovascular Therapeutics vol26 no 4 pp 269ndash275 2008

[178] Y C Chi S P Lin and Y C Hou ldquoA new herb-drug interactionof Polygonum cuspidatum a resveratrol-rich nutraceuticalwith carbamazepine in ratsrdquo Toxicology and Applied Pharma-cology vol 263 no 3 pp 315ndash322 2012

[179] P Detampel M Beck S Krahenbuhl and J Huwyler ldquoDruginteraction potential of resveratrolrdquo Drug Metabolism Reviewsvol 44 no 3 pp 253ndash265 2012

[180] M A Correia and P R O de Montellano ldquoInhibition of cyto-chrome P450 enzymesrdquo in Cytochrome P450 pp 247ndash322Springer Berlin Germany 3rd edition 2005

[181] Y Sahali-Sahly S K Balani J H Lin and T A Baillie ldquoInvitro studies on the metabolic activation of the furanopyridineL- 754394 a highly potent and selective mechanism-basedinhibitor of cytochrome P450 3A4rdquo Chemical Research inToxicology vol 9 no 6 pp 1007ndash1012 1996

[182] H Iwata Y Tezuka S Kadota A Hiratsuka and T WatabeldquoIdentification and characterization of potent CYP3A4inhibitors in Schisandra fruit extractrdquo Drug Metabolism andDisposition vol 32 no 12 pp 1351ndash1358 2004

[183] R Venkataramanan V Ramachandran B J Komoroski SZhang P L Schiff and S C Strom ldquoMilk thistle a herbalsupplement decreases the activity of CYP3A4 and uridinediphosphoglucuronosyl transferase in human hepatocyte cul-turesrdquo Drug Metabolism and Disposition vol 28 no 11 pp1270ndash1273 2000

[184] R Zuber M Modriansky Z Dvorak et al ldquoEffect of silybinand its congeners on human livermicrosomal cytochrome P450activitiesrdquo Phytotherapy Research vol 16 no 7 pp 632ndash6382002

[185] H-T Yao Y-W Chang S-J Lan and T-K Yeh ldquoThe inhibitoryeffect of tannic acid on cytochrome P450 enzymes andNADPH-CYP reductase in rat and human liver microsomesrdquoFood and Chemical Toxicology vol 46 no 2 pp 645ndash653 2008

[186] C Jaikang K Niwatananun P Narongchai S Narongchai andC Chaiyasut ldquoInhibitory effect of caffeic acid and its derivativeson human liver cytochrome P450 3A4 activityrdquo Journal ofMedicinal Plants Research vol 5 no 15 pp 3530ndash3536 2011

[187] I Stupans G Stretch and P Hayball ldquoOlive oil phenols inhibithuman hepatic microsomal activityrdquo Journal of Nutrition vol130 no 9 pp 2367ndash2370 2000

[188] I Stupans H-W Tan A Kirlich K Tuck P Hayball and MMurray ldquoInhibition of CYP3A-mediated oxidation in humanhepatic microsomes by the dietary derived complex phenolgallic acidrdquo Journal of Pharmacy and Pharmacology vol 54 no2 pp 269ndash275 2002

[189] J K Yano M R Wester G A Schoch K J Griffin C DStout and E F Johnson ldquoThe structure of human microsomal


cytochrome P450 3A4 determined by X-ray crystallography to205-A resolutionrdquoThe Journal of Biological Chemistry vol 279no 37 pp 38091ndash38094 2004

[190] P A Williams J Cosme D M Vinkovic et al ldquoCrystal struc-tures of human cytochrome P450 3A4 bound to metyraponeand progesteronerdquo Science vol 305 no 5684 pp 683ndash6862004

[191] J Sridhar J Liu M Foroozesh and C L K Stevens ldquoInsightson cytochrome P450 enzymes and inhibitors obtained throughQSAR studiesrdquoMolecules vol 17 no 8 pp 9283ndash9305 2012

[192] D F V Lewis and B G Lake ldquoMolecular modelling and quan-titative structure-activity relationship studies on the interactionof omeprazole with cytochrome P450 isozymesrdquo Toxicologyvol 125 no 1 pp 31ndash44 1998

[193] S Ekins G Bravi J H Wikel and S A Wrighton ldquoThree-dimensional-quantitative structure activity relationship analy-sis of cytochrome P-450 3A4 substratesrdquo Journal of Pharmacol-ogy and Experimental Therapeutics vol 291 no 1 pp 424ndash4331999

[194] S Ekins M J de Groot and J P Jones ldquoPharmacophore andthree-dimensional quantitative structure activity relationshipmethods for modeling cytochrome p450 active sitesrdquo DrugMetabolism and Disposition vol 29 no 7 pp 936ndash944 2001

[195] A Galetin S E Clarke and J B Houston ldquoMultisite kineticanalysis of interactions between prototypical CYP3A4 sub-group substrates midazolam testosterone and nifedipinerdquoDrug Metabolism and Disposition vol 31 no 9 pp 1108ndash11162003

[196] K Ohkura Y Kawaguchi Y Watanabe Y Masubuchi Y Shi-nohara and H Hori ldquoFlexible structure of cytochrome P450promiscuity of ligand binding in the CYP3A4 heme pocketrdquoAnticancer Research vol 29 no 3 pp 935ndash942 2009

[197] K E Kenworthy S E Clarke J Andrews and J B HoustonldquoMultisite kinetic models for CYP3A4 simultaneous activationand inhibition of diazepam and testosteronemetabolismrdquoDrugMetabolism and Disposition vol 29 no 12 pp 1644ndash1651 2001

[198] M Ekroos and T Sjogren ldquoStructural basis for ligand promis-cuity in cytochrome P450 3A4rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 103 no37 pp 13682ndash13687 2006

[199] I G Denisov D J Frank and S G Sligar ldquoCooperative prop-erties of cytochromes P450rdquo Pharmacology ampTherapeutics vol124 no 2 pp 151ndash167 2009

[200] W M Atkins ldquoNon-Michaelis-Menten kinetics in cytochromeP450-catalyzed reactionsrdquo Annual Review of Pharmacology andToxicology vol 45 pp 291ndash310 2005

[201] J M Hutzler and T S Tracy ldquoAtypical kinetic profiles in drugmetabolism reactionsrdquo Drug Metabolism and Disposition vol30 no 4 pp 355ndash362 2002

[202] D R Davydov and J R Halpert ldquoAllosteric P450 mechanismsmultiple binding sites multiple conformers of bothrdquo ExpertOpinion on Drug Metabolism and Toxicology vol 4 no 12 pp1523ndash1535 2008

[203] I G Denisov and S G Sligar ldquoA novel type of allosteric regula-tion functional cooperativity in monomeric proteinsrdquo Archivesof Biochemistry and Biophysics vol 519 no 2 pp 91ndash1022012

[204] D F Lewis B G Lake and M Dickins ldquoQuantitative struc-ture-activity relationships (QSARs) in inhibitors of variouscytochromes P450 the importance of compound lipophilicityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 22no 1 pp 1ndash6 2007

[205] D F V Lewis B G Lake and M Dickins ldquoQuantitativestructure-activity relationships (QSARs) in CYP3A4 inhibitorsthe importance of lipophilic character and hydrogen bondingrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 21no 2 pp 127ndash132 2006

[206] B Mao R Gozalbes F Barbosa et al ldquoQSAR modeling of invitro inhibition of cytochrome P450 3A4rdquo Journal of ChemicalInformation and Modeling vol 46 no 5 pp 2125ndash2134 2006

[207] P Matouskova H Bartıkova I Bousova et al ldquoEffect ofdefined green tea extract in various dosage schemes on drug-metabolizing enzymes in mice in vivordquo Journal of FunctionalFoods vol 10 pp 327ndash335 2014

[208] U F Ezuruike and J M Prieto ldquoThe use of plants in the tradi-tional management of diabetes in Nigeria pharmacological andtoxicological considerationsrdquo Journal of Ethnopharmacologyvol 155 no 2 pp 857ndash924 2014

[209] C Bunchorntavakul and K R Reddy ldquoReview article herbaland dietary supplement hepatotoxicityrdquoAlimentary Pharmacol-ogy andTherapeutics vol 37 no 1 pp 3ndash17 2013

[210] E J Y Kim Y Chen J Q Huang et al ldquoEvidence-based tox-icity evaluation and scheduling of Chinese herbal medicinesrdquoJournal of Ethnopharmacology vol 146 no 1 pp 40ndash61 2013

[211] V S Neergheen-Bhujun ldquoUnderestimating the toxicologicalchallenges associated with the use of herbal medicinal productsin developing countriesrdquo BioMed Research International vol2013 Article ID 804086 9 pages 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


capacity enable it to can act several-fold more efficiently inthe intestine than in the liver [20 27 28] Furthermore theintestine receives not only dietary compounds but also phaseI and II metabolites that have been excreted back into theintestine through the enterohepatic cycle [29 30] All thesefacts indicate the importance of intestinal CYP3A4 activityin the metabolism of dietary constituents In rodents theisofrom CYP3A is expressed predominantly in the liver withonly scant expression observed in the intestine [31ndash33] Thedifferent isoforms and distinct expression levels and patternsfor P450s in the intestine between humans and rodentslimit the suitability of rodents as a model to predict drugmetabolism or oral bioavailability in human [34]This pointsthe importance of studying the effects of ingested polyphenolsand other dietary substrates on the metabolism of intesti-nal CYP3A4 in humans or in models other than rodentsrsquointestine The latter include cell cultures microsomes andmicroorganisms that express the specific P450 of interest or awhole array of P450s [35ndash39]

The active site of a substrate-free cytochrome P450 con-tains one-heme iron center anchored by the four bonds of theheme group fifth proximal ligand of the conserved cysteineand water molecule as the sixth distal ligand [1]The catalyticmechanisms of P450 enzymes are thoroughly investigatedin the literature as demonstrated in a scheme based onprevious publications (Figure 1) [1 40ndash42] Like most otherP450 enzymes CYP3A4 acts as a monooxygenase (eg itcatalyzes the insertion of one atom of oxygen into an organicsubstrate while another oxygen atom is reduced to water)[43]The substrate chemical characteristics and the preferredposition of hydroxyl insertion change from one family ofP450 to another [3 44ndash46] P450 enzymes play a majorrole in phase I metabolism of dietary xenobiotics includingpolyphenols whereby a hydroxyl group is introduced to themolecule These metabolic products are more water-solubleand become available to phase II enzymes The latter includeUDP-glucuronosyl transferases and sulfotransferases thatadd to the increased water solubility of the hydroxylatedpolyphenols producing glucuronides and sulfates which arethen eliminated from the body [29 47 48]

In recent studies evidence has accumulated to indicatepotent interactions between CYP3A4 and edible phytochem-icals These compounds some of which are abundant in ourdiet belong to the large and diverse family of polypheno-lics including flavonoids phenolic acids phenolic alcoholstilbenoids and lignans [49ndash53] It is commonly acceptedthat the powerful antioxidant activity of polyphenolic com-pounds is due to their free-radical scavenging capacity andtheir iron-chelating activity [54ndash56] Reviews of the healthbenefits of polyphenols demonstrate that these compoundshave numerous therapeutic effects against several diseases(eg atherosclerosis certain forms of carcinogenic processesand cardiovascular and neurodegenerative diseases) [57ndash60] Among the therapeutic implications of polyphenols onhuman health the interactions between polyphenols andcytochrome P450 have been recently reviewed [56 61ndash64]These interactions were highlighted following the increaseduse of herbal medicines and supplements As many of theherbs used in these preparations are known to be rich in

polyphenolics their interaction with the major enzyme ofpresystemic metabolism has attracted significant researchattention [56 65ndash67] Since cytochrome P450 enzymes areresponsible for the metabolism of a wide range of drugs andpolyphenols which might also change their antimicrobialpotential and human toxicity the simultaneous consumptionof drugs herbals and plant foods raises concerns The coad-ministration of active constituents derived from food or herbsand prescribed drugs may lead to undesirable clinical effectswhichmay include increased toxicity andor treatment failure[67ndash69]

Here we focus on the interactions of polyphenols withCYP3A4 the major enzyme in the gut and liver metabolismof drugs and xenobiotics The effects of several subcategoriesof polyphenols on the expression and activity of CYP3A4(inhibition or induction) are reviewed (Table 1) Structuraland physicochemical considerations that define these inter-actions are also reviewed

2 CYP3A4 and Food-Drug Interactions

Drug-metabolizing P450s such as CYP3A4 have relaxedselectivity and are able to bind and metabolize a large arrayof substrates of different size shapes and chemical propertiesfor example many dietary polyphenols Crystal structuresbiophysical studies and molecular dynamics have providedimportant insights into how drug-metabolizing P450s espe-cially CYP3A4 structurally adapt to a variety of inhibitorsand substrates [70] Indeed CYP3A4 is involved in themetabolism of over 50 of marketed drugs that undergometabolic elimination [71]The high level of CYP3A4 expres-sion in the intestine as well as its broad substrate specificitymay explain the accumulating data regarding its suscepti-bility to modulation by food constituents [38 61 72ndash75]Examples of metabolic food-drug interactions involving themodulation of CYP3A4 activity by components from dietaryand herbal sources are accumulating including those ofgrapefruit with over 85 drugs for example cyclosporine andfelodipine [27 76ndash78] and those of St Johnrsquos wort [54 79 80]and red wine [38 75 81] with cyclosporine In most of thesecases components in foods drinks food additives and orallyadministered medicines were shown to inhibit CYP3A4activity and as a result increase the actual dose of the drugthat reaches the blood circulation in its active form whichoften causes unfavorable and long-lasting interactions andprobably fatal toxicity [82 83] Continuous exposure to thesecompounds especially those that activate the xenobioticnuclear receptor PXR (pregnane X receptor) may lead ina feedback fashion to increased expression of CYP3A4 inthe intestine making the food-drug interaction even morecomplex during extended periods of use [84ndash87] Drug-drugfood-drug and herb-drug interactions in the liver have beenwell documented in the literature [72 88ndash90] An intensiveCYP3A4-dependent intestinal metabolism of low-absorbedcompounds such as most polyphenols might be expected[29 54 91ndash93] However to the best of our knowledge theresearch in this area is limited and additional data are needed


O

O

O

O

O

O

O

O

O

O O

O O

O

O

O

O

O

O

O

O

O

OH

OH

H2O

H2O

H2O

Fe3+

Fe3+

Fe3+

Fe4+

Fe3+

Fe3+

Fe3+

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Fe2+

2eminus

H++

H+

H+

Oxidaseshunt

shunt

shunt

Peroxide

AutoxidationOHminus

Ominus

H2O2

O2

eminus

eminus

O2minus

∙

O2

minus

2H+


3 Polyphenols







Flavonoids

Flavonols


Quercetin


[87 151 153]

Flavones






Nonflavonoids


Lignans



[183 184]



Polyphenols

Phenolicacids



Hydroxybenzoicacids


Non flavonoids







Flavonoids












































50values of the









[185]



50of 072 120583M In


50values















50activity values








References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

O

O

O

O

O

O

O

O O

O O

O

O

O

O

O

O

O

O

O

OH

OH

H2O

H2O

H2O

Fe3+

Fe3+

Fe3+

Fe4+

Fe3+

Fe3+

Fe3+

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Cys

Fe2+

2eminus

H++

H+

H+

Oxidaseshunt

shunt

shunt

Peroxide

AutoxidationOHminus

Ominus

H2O2

O2

eminus

eminus

O2minus

∙

O2

minus

2H+


3 Polyphenols







Flavonoids

Flavonols


Quercetin


[87 151 153]

Flavones






Nonflavonoids


Lignans



[183 184]



Polyphenols

Phenolicacids



Hydroxybenzoicacids


Non flavonoids







Flavonoids












































50values of the









[185]



50of 072 120583M In


50values















50activity values








References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Flavonoids

Flavonols


Quercetin


[87 151 153]

Flavones






Nonflavonoids


Lignans



[183 184]



Polyphenols

Phenolicacids



Hydroxybenzoicacids


Non flavonoids







Flavonoids












































50values of the









[185]



50of 072 120583M In


50values















50activity values








References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































50values of the









[185]



50of 072 120583M In


50values















50activity values








References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























50activity values








References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References




































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Interactions between CYP3A4 and Dietary ...

Documents

Transcript of Review Article Interactions between CYP3A4 and Dietary ...