Review Article Modulation of Metabolic Detoxification ...

Review ArticleModulation of Metabolic DetoxificationPathways Using Foods and Food-Derived ComponentsA Scientific Review with Clinical Application

Romilly E Hodges1 and Deanna M Minich23

1University of Bridgeport 126 Park Avenue Bridgeport CT 07748 USA2Institute for Functional Medicine 505 S 336th Street Suite 500 Federal Way WA 98003 USA3University of Western States 2900 NE 132nd Avenue Portland OR 97230 USA

Correspondence should be addressed to Deanna M Minich deannaminichhotmailcom

Received 5 January 2015 Accepted 20 March 2015

Academic Editor H K Biesalski

Copyright copy 2015 R E Hodges and D M Minich This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Research into human biotransformation and elimination systems continues to evolve Various clinical and in vivo studies havebeen undertaken to evaluate the effects of foods and food-derived components on the activity of detoxification pathways includingphase I cytochrome P450 enzymes phase II conjugation enzymes Nrf2 signaling andmetallothioneinThis review summarizes theresearch in this area to date highlighting the potential for foods and nutrients to support andor modulate detoxification functionsClinical applications to alter detoxification pathway activity and improve patient outcomes are considered drawing on the growingunderstanding of the relationship between detoxification functions and different disease states genetic polymorphisms and drug-nutrient interactions Some caution is recommended however due to the limitations of current research as well as indicationsthat many nutrients exert biphasic dose-dependent effects and that genetic polymorphisms may alter outcomes A whole-foodsapproach may therefore be prudent

1 Introduction

Food-based nutrients have been and continue to be investi-gated for their role in the modulation of metabolic pathwaysinvolved in detoxification processes Several publicationsto date have leveraged cell animal and clinical studies todemonstrate that food-derived components and nutrientscan modulate processes of conversion and eventual excretionof toxins from the body [1] In general the nature of thesefindings indicates that specific foods may upregulate orfavorably balance metabolic pathways to assist with toxinbiotransformation and subsequent elimination [2 3] Variouswhole foods such as cruciferous vegetables [2 4 5] berries[6] soy [7] garlic [8 9] and even spices like turmeric[10 11] have been suggested to be beneficial and commonlyprescribed as part of naturopathic-oriented and functionalmedicine-based therapies [12 13]

While these foods are important to note the sciencein this active area of inquiry continues to evolve to reveal

new findings about food-based nutrients and their effecton health Thus the purpose of this review article is tosummarize the science to date on the influence of wholefoods with a special focus directed towards phytonutri-ents and other food-based components on influencing spe-cific metabolic detoxification pathways including phase Icytochrome enzymes phase II conjugation enzymes antiox-idant support systems and metallothionein upregulation forheavy metal metabolism Based on this current science thepaper will conclude with clinical recommendations that maybe applied in a personalized manner for patients via thediscretion of a qualified health professional

2 The Metabolic Pathways of Detoxification

Discussion of physiological pathways for detoxification hasbeen mainly centered around phase I and phase II enzymesystems This review will cover phase I cytochrome P450

Hindawi Publishing CorporationJournal of Nutrition and MetabolismVolume 2015 Article ID 760689 23 pageshttpdxdoiorg1011552015760689

2 Journal of Nutrition and Metabolism

enzymes as well as phase II enzymes specifically UDP-glucuronosyl transferases glutathione S-transferases aminoacid transferases N-acetyl transferases and methyltrans-ferases Note that there are other important classes of phase Ienzymes namely hydroxylation and reduction which are notcovered in this review While these important enzymes arepivotal to consider this review of the effect of food on detox-ification will also extend into other pathways including waysto promote gene expression of antioxidant-related enzymesand of metallothionein an endogenous protein carrier forheavy metals Each of these four classes of detoxification-related pathways will be discussed within the context ofnutrients

21 Phase I Cytochrome P450 Enzymes Initially the ldquophasesrdquoof detoxification were described as functionalization (orphase I) or the addition of oxygen to form a reactive siteon the toxic compound and conjugation (phase II) or theprocess of adding a water-soluble group to this now reactivesite [14 15] The ldquoPhase Irdquo cytochrome P450 superfamily ofenzymes (CYP450) is generally the first defense employedby the body to biotransform xenobiotics steroid hormonesand pharmaceuticals These microsomal membrane-boundheme-thiolate proteins locatedmainly in the liver but also inenterocytes kidneys lung and even the brain are responsiblefor the oxidation peroxidation and reduction of severalendogenous and exogenous substrates [13 15 16] Specificallythe function of CYP450 enzymes is to add a reactive groupsuch as a hydroxyl carboxyl or an amino group throughoxidation reduction andor hydrolysis reactions [15] Theseinitial reactions have the potential to create oxidative damagewithin cell systems because of the resulting formation ofreactive electrophilic species

It is accepted that any variability in the number ofCYP450enzymes could have benefit(s) andor consequence(s) forhow an individual responds to the effect(s) of (a) toxin(s)Clinical application of the knowledge of these phase ICYP450 enzymes has been primarily addressed within phar-macology to understand the nature of drug interactions sideeffects and interindividual variability in drug metabolism[15] The ability of an individual to metabolize 90 ofcurrently used drugs will largely depend on the geneticexpression of these enzymes [17] It is established that manyof these CYP450 genes are subject to genetic polymor-phisms resulting in an altered expression and function ofindividual enzymes Currently there exist some laboratorytests to identify the presence of these genetic variants It isconceivable that having knowledge about foods and theirindividual (phyto)nutrients especially in the case of dietarysupplements and functional foods could be worthwhilefor clinicians to consider for patients who are taking apolypharmacy approach Furthermore as nutritional strate-gies become more personalized it would seem that thisinformation could be interfaced with a patientrsquos knownCYP450 polymorphisms to determine how to best optimizehealth outcomes

211 CYP1 Enzymes TheCYP1A family is involved inmetab-olizing procarcinogens hormones and pharmaceuticals

It is well-known for its role in the carcinogenic bioactivationof polycyclic aromatic hydrocarbons (PAHs) heterocyclicaromatic aminesamides polychlorinated biphenyls (PCBs)and other environmental toxins [18 19] LowCYP1A2 activityfor example has been linked to higher risk of testicularcancer [20] However due to their rapid conversion tohighly reactive intermediates excessive activity of CYP1Aenzymes without adequate phase II support may enhancethe destructive effects of environmental procarcinogens [21]Indeed genetic polymorphisms in this cytochrome familyhave been suggested as useful markers for predispositionto certain cancers [15] CYP1 enzymes are also involvedin the formation of clinically relevant estrogen metabolitesCYP1A11A2 and CYP1B1 catalyze the 2-hydroxylation and4-hydroxylation of estrogens respectively [22] The potentialrole of 4-hydroxyestradiol in estrogen-related carcinogenesisvia the production of free radicals and related cellular damage[22] has prompted investigation into factors that modulateCYP1 enzymes

Various foods and phytonutrients alter CYP1 activity(Tables 1(a) and 1(b)) Cruciferous vegetables have beenshown in humans to act as inducers of CYP1A1 and 1A2and animal studies also suggest an upregulation of CYP1B1[4 23ndash27]The inductory effect of crucifers onCYP1A2 seemsespecially well established Clinical studies also indicatethat resveratrol and resveratrol-containing foods are CYP1A1enhancers [28] Conversely berries and their constituentpolyphenol ellagic acid may reduce CYP1A1 overactivity[6] and apiaceous vegetables and quercetin may attenuateexcessive CYP1A2 action [24 29] Cruciferous vegetables andberries have been suggested as possible modulators of estro-gen metabolites berries for their reducing effect on CYP1A1[6] and cruciferous vegetables for their stronger induction ofCYP1A versus 1B1 enzymes [25ndash27 30] Chrysoeriol presentin rooibos tea and celery acts selectively to inhibit CYP1B1in vitro [31] and may be especially relevant to patients withCYP1B1 overactivity However further research is needed toconfirm this finding

Many foods appear to act as both inducers and inhibitorsof CYP1 enzymes an effect which may be dose dependentor altered by the isolation of bioactive compounds derivedfrom food Curcumin at 01 of the diet has been shown inanimals to induce CYP1A1 for example [35] yet a diet of 1turmeric was inhibitory [46] Black tea at 54mLd inducedboth CYP1A1 and 1A2 [33] yet 20mgkg of theaflavins wasinhibitory to CYP1A1 [45] Soybean intake at 100mgkgupregulated CYP1A1 activity [7] yet at 1 gkg black soybeanextract [44] and 200mg daidzein twice daily [49] its effectwas inhibitory Further research is needed to confirm differ-ent dose effects and impact in humans

Varied effects may also occur from different members ofthe same food group Seemingly contradictory to researchshowing that cruciferous vegetables activate CYP1 enzymeskale (another member of the cruciferous family) appears toinhibit CYP1A2 (as well as 2C19 2D6 and 3A4) in animals[51]Thedose used at 2 gkg per day is 15-fold higher than thetypical level of human consumption [51] and more researchwould be required to determine whether lower intake levelswould also have a similar effect The same authors also tested

Journal of Nutrition and Metabolism 3

Table 1 (a) Human and in vivo example nutrient inducers of CYP1 enzymes (b) Human and in vivo example nutrient inhibitors of CYP1enzymes

(a)

Enzyme Food beverage or bioactive compoundsFood sources in italics Type of study Dosages used and references

Cruciferous vegetables Clinical 500mgd indole-3-carbinol [23]Resveratrol

Grapes wine peanuts soy and itadori tea [32] Clinical 1 gd resveratrol [28] note highdose used

Green tea In vivo 45mLdrat (avg 150 g animalweight) green tea [33]

Black tea In vivo 54mLdrat (avg 150 g animalweight) black tea [33]

CYP1A1Curcumin

Turmeric curry powder [34] In vivo 1000mgkgdrat curcumin [35]or about 150mg per rat per day

Soybean In vivo 100mgkg soybean extract [7]Garlic In vivo 30 to 200mgkg garlic oil [36]

Fish oil In vivo 205 gkg fish oil [36] note highdose used

Rosemary In vivo Diet of 05 rosemary extract[37]

AstaxanthinAlgae yeast salmon trout krill shrimp and crayfish

[38]In vivo Diets of 0001ndash003 astaxanthin

for 15 days [39]

Cruciferous vegetables Clinical

7ndash14 gkg cruciferous vegetablesincluding frozen broccoli andcauliflower fresh daikon radish

sprouts and raw shreddedcabbage and red and green [24]

500 gd broccoli [4]250 gd each of Brussel sprouts

and broccoli [25]500 gd broccoli [26]

CYP1A2 Green tea In vivo

45mLdrat (avg 150 g animalweight) green tea [33]

Green tea (25wv) as solebeverage [40]


Chicory root In vivo Diet of 10 dried chicory root[41]



for 15 days [39]

CYP1B1Curcumin

Turmeric curry powder [34] In vivo Diet of 01 curcumin [35]

Cruciferous vegtables In vivo 25ndash250mgkg indole-3-carbinol[27]

(b)


Black raspberry In vivo Diet of 25 black raspberry [6]Blueberry In vivo Diet of 25 blueberry [6]

CYP1A1

Ellagic acidBerries pomegranate grapes walnuts and blackcurrants

[42]In vivo 30mgkgd ellagic acid [43]

400 ppm ellagic acid [6]

Black soybean In vivo 1 gkg black soybean seed coatextract [44] note high dose used

Black tea In vivo 20mgkg theaflavins [45]Turmeric In vivo Diet of 1 turmeric [46]


(b) Continued


Apiaceous vegetables Clinical

4 gkg apiaceous vegetablesincluding frozen carrots andfresh celery dill parsley and

parsnips [24]Quercetin

Apple apricot blueberries yellow onion kale alfalfasprouts green beans broccoli black tea and chili powder

[47 48]

Clinical 500mgd quercetin [29]

CYP1A2Daidzein

Soybean [49] Clinical 200mg twice daily dosing ofdaidzein [49]

Grapefruit Clinical 300mL grapefruit juice [50]

Kale In vivo2 gkgd kale as freeze-dried kale

drink[51]

Garlic In vivo 100mgkg garlic oil [52]

Chamomile In vivo Free access to 2 chamomile teasolution [53]

Peppermint In vivo Free access to 2 peppermint teasolution [53]

Dandelion In vivo Free access to 2 dandelion teasolution [53]

Turmeric In vivo Diet of 1 turmeric [46]

the effects of an equivalent volume of cabbage consumptionand found no such inhibitory effect pointing to the possi-bility that different cruciferous vegetables may have distincteffects on cytochrome activity

212 CYP2A-E Enzymes The large CYP2 family of enzymesis involved in the metabolism of drugs xenobiotics hor-mones and other endogenous compounds such as ketonesglycerol and fatty acids [15 54] Some notable polymor-phisms occur in the CYP2C and CYP2D subgroups leadingto the classification of patients as ldquopoor metabolizersrdquo of var-ious pharmaceuticals warfarin and CYP2C9 antiarrhythmiaagents metoprolol and propafenone and CYP2D6 pheny-toin cyclobarbital omeprazole and CYP2C19 for example[15 17] CYP2D polymorphisms may be associated withParkinsonrsquos disease and lung cancer [15] Clinical evidenceexists for the induction of CYP2A6 by quercetin and broc-coli [4 29] (Table 2(a)) In animals chicory appears toinduce CYP2A enzymes [41] and rosemary and garlic mayupregulate CYP2B activity [9 37] Clinical studies usingresveratrol and garden cress indicate CYP2D6 inhibition[28 55] (Table 2(b)) Ellagic acid green tea black tea andcruciferous vegetables also appear to inhibit various CYP2enzymes

CYP2E1 enzymes have also attracted particular interestfor their role in various diseases 2E1 metabolizes nervoussystem agents such as halothane isoflurane chlorzoxazoneand ethanol and bioactivates procarcinogenic nitrosaminesand aflatoxin B1 [15 65] It produces free radicals regardlessof substrate [15] and CYP2E1 polymorphisms have beenassociated with altered risk for coronary artery disease [66]

and gastric cancer [67] CYP2E1-induced oxidative stress hasalso been shown to lead to impaired insulin action via thesuppression of GLUT4 expression [68] Attenuation of 2E1overactivity may therefore be an important consideration inhigh-risk patients

Watercress and garlic are CYP2E1 inhibitors in humans[59 60] In vivo evidence also suggests that N-acetyl cys-teine ellagic acid green tea black tea dandelion chrysinand medium chain triglycerides (MCTs) may downregulateCYP2E1 [33 43 54 61 63 64] MCT oil may specificallyattenuate the ethanol-induced upregulation of CYP2E1 andproduction of mitochondrial 4-hydroxynonenal a marker ofoxidative stress [64]

213 CYP3A Enzymes The occurrence of the differentCYP3A isoforms is tissue-specific [15] Rooibos tea garlicand fish oil appear to induce the activity of CYP3A 3A1and 3A2 [8 36 69 70] (Table 3(a)) Possible inhibitory foodsinclude green tea black tea and quercetin [33 56 71 72](Table 3(b)) The most clinically relevant of the enzymes isCYP3A4 which is expressedmainly in the liver and to a lesserextent in the kidney [13] Caffeine testosterone progesteroneand androstenedione are substrates of the CYP3A4 enzymesystem as are various procarcinogens including PAHs andaflatoxin B1 [15] To date however the principal driverfor research on CYP3A4 has been due to its role in themetabolism of over 50 percent of all pharmaceuticals [73]The potential for drug interaction with this single enzymecoupled with the wide interindividual differences in enzy-matic activity generates some level of risk in administrationof high doses and multiple drugs as well as food-drug


Table 2 (a) Human and in vivo example nutrient inducers of selected CYP2 enzymes (b) Human and in vivo example nutrient inhibitors ofselected CYP2 enzymes

(a)


CYP2A Chicory root In vivo Diet of 10 dried chicory root[41]

CYP2A6

QuercetinApple apricot blueberries yellow onion kale alfalfasprouts green beans broccoli black tea and chili

powder [47 48]


Broccoli Clinical 500 gd broccoli [4]

CYP2B1


Garlic In vivo05 and 20mmolkg diallyl

sulfide or about 75 and 300mgrespectively [9]

CYP2B2 Rosemary In vivo Diet of 05 rosemary extract[37]

CYP2E1Fish oil In vivo 205 gkg fish oil [36] note high

dose used


(b)


Ellagic acidBerries pomegranate grapes walnuts and

blackcurrants [42]In vivo 10 and 30mgkgd ellagic acid

[43]

CYP2B Green tea In vivo 100mgkgd green tea extract[56]

Cruciferous vegetables In vivo 3 and 12mgkgd sulforaphane[57]

CYP2B1 Turmeric In vivo Diet of 1 turmeric [46]


CYP2C Black tea In vivo 54mLdrat (avg 150 g animalweight) black tea [33]


blackcurrants [42]In vivo 30mgkgd ellagic acid [43]

CYP2C6Ellagic acid

Berries pomegranate grapes walnuts andblackcurrants [42]

In vivo 30mgkgd ellagic acid [43]

CYP2C9

ResveratrolGrapes wine peanuts soy and itadori tea [32] Clinical 1 gd resveratrol [28] note high

dose usedMyricetin

Onions berries grapes and red wine [58] In vivo 2 and 8mgkg myricetin [58]

CYP2C19 Kale In vivo 2 gkgd kale as freeze-dried kaledrink [51]


dose used

CYP2D6 Garden cress Clinical 75 g twice daily intake of gardencress seed powder [55]

Kale In vivo 2 gkgd kale as freeze-dried kaledrink [51]


(b) Continued


Watercress Clinical 50 g watercress homogenate[59]

Garlic Clinical andin vivo

02mgkg diallyl sulfideequivalent to high human garlic

consumption [60]100mgkg garlic oil [52]

200mgkg diallyl sulfide [8]30 to 200mgkg garlic oil [36]Diet of 2 and 5 garlic powder

[61]N-acetyl cysteine

Allium vegetables [54] In vivo 25mgkg and 50mgkg N-acetylcysteine [54]

CYP2E1Ellagic acid


In vivo 10 and 30mgkgd ellagic acid[43]



Dandelion In vivo 05 and 2 gkg dandelion leafwater extract [62]

ChrysinHoney honeycomb [63] In vivo 20 and 40mgkgd chrysin [63]

Medium-chain triglycerides (MCTs)Coconut and coconut oil In vivo 32 calories as MCTs [64]

and herb-drug interactions Grapefruit juice is perhaps themost well-known food inhibitor of this enzyme [74] thoughresveratrol and garden cress a member of the cruciferousvegetable family appear to have similar effects in humansalbeit at intakes above what would be expected without high-dose supplementation [28 55] Curcumin may upregulate3A4 activity [11]

Once again there are indications that a biphasic effectmay be seen from dietary bioactive compounds Davenportand Wargovich (2005) found that shorter-term or lowerdosing with garlic organosulfur compounds produced poten-tially anticarcinogenic effects but that longer-term higherdoses (200mgkg) of allyl sulfides led to minor hepatictoxicity [8] One garlic clove contains only 2500ndash4500120583gof the allyl sulfide precursor allicin [76] so the higher doseis much more than would be consumed in a typical humandiet In another example two components of cruciferousvegetables sulforaphanes and indole-3-carbinol inhibitedand increased activity respectively [57 75] highlighting thepotential for human studies using whole foods to clarify theoutcome of consumption

214 CYP4 Enzymes Less is known about this family ofenzymes since it is thought to play a smaller role indrug metabolism It is however understood to be a pri-marily extrahepatic family of cytochromes inducible byclofibrate and ciprofibrate (hypolipidemic drugs) NSAIDsprostaglandins and toxicants such as phthalate esters [15 77]The CYP4B1 isoform is involved in the metabolism of MCTs

(medium chain triglycerides) as well as the bioactivation ofpneumotoxic and carcinogenic compounds [78]

Polymorphisms and overexpression of this subgroupmaybe associated with bladder cancer [15] and colitis [79] Areport by Ye et al (2009) which examined the link betweencolitis and CYP4B1 activity found that the promotion ofCYP4B1 activity by caffeic acid (found in caffeine-containingfoods) (Table 4) correlated with reduced inflammation anddisease activity [79] Green tea may act to induce CYP4A1 assuggested by animal studies [40] More research is needed toclearly identify food influences on this enzyme family

22 Phase II Conjugation Enzymes After a xenobiotic hasgone through the process of becoming hydrophilic throughreactions overseen by CYP450 enzymes its reactive site canbe conjugated with an endogenous hydrophilic substanceThis reaction is often referred to as ldquophase II detoxificationrdquoConjugation involves the transfer of a number of hydrophiliccompounds (via their corresponding enzymes) includingglucuronic acid (glucuronyl transferases) sulfate (sulfotrans-ferases) glutathione (glutathione transferases) amino acids(amino acid transferases) an acetyl group (N-acetyl trans-ferases) and a methyl group (N- and O-methyltransferases)[81]The result of the collective activity of these enzymes is anincrease in the hydrophilicity of the metabolite theoreticallyleading to enhanced excretion in the bile andor urine [81]Similar to the CYP450 enzymes genetic polymorphisms canhave profound influence on the function of these conjugating



(a)


CYP3A Rooibos tea In vivo Rooibos tea 4 gL simmered for 5minutes as sole beverage [69]

CYP3A1Garlic In vivo

30 to 200mgkg garlic oil [36]80 and 200mgkg garlic oil 3 times

weekly [70]

Fish oil In vivo 205 gkg fish oil [36] note high doseused

CYP3A2 Garlic In vivo 200mgkg diallyl sulfide [8]Cruciferous vegetables In vivo 50mgkgd indole-3-carbinol [75]

CYP3A4 CurcuminTurmeric curry powder [34] In vivo 50 and 100mgkg curcumin [11]

(b)


CYP3A

Green tea In vivo


400mgkg green tea extract [71]100mgkgd green tea extract

[56]



powder [47 48]

In vivo 10 and 20mgkg [72]

CYP3A2 Cruciferous vegetables In vivo 12mgkgd sulforaphane [57]

Grapefruit Clinical 200mL grapefruit juice 3 timesdaily [74]


dose used

CYP3A4 Garden cress Clinical 75 g twice daily dose of gardencress seed powder [55]

Soybean In vivo 100mgkg soybean extract [7]


MyricetinOnions berries grapes and red wine [58] In vivo 04 2 and 8mgkg myricetin

[58]

Table 4 Human and in vivo example nutrient inducers of selected CYP4 enzymes


CYP4A1 Green tea In vivo Green tea (25wv) as sole beverage [40]

CYP4B1 Caffeic acidCoffee [80] In vivo 179mgkg caffeic acid [79]

enzymes [82] with potential implication in the developmentof several forms of cancer [83]

It is conceivable that modulation of phase II enzymesby food-based bioactive compounds may be advantageousin patients who have altered enzyme activity due to genetic

polymorphisms or who have a high toxic burden due tochronic exposure to environmental pollutants overactivephase I activity or hormonal imbalance For exampleJames et al (2008) suggest that upregulation of glucuronida-tion and sulfonation by certain bioactive compounds may be


a useful consideration for the elimination of environmentalPCBs [19]

221 UDP-Glucuronosyltransferases This class of enzymescomprising multiple proteins and even subfamilies plays anessential role in enhancing the elimination of biotransformedtoxins in urine and feces as well as metabolizing steroidhormones and bilirubin [84 85]Their function is to catalyzethe covalent linkage of glucuronic acid fromUDP-glucuronicacid to an accepting functional group on the molecule aprocess referred to as glucuronidation [86] Glucuronidationoccurs primarily in the liver but can occur in other tissuessuch as the small intestine [86 87] Bilirubin specificallyis principally conjugated by UGT1A1 in hepatocytes [88]and then excreted with bile into the intestinal tract It hasbeen estimated that 40ndash70 of all medications are subjectto glucuronidation reactions in humans thereby suggestingthe significance of this conjugation enzyme family [88]Since UDP-glucuronosyltransferases (UGTs) also metabolizephytochemicals alterations in their effects may be seen withgenetically downregulated enzyme activity flavonoids areconjugated with glucuronide and sulfate therefore UGTor sulfotransferase (SULT) polymorphisms may producevariability in phytochemical clearance and efficacy [89]

Clinical and observational studies point to cruciferousvegetables resveratrol and citrus as foods and bioactivecompounds that induce UGT enzymes [25 28 90ndash92](Table 5(a)) Animal studies also suggest the potential forother foods and nutrients including dandelion rooibostea honeybush tea rosemary soy ellagic acid ferulic acidcurcumin and astaxanthin to enhance UGT activity [37 3953 93ndash95] Interestingly the effect of resveratrol was seenonly in individuals with low baseline enzyme levelsactivitysuggesting that some phytochemicals may modulate ratherthan outright induce enzymatic activity [28] In additionmany studies note that effects are variable depending ongender and genotype [85 90 92] for example women withthe UGT1A1 lowast28 polymorphism (77) were responsive tocitrus intervention whereas those with other genetic variantswere not [92]

Meaningful interpretations of these studies may stillbe elusive however in one combined dietary trial theconsumption of 10 servings per day of a combination ofcruciferous vegetables soy foods and citrus fruits did nothave a significant effect on UGT enzyme activity comparedwith a diet devoid of fruits and vegetables [85] The authorshypothesize that these results may be due to their choice ofspecific foods within those groups or due to Nrf2 activation(discussed in subsequent sections) when fruits and vegetableswere avoided

The effects of UGT activity may also be enhanced by D-glucaric acid by theoretical inhibition of beta-glucuronidaseenzymes [100] Beta-glucuronidase enzymes act to reverseUGT conjugation reactions D-glucaric acid is found inmanyfruits vegetables and legumes (Table 5(b)) When testedin humans however a diet supplemented with cruciferousvegetables (23 cup broccoli 12 cup cabbage and 12 cupradish sprouts) citrus fruits (1 cup grapefruit juice 12 cuporange juice 1 cup orangegrapefruit segments and 1 orange

peel) and soy foods was found to have no effect on beta-glucuronidase activity [101] (amounts standardized for 55 kgbody weight) indicating that the clinical effects of D-glucaricacid consumption still need further clarification

In vivo research suggests that polyphenol extracts ofcertain berries specifically strawberries and blackcurrantmay inhibit beta-glucuronidase activity in the intestinallumen Kosmala et al (2014) observed this effect using bothstrawberry pomace water extract and water-alcohol extractcontaining 51 and 171 ellagic acid and 02 and 109proanthocyanidins respectively [100] Jurgonski et al (2014)found a similar inhibitory effect using a diet of 15 blackcur-rant extract (total polyphenolic content 668 g100 g extract)[102] Interestingly the highest levels of beta-glucuronidaseactivity were seen in rabbits fed a high fat diet (32 caloriesfrom fat including 10 from lard) without blackcurrantextract supplementation suggesting that dietary fat may alsoalter enzyme activity [102]

Inhibition of UGT enzymatic activitymay be a considera-tion for modulation of hormone levels and the risk of certaincancers such as prostate cancer [84] In vitro studies suggestthat various foods and food-based components may inhibitUGT activity including green and black tea quercetin rutinnaringenin allspice peppermint oil cacao and silymarin[84] although further research is needed to evaluate their invivo and clinical effects

222 Sulfotransferases As the name of this superfamilyof enzymes might suggest SULTs are responsible for thetransfer of a sulfuryl group donated by 31015840-phosphoadenosine-51015840-phosphosulfate (PAPS) to hydroxyl or amine groupsparticularly in the areas of liver intestine adrenal glandbrain and skin tissues [103] This process is often referredto as sulfation but is more accurately termed sulfonation orsulfurylation Decreased function of these enzymes throughgenetic variability or presence of environmental chemicalscan lead to eventual interference with thyroid hormoneestrogen and androgen levels [104 105] as well as variablepolyphenol effects [106] since the active forms of thesecompounds can be degraded via sulfonation Typically oncecompounds have been conjugated with sulfate there is lessreactivity and toxicity incurred from the precursor molecule[105]

Few in vivo studies have examined the effects of dietarycomponents on SULT activity although caffeine and retinoicacid are possible SULT inducers according to animal studies[107 108] (Table 6(a)) Although it is uncertain how their out-comes will translate in vivo various in vitro studies have indi-cated the possibility of sulfotransferase inhibition (includingcompetitive inhibition) by wine anthocyanins and flavonolssynthetic food colors (especially red colors) apple and grapejuice catechins including epigallocatechin gallate quercetincurcumin resveratrol flavonoids (apigenin chrysin fisetingalangin kaempferol quercetin myricetin naringenin andnaringin) and certain phytoestrogens (daidzein genistein)[3 105] Pyridoxal-6-phosphate the active form of vitaminB6 (which is widely distributed in foods) may also be a com-petitive SULT inhibitor according to one in vitro study [109]although human tissue concentrations and clinical effects


Table 5 (a) Human and in vivo example nutrient inducers of UGT enzymes (b) Selected dietary sources of D-glucaric acid(a)



Approximately 5 and 10 servingsd of cruciferousvegetables including frozen broccoli cauliflower freshcabbage (red and green) and fresh radish sprouts [90]

250 gd each of Brussel sprouts and broccoli [25]2 oz (568 g) watercress three times daily [91]

ResveratrolGrapes wine peanuts soy and itadori tea

[32]Clinical 1 gd resveratrol [28] note high dose used

Citrus Observational 05+ servingsday of citrus fruits or foods [92]Dandelion In vivo Free access to 2 dandelion tea solution [53]

Rooibos tea In vivo Rooibos tea as sole beverage concentration 2 g tealeaves100mL water steeped for 30 minutes [93]

UGTs Honeybush tea In vivo Honeybush tea as sole beverage concentration 4 g tealeaves100mL water steeped for 30 minutes [93]

Rosemary In vivo Diet of 05 rosemary extract [37]Soy In vivo 150 and 500mgkg soy extract [94]


blackcurrants [42]In vivo Diet of 1 ellagic acid [95]

Ferulic acidWhole grains roasted coffee tomatoes

asparagus olives berries peas vegetablesand citrus [96]

In vivo Diet of 1 ferulic acid [95]

CurcuminTurmeric curry powder [34] In vivo Diet of 1 curcumin [95]

AstaxanthinAlgae yeast salmon trout krill shrimp

and crayfish [38]In vivo Diets of 0001ndash003 astaxanthin for 15 days [39]

(b)

Legumes Mung bean seeds adzuki bean sprouts [97]

Vegetables and fruitsOranges spinach apples carrots alfalfa sprouts cabbage Brussel sproutscauliflower broccoli grapefruit grapes peaches plums lemons apricots sweetcherries corn cucumber lettuce celery green pepper tomato and potatoes[97ndash99]

may be vastly different Of note caffeic acid demonstrates invitro SULT-inhibitory properties [105] This finding conflictswith its in vivo ability to induce SULT enzymes as describedby Zhou et al (2012) [107] highlighting the difficulty ofextrapolating meaningful conclusions from in vitro data

SULT enzyme activity is dependent on a depletablereserve of inorganic sulfate [112] Dietary sources of sulfur-containing compoundsmay therefore play an essential role inSULT function by providing the substrate for enzyme action(Table 6(b))

223 Glutathione S-Transferases Similar to the aforemen-tioned categories of conjugating enzymes glutathione S-transferases (GSTs) include a complex of enzymes whosemain function is to attach a glutathione group to a bio-transformed metabolite The production of these enzymescan be induced through the production of reactive oxygen

species and via gene transcription involving the antioxidant-responsive element (ARE) and the xenobiotic-responsiveelement (XRE) which will be subsequently discussed in thispaper [113]

Cruciferous and allium vegetables and resveratroldemonstrate ability to induce GSTs in humans [28 114ndash117](Table 7(a)) Observational research also associates citrusconsumption with increased GST activity [115] In vivodata also suggest many foods and food constituents to beupregulators of these enzymes including garlic fish oilblack soybean purple sweet potato curcumin green tearooibos tea honeybush tea ellagic acid rosemary ghee andgenistein [36 43 44 70 93 118ndash123] Conjugated linoleicacid has been shown to be at least partly responsible for theeffect of ghee [122] It is possible that the effects of at leastsome of these foods and bioactive compounds may be due totheir upregulation of the Nrf2 signaling pathway


Table 6 (a) In vivo example nutrient inducers of sulfotransferases (SULTs) (b) Selected dietary sources of sulfur-containing compounds(adapted from [110])

(a)


SULTs

CaffeineCoffee cocoa black tea and green tea [111] In vivo 2 10 and 50mgkg caffeine [107]

Retinoic acid (bioactive form of vitamin A)Meat (especially liver) fish egg and dairy productscontain retinol apple apricot artichokes arugula

asparagus and other plant foods contain provitamin Acarotenes [111]

In vivo 2 10 and 50mgkgd retinoic acidsuspension in corn oil [108]

(b)

Animal products Fish shellfish lamb beef chicken pork duck goose turkey egg and cheeseLegumes Lentils peas and butter beansGrains Barley oatmeal

Vegetables and fruits Cabbage horseradish Brussel sprouts leeks cress haricot beans apricots peachesspinach and watercress

Nuts and seeds Brazil nuts almonds peanuts and walnutsHerbs and spices Mustard ginger

Genetic variances gender and even possibly body weightappear to play a role in the effects of dietary factors onGST enzymes [114ndash116] Clinical investigation of cruciferousand allium vegetables by Lampe et al (2000) found that anupregulated effect was most marked in women indicatinggender variability and that the effect was also genotype-dependent occurring only in GSTM1-null individuals [116]The same investigators also found that apiaceous vegetablesinhibited GST activity but only in GSTM1+ men [116](Table 7(b)) High doses of quercetin and genistein have alsoshown inhibitory effects [123 126]

There is evidence that at least some of these foods andphytonutrients may exert modulatory rather than absoluteinductiveinhibitory effects Chow et al (2010) found thatresveratrol increased GST only in those with low baselineenzyme levels or activity [28] It is also noteworthy thatbioactive components of crucifers including isothiocyanatesare substrates for GST enzymes and that GST genotypemay therefore alter the response to cruciferous vegetablesconsumption on other mechanisms such as glutathioneperoxidase and superoxide dismutase [134 135] GSTM1-null genotype is associated with a more rapid excretion ofisothiocyanates leading some researchers to conclude thatthe benefits of cruciferous vegetable consumption may belessened in individuals with this genetic variation [89]

Support for glutathione conjugation also involvesenhancing reduced glutathione (GSH) status Glutathioneis a low-molecular weight tripeptide containing residues ofcysteine glutamate and glycine [136] Most glutathione fromfoods and supplements is poorly absorbed so liposomaldelivery has been used [137] The sulfur-containing aminoacids methionine and cystine are important precursors toglutathione formation their depletion leads to depressed

GSH levels [138] N-acetyl cysteine has also been used torestore depleted GSH levels in a clinical setting [139]

Various nutrients may also enhance endogenous glu-tathione synthesis including vitamin B6 magnesium andselenium [140 141] Curcuminoids (from turmeric) sily-marin (from milk thistle) folic acid and alpha-lipoic acidhave been shown in humans to restore depleted GSH[129 130 142 143] In animal studies cruciferous vegetablesand artichoke have also demonstrated a GSH-protectiveeffect [131ndash133] There is therefore the potential to improveglutathione status via diet or supplementation (Table 7(c))

224 Amino Acid Transferases Amino acids of various types(eg taurine glycine) whether endogenous or exogenous(from dietary sources) in origin can be utilized for attachingtomolecules for their excretion For the benefit of providing asubstrate to these enzymes it is generally thought that dietaryprotein is required for an effective detoxification protocolTable 8 lists amino acids used in phase II conjugation reac-tions and selected food sources

225 N-Acetyl Transferases (NAT) This class of enzymes isresponsible for the transfer of an acetyl group to convertaromatic amines or hydrazines to aromatic amides andhydrazides which is significant for those taking pharma-ceuticals such as isoniazid hydralazine and sulphonamides[83] Polymorphisms in genes for this category of enzymesleading to slowmetabolism have been shown to be associatedwith hepatoxicity during drug treatment [146] One smallhuman study found that 500mg quercetin daily enhancedNAT activity [29] However more research is needed tounderstand the relationship between dietary nutrients andNAT function


Table 7 (a) In vivo example nutrient inducers of glutathione S-transferases (GSTs) (b) In vivo example nutrient inhibitors of glutathioneS-transferases (GSTs) (c) Selected dietary sources of nutrients for glutathione support ([111] unless otherwise noted)

(a)


Cruciferous vegetables Clinicalobservational

Approximately 5 and 10 servingsd ofcruciferous vegetables including frozenbroccoli cauliflower fresh cabbage (redand green) and fresh radish sprouts [114]gt312 gd cruciferous vegetables [115]45 cups of cruciferous vegetablesd

including 05 cups of radish sprouts 1 cupof frozen cauliflower 2 cups of frozen

broccoli and 1 cup of fresh cabbage [116]300 gd cooked Brussels sprouts [117]

Allium vegetables Clinical3 tbsp fresh chives 133 cups of freshleeks 1 tsp garlic and 05 cups of fresh

onion [116]Resveratrol

Grapes wine peanuts soy and itadori tea[32]

Clinical 1 gd resveratrol [28] note high dose used

Citrus Observational invivo

gt76 gd citrus [115]20mg limonoid mixture every 2 days

[124]

Garlic In vivo30 to 200mgkg garlic oil [36]

80 and 200mgkg garlic oil 3 timesweekly [70]

GSTs Fish oil In vivo 205 gkg fish oil [36] note high dose used

Black soybean In vivo 1 gkg black soybean seed coat extract[44]

Purple sweet potato In vivo 100 and 200mgkg anthocyanin extractfrom purple sweet potato [118]

Curcumin In vivo Diet of 2 curcumin [119]

Green tea In vivo Equivalent of 4 cupsd (200mL each) ofgreen tea [120]

Rooibos tea In vivoRooibos tea as sole beverage

concentration 2 g tea leaves100mL watersteeped for 30 minutes [93]

Honeybush tea In vivoHoneybush tea as sole beverage




Rosemary In vivo 20mgkg carnosic acid 3 times weekly[121]

Ghee (clarified butter) In vivo 195mg CLA (conjugated linoleic acid)gfat [122]

Genistein (kidney GSTs)Fermented soy (egmiso tempeh) containsup to 40 bioavailable genistein versus 1

or less in other soy products [125]

In vivo 15 gkg genistein [123] note high doseused

(b)



1 tsp fresh dill weed 05 cups of freshcelery 3 tbsp fresh parsley 125 cups ofgrated parsnips and 075 cups of frozen

carrots [116]


(b) Continued


GSTsQuercetin

Apple apricot blueberries yellow onionkale and alfalfa sprouts green beans

broccoli black tea and chili powder [47 48]

In vivo 2 gkg quercetin [126] note high dose used

Genistein (liver GSTs)Fermented soy (egmiso tempeh)

containsup to 40 bioavailable genisteinversus 1 or less in other soy products [125]


(c)

Vitamin B6 Turkey pork chicken beef amaranth lentils pistachio nuts sunflower seeds garlic andprunes

Magnesium Nuts seeds beans and whole grainsSelenium Brazil nuts pork turkey lamb chicken and eggMethionine Turkey pork chicken beef egg Brazil nuts soybean sesame seeds and spirulinaCystine Pork turkey chicken egg soybean spirulina sesame seeds and oatsGlycine Turkey pork chicken amaranth soybean peanuts pumpkin seed and beef

Folate (dietary form of folic acid) Mung bean adzuki bean and other legumes liver sunflower seeds quinoa spinachasparagus avocados mustard greens and artichokes

Alpha-lipoic acid Spinach broccoli tomato peas Brussels sprouts and visceral meats [127 128]Functional foods Turmeric milk thistle cruciferous vegetables and artichoke [129ndash133]

Table 8 Amino acids used in phase II conjugation and selected food sources

Glycine Turkey pork chicken soybean seaweed eggs amaranth beef mollusks peanuts pumpkin seedsalmonds duck goose mung beans sunflower seeds lentils lamb bison lobster and fish [111]

TaurineMany cooked meats and fish supply taurine Taurine is also synthesized in the body from cystine(requiring niacin and vitamin B6) and homocysteine (requiring additionally betaine and serine)[144]

Glutamine Plant and animal proteins such as beef pork chicken dairy products spinach parsley andcabbage [145]

Ornithine Ornithine is synthesized endogenously via the urea cycle requiring arginine and magnesium [144]

ArginineTurkey and pork are especially rich sources also chicken pumpkin seeds soybean butternutsegg peanuts walnuts split peas mollusks almonds sesame seeds lentils fava beans mungbeans pine nuts beef sunflower seeds and white beans [111]

226 Methyltransferases Relatively significant attention hasbeen given in various medical communities to this classof phase II enzymes due to the increasing importance ofmethylation for reducing disease riskThe conjugating donorcompound in methyltransferase reactions is a methioninegroup from S-adenosyl-L-methionine (SAMe) [147] Cate-chol O-methyltransferase (COMT) is one of the prominentmethyltransferases that has received wide attention due to itsrole in estrogen detoxification [148]

Support formethylation consists of nutrient cofactors andmethyl donors such as methionine vitamin B12 vitaminB6 betaine folate and magnesium [144] Various foodscan provide these nutrients (Table 9) Conversely a highsucrose dietmay inhibitmethylation enzymes such as COMT[149]

3 Gene Induction of Phase II Detoxificationand Antioxidant Enzymes through Nrf2

The transcription factor Nrf2 [nuclear factor erythroid 2(NF-E2) p45-related factor 2] is key to regulating the bodyrsquosdetoxification and antioxidant system When activated Nrf2dissociates from the cytosolic protein Keap1 (Kelch-like ECHassociated protein 1) and translocates to the nucleus to bindto AREs in the promoterenhancer portion of genes asso-ciated with phase II detoxification and antioxidant enzymegenes [150] (Figure 1) Nrf2-deficient animals experienceincreased toxicity from drugs [151] carcinogens allergensand environmental pollutants [152] and do not respond aswell to the anti-inflammatory effects of phytochemicals [153]indicating the essentiality of these enzymes Conversely Nrf2


Table 9 Selected dietary sources of nutrients for methylation support (adapted from [111])

MethionineMeats poultry fish shellfish egg nuts (especially Brazil nuts) seeds (especially sesame seeds andpumpkin seeds) spirulina teff soybeans Lower amounts found in other legumes and wholegrains (especially teff and oats)

Vitamin B12 Meats and meat products (especially liver and kidney) poultry fish shellfish and eggs

Vitamin B6 Meats nuts (especially pistachio) garlic whole grains seeds (especially sesame and sunflowerseeds) legumes (especially chickpeas and lentils) and prunes

Betaine Quinoa beets spinach whole grains (especially rye kamut bulgur amaranth barley and oats)sweet potato meats and poultry

FolateBeans and legumes (especially mung beans adzuki beans chickpeas and lentils) liver nuts(especially peanuts) seeds (especially sunflower seeds) spinach asparagus mustard greens andavocado

Magnesium Seeds (especially pumpkin seeds and sesame seeds) beans (especially soybeans) nuts (especiallyBrazil nuts and almonds) and whole grains (especially amaranth)

Keap1Keap1Nrf2Nrf2

ARE

Nrf2

Ubiquitination and proteasomal degradation

Oxidative stress Nrf2 inducers

Transcription of phase II detoxification and antioxidant enzymes

Cytosol

Nucleus

Figure 1 Nrf2Keap1 signaling (created from text in [154])

induction is considered protective against various oxidativestress-related conditions such as cancer kidney dysfunctionpulmonary disorders arthritis neurological disease andcardiovascular disease [154]

Research demonstrates that dietary components espe-cially phytochemicals not only scavenge reactive oxygenspecies thereby acting as direct antioxidants but also reg-ulate Nrf2 activity [150] In vivo evidence exists for Nrf2-modulation by curcumin [155ndash158] broccoli constituents[159 160] garlic [161ndash163] epicatechins [164ndash167] resvera-trol [168 169] ginger [170 171] purple sweet potato [118]isoflavones [172 173] coffee [174] rosemary [175 176]blueberry [166 177] pomegranate [178] naringenin [179]ellagic acid [166] astaxanthin [166] and 120574-tocopherol [180](Table 10(a)) A clinical trial by Magbanua et al (2011)investigating the Nrf2 modulation effects of fish oil andlycopene in the context of prostate cancer risk also demon-strated that these dietary compounds can upregulate Nrf2signaling and response to oxidative stress in humans [181]Direct comparison of the magnitude of effect between thesecompounds can be difficult to gauge Some information on

their relative effects is provided by Kavitha et al (2013) whoranked the order of potency of the compounds they tested(from highest to lowest) as chlorophyllin (a semisyntheticcompound derived from chlorophyll) blueberry ellagic acidastaxanthin and EGCG [166]

Various studies point to the advantageous effects ofwhole foods and food combinations versus specific bioactivecompounds Zhou et al (2014) for example illustrate howorganosulfur compounds are not the only Nrf2-enhancingbioactive compounds in garlic garlic carbohydrate deriva-tives also show Nrf2-modulatory activity [186] Balstad et al(2011) in testing the effects of a combination of food extractson Nrf2 activity in mice found that the combination pro-duced a larger-than-expected effect indicating an additive orsynergistic effect [176] By their calculations the food extractthey used equated to a human (70 kg) dose of 14ndash23 g each ofturmeric rosemary and thyme which is clearly not practicalfor clinical application as well as 140ndash233 g each of coffee redonion and broccoli Calabrese et al (2010) and Houghton etal (2013) have also argued that Nrf2 inducers exhibit biphasiceffects with lower doses demonstrating stimulatory effects


Table 10 (a) In vivo example nutrient inducers of the Nrf2 pathway (b) In vivo example nutrient inhibitors of the Nrf2 pathway(a)

Enzyme Food beverage or bioactive compoundsFood sources in italics

Type ofstudy Dosages used and references

Fish oil Clinical 3 times 1 gd fish oil containing 1098mg EPA and549mg DHA [181]

LycopeneTomatoes rose hips guava watermelon and papaya [111] Clinical 2 times 15mgd lycopene [181]

CurcuminTurmeric curry powder [34] In vivo

200mgkgd curcumin [155]75mgkgd curcumin [156]50mgkgd curcumin [157]200mgkgd curcumin [158]

Cruciferous vegetables In vivo 05mgkgd sulforaphane [159]Diet of 15 crushed broccoli seed [160]

Garlic In vivo50 and 100mgkgd diallyl disulfide [161]

250mgkgd raw garlic [162]25mgkg S-allyl cysteine [163]

CatechinsTea (especially green tea) cocoa legumes and grapes [182] In vivo

5 15 and 45mgkg epicatechin [164]15mgkg epicatechin [165]

20mgkgTheaphenon E (95 EGCG)[166]

5 15 and 30mgkg epicatechin [167]Resveratrol

Grapes wine peanuts soy and itadori tea [32] In vivo 10mgkgd [168]20mgkgd [169]

Nrf2 Ginger In vivo 100mgkgd [6]-shogaol [170]10 and 100mgkg dried ginger extract [171]

Purple sweet potato In vivo 100 and 200mgkg anthocyanin extract frompurple sweet potato [118]

IsoflavonesSoy kudzu root and red clover [183] In vivo 80mgkgd soy isoflavones [172]

60 and 120mgkg puerarin from kudzu root [173]

Coffee In vivo 20mLd coffee to an average animal weight of200 g plusmn 10 g [174]

Rosemary In vivo 50 and 100mgkg carnosic acid [175]5mganimal carnosol extract [176]

Blueberry In vivo 200mgkg blueberry [166]06 and 10 gday [177]

Pomegranate In vivo 1 and 10 gkg pomegranate extract [178] note highdoses used

NaringeninCitrus [179] In vivo 50mgkgd naringenin [179]



AsthaxanthinAlgae yeast salmon trout krill shrimp and crayfish [38] In vivo 15mgkg astaxanthin [166]

120574-tocopherolNuts seeds whole grains vegetable oils and legumes [111] In vivo 208mgkg 120574-tocopherol [180]

(b)

Enzyme Food beverage or bioactive compounds Type of study Dosages used and references

Nrf2 Luteolin In vivo 40mgkg luteolin three times per week[184]

Quercetin In vivo 50mgkgd quercetin [185]


and higher doses exhibiting Nrf2-interference [187 188]These data suggest that the doses found in whole foods maybe more beneficial than supplements at supraphysiologicaldoses In fact it may well be their weak prooxidant effectsthat stimulate Nrf2 inducersrsquo favorable antioxidant responses[188]

Nonuniform activities of different foods within the samefood group should once again be considered in their recentreview of the effects of plant-derived compounds on Nrf2activation Stefanson and Bakovic (2014) noted that pak choivia presumed Nrf2 activation was more effective at reducinginflammation in the colon than broccoli and that broc-coli upregulated some additional Nrf2-related antioxidantenzymes compared with pak choi [189] Interestingly thiseffect was only apparent when steamed rather than cookedbroccoli was used [189] indicating that food preparationmaybe an important consideration

Conversely to its role in cancer prevention overex-pression of Nrf2 is found in many cancer cells and hasbeen shown to promote tumor growth and resistance toanticancer therapy [154] Consequently the inhibition ofNrf2signaling may be clinically relevant for patients receivingcancer chemotherapy [184 185] Overexpression of Nrf2 andCYP2E1 has also been associated with impaired GLUT4activity and insulin resistance [68] As noted above supple-mentation (above levels normally consumed through diet)with certain phytochemicals may have inhibitory effects onNrf2 activation including luteolin [184] and quercetin [185](Table 10(b)) Vitamins A C and E and N-acetyl cysteinehave also been implicated as Nrf2 inhibitors at high doses[188] These findings point to the need for further researchto clarify outcomes as they relate to specific disease states aswell as potential biphasic dose effects

4 Metallothionein

Metallothionein a cysteine-rich protein with the ability tobind divalent cations including toxicmetals such asmercurycadmium lead and arsenic is gaining recognition as animportant component in heavy metal detoxification [190ndash192] Similar to the upregulation of phase II and antioxidantenzymes metallothionein can be induced at specific pro-moter regions of genes by stimuli such as heavymetals oxida-tive stress glucocorticoids and even zinc [192] In additionto sequestering heavy metals it is capable of scavenging freeradicals and reducing injury from oxidative stress [192] aswell as inhibiting NF-120581B signaling [193]

Dietary patterns and nutrients may result in changesin metallothionein production Lamb et al (2011) reporteda 54 increase in metallothionein mRNA production in asmall clinical trial in women with fibromyalgia followingan elimination diet in conjunction with a phytonutrient-rich medical food consisting of hops pomegranate pruneskin and watercress [194] Zinc supplementation (15mgday)to healthy men over 10 days led to significantly increasedmetallothionein mRNA up to 2-fold in leukocytes and upto 4-fold from dried blood spots [195] Metallothionein hasbeen shown to be decreased in the intestinal mucosa of

patients with inflammatory bowel disease (IBD) howeverzinc supplementation (300mg zinc aspartate equal to 60mgelemental zinc per day for 4 weeks) in 14 zinc-deficientpatients with IBD resulted in slightly higher metallothioneinconcentration in the intestinal mucosa [196] Cruciferousphytonutrients may also modulate metallothionein expres-sion as suggested by a 10-fold increase following a single oraldose of 50 120583mol sulforaphane to rats [197] Chromium mayinhibit zinc-induced metallothionein expression accordingto animal studies by Kimura et al (2011) [198] Early-stagein vitro studies also suggest that quercetin and Cordycepssinensis a mushroom native to the Himalayan region mayupregulate metallothionein expression [199 200]

5 Clinical Applications

With the continued emergence of data supporting the role oftoxins in chronic disease processes it is becoming increas-ingly necessary for clinicians to understand how to providetherapeuticmodalities to reduce toxin load in patients In thispaper several studies regarding the influence of foods andfood-based nutrients on the systems of detoxification werepresented From the current information presented listedbelow are some key concepts for translation into the clinicalsetting

51 Nonclinical versus Clinical Studies One of the limitationsthat comes to the forefront in this collection of studies ishow the information in many cases is constrained primarilyto studies in cells or animals It remains questionable as towhether similar effects would be seen in humans atmoderatereasonable doses In the cell studies it is difficult to anticipatefindings due to the lack of pleiotropic activity that occursin a complex living system with multiple detoxificationsystems working simultaneously Along similar lines animalstudies are often difficult to extrapolate to individuals dueto the degree of variability in genotype and environmentalphenotype seen in the diverse human population Thereforeat this time it is best to take precaution in firmly advocatingfoods or food-based nutrients that only have cell or animaldata as support It is best to rely on the clinical studiesthat have been published to date in making more firmrecommendations

52 Single Agent versus Lifestyle While this paper focuseson isolated nutrients and foods that contain those nutrientsit might be optimal from a clinical perspective to considerhow an entire lifestyle might induce or inhibit the arrayof detoxification enzymes For example this paper has notaddressed behaviors like smoking physical activity or stressThe modern clinician needs to weigh all these variablesagainst each other Yet science has not fully demonstratedthe individual impacts of these factors along with all of themtogether Therefore at this time a dietary pattern favoringwhole unprocessed plant-based foods and the removal orreduction of toxic substances in onersquos environment is a two-prong approach that would seem to have the best overarchingscientific underpinning


53 Modulating versus InhibitingInducing Effects In severalinstances certain foods exhibited a particular activity on anenzyme while at higher doses they had another oppositeeffect Essentially many foods serve as what is commonlyreferred to as being ldquobifunctional modulatorsrdquo possessingthe ability to effectively induce or inhibit detoxificationenzyme activity based on the dose response Therefore theresulting clinical takeaway might be to encourage patientsto follow a mixed varied diet full of different plant-basedwhole foods Smaller amounts of many compounds might bemore therapeutic and supportive for biochemical pathwaysrather than overriding signals derived from high concen-trations of nutrients through high-dose supplementation orthe repeat daily ingestion of large quantities of the samefood

54 Polypharmacy For patients who are taking multiplepharmaceuticals it is important to knowwhich detoxificationsystems will be influenced by nutrients and foods so that sideeffects are minimized or avoided

55 Dietary Supplements versus Foods Since there can bepotent effects of food-based nutrients on detoxification path-ways it would be best for the average patient to followas indicated above a mixed complex and whole-foodsdiet Additionally dietary supplements may be a helpfuladjunct in patients in which the practitioner has informationabout the patientrsquos genetic variability so that nutrients canbe tailored accordingly Without a full understanding of apatientrsquos SNPs (single nucleotide polymorphisms) it becomesdifficult to make accurate assessments about nutrients anddosing

56 Duration of Dosing Another factor to consider in ther-apeutic intervention is the timing and duration of the doseof nutrient or the food In some of the research presentedhere effects on detoxification enzymes were seen after severaldays of food intake or supplementation while in other casesinduction of an enzyme might be fairly rapid followed byefficient adaptability This variable needs to be consideredin further clinical research and requires close monitoring inclinical practice

57 Foods Known to Impact Detoxification Based on the foursystems examined in this paper there are several foods whichseem to have demonstrated an influence on detoxificationsystems Many of them have been acknowledged as part ofnaturopathic medicine Hence it would be useful to have aknowledge base of this cumulative set of foods as patientsembark upon detoxification protocols This recent scientificupdate notes clinical evidence of effects from cruciferousvegetables (in combination and specifically watercress gar-den cress and broccoli) allium vegetables apiaceous veg-etables grapefruit resveratrol fish oil quercetin daidzeinand lycopene Many other foods beverages and nutrientbioactive compounds based on this review of scientificliterature are also suggested as modulators of detoxificationenzymes in vivo (Table 11)

Table 11 Food beverages and bioactive compounds with demon-strated or potential clinical impact on detoxification systems

Food or beverage Nutrient bioactivecompounds

Allium vegetables AstaxanthinApiaceous vegetables Caffeic acidBlack raspberry Catechins (including EGCG)Black tea ChrysinBlueberry CurcuminChamomile tea DaidzeinChicory root Ellagic acidCitrus Ferulic acidCoffee Fish oilCruciferous vegetables (with potential Genisteinfor distinct effects of different Luteolincrucifers) LycopeneDandelion tea MCTsGarlic MyricetinGhee N-acetyl cysteineGinger NaringeninGrapefruit QuercetinGreen tea ResveratrolHoneybush tea Retinoic acid (vitamin A)Peppermint teaPomegranatePurple sweet potatoRooibos teaRosemarySoybeanblack soybeanTurmeric

6 Conclusions

Over the past decade there has been investigation intonutrigenomic and epigenetic influences of food constituentson chronic diseases [201 202] Similarly studies have revealedthat exposure to and accumulation of toxins play a significantrole in cardiovascular disease type 2 diabetes and obesity[203ndash207] Thus onersquos dietary intake and environmentalinfluences may have large bearing on the incidence ofchronic disease In fact these influences may be significantnot just for the individual but for several generations dueto the transgenerational inheritance of epigenetic changes[208 209] Therefore it would seem that designing clinicalrecommendations to maximize the effects of food and reducethe impact of toxins is essential However it is not withoutcaution and critical thinking that a detoxification protocolshould be assembled for patients by trained clinicians Thereremain many unresolved issues regarding knowing how andwhat foods modulate detoxification pathways


Conflict of Interests

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

Authorsrsquo Contribution

All authors read and approved the final version of the paper

References

[1] W Baer-Dubowska and H Szaefer ldquoModulation of carcinogen-metabolizing cytochromes P450 by phytochemicals in humansrdquoExpert Opinion on Drug Metabolism and Toxicology vol 9 no8 pp 927ndash941 2013

[2] H Steinkellner S Rabot C Freywald et al ldquoEffects of crucif-erous vegetables and their constituents on drug metabolizingenzymes involved in the bioactivation of DNA-reactive dietarycarcinogensrdquo Mutation Research vol 480-481 pp 285ndash2972001

[3] Y J Moon X Wang and M E Morris ldquoDietary flavonoidseffects on xenobiotic and carcinogen metabolismrdquo Toxicologyin Vitro vol 20 no 2 pp 187ndash210 2006

[4] N Hakooz and I Hamdan ldquoEffects of dietary broccoli onhuman in vivo caffeine metabolism a pilot study on a groupof Jordanian volunteersrdquo Current DrugMetabolism vol 8 no 1pp 9ndash15 2007

[5] D James S Devaraj P Bellur S Lakkanna J Vicini andS Boddupalli ldquoNovel concepts of broccoli sulforaphanes anddisease induction of phase II antioxidant and detoxifica-tion enzymes by enhanced-glucoraphanin broccolirdquo NutritionReviews vol 70 no 11 pp 654ndash665 2012

[6] H S Aiyer and R C Gupta ldquoBerries and ellagic acid pre-vent estrogen-inducedmammary tumorigenesis bymodulatingenzymes of estrogen metabolismrdquo Cancer Prevention Researchvol 3 no 6 pp 727ndash737 2010

[7] Bogacz A P Ł Mikołajczak P Ł Mikołajczak et al ldquoTheinfluence of soybean extract on the expression level of selecteddrug transporters transcription factors and cytochrome P450genes encoding phase I drug-metabolizing enzymesrdquoGinekolo-gia Polska vol 85 no 5 pp 348ndash353 2014

[8] D M Davenport and M J Wargovich ldquoModulation ofcytochrome P450 enzymes by organosulfur compounds fromgarlicrdquo Food and Chemical Toxicology vol 43 no 12 pp 1753ndash1762 2005

[9] C K Lii C W Tsai and C C Wu ldquoGarlic allyl sulfides displaydifferential modulation of rat cytochrome P450 2B1 and theplacental form glutathione S-transferase in various organsrdquoJournal of Agricultural and Food Chemistry vol 54 no 14 pp5191ndash5196 2006

[10] C M Kaefer and J A Milner ldquoThe role of herbs and spices incancer preventionrdquo Journal of Nutritional Biochemistry vol 19no 6 pp 347ndash361 2008

[11] Y W Hsieh C Y Huang S Y Yang et al ldquoOral intake ofcurcumin markedly activated CYP 3A4 in vivo and ex-vivostudiesrdquo Scientific Reports vol 4 article 6587 2014

[12] M Murray and J Pizzorno Encyclopedia of Natural MedicinePrima Publishing Rocklin Calif USA 2nd edition 1998

[13] Institute for Functional Medicine Textbook of FunctionalMedicine Johnston Printing Boulder Colo USA 2006

[14] V Ullrich ldquoCytochrome P450 and biological hydroxylationreactionsrdquoTopics in Current Chemistry vol 83 pp 67ndash104 1979

[15] P B Danielson ldquoThe cytochrome P450 superfamily biochem-istry evolution and drugmetabolism in humansrdquoCurrent DrugMetabolism vol 3 no 6 pp 561ndash597 2002

[16] A J Paine ldquoHepatic cytochrome P-450rdquo Essays in Biochemistryvol 17 pp 85ndash126 1981

[17] Q Chen T Zhang J F Wang and D Q Wei ldquoAdvances inhuman cytochrome P450 and personalized medicinerdquo CurrentDrug Metabolism vol 12 no 5 pp 436ndash444 2011

[18] Q Ma and A Y H Lu ldquoCYP1A induction and human riskassessment an evolving tale of in vitro and in vivo studiesrdquoDrugMetabolism and Disposition vol 35 no 7 pp 1009ndash1016 2007

[19] M O James J C Sacco and L R Faux ldquoEffects of food naturalproducts on the biotransformation of PCBsrdquo EnvironmentalToxicology and Pharmacology vol 25 no 2 pp 211ndash217 2008

[20] K Vistisen S Loft J H Olsen et al ldquoLow CYP1A2 activityassociated with testicular cancerrdquo Carcinogenesis vol 25 no 6pp 923ndash929 2004

[21] N Bozina V Bradamante and M Lovric ldquoGenetic polymor-phism of metabolic enzymes P450 (CYP) as a susceptibilityfactor for drug response toxicity and cancer riskrdquo Arhiv zaHigijenu Rada i Toksikologiju vol 60 no 2 pp 217ndash242 2009

[22] Y Tsuchiya M Nakajima and T Yokoi ldquoCytochrome P450-mediatedmetabolism of estrogens and its regulation in humanrdquoCancer Letters vol 227 no 2 pp 115ndash124 2005

[23] J J Michnovicz and H L Bradlow ldquoInduction of estradiolmetabolism by dietary indole-3-carbinol in humansrdquo Journal ofthe National Cancer Institute vol 82 no 11 pp 947ndash949 1990

[24] S Peterson Y Schwarz S S Li et al ldquoCYP1A2 GSTM1 andGSTT1 polymorphisms and diet effects on CYP1A2 activity ina crossover feeding trialrdquo Cancer Epidemiology Biomarkers andPrevention vol 18 no 11 pp 3118ndash3125 2009

[25] D G Walters P J Young C Agus et al ldquoCruciferous vegetableconsumption alters the metabolism of the dietary carcinogen2-amino-1-methyl-6-phenylimidazo[45-b]pyridine (PhIP) inhumansrdquo Carcinogenesis vol 25 no 9 pp 1659ndash1669 2004

[26] M A Kall O Vang and J Clausen ldquoEffects of dietary broccolion human in vivo drug metabolizing enzymes evaluation ofcaffeine oestrone and chlorzoxazone metabolismrdquo Carcinogen-esis vol 17 no 4 pp 793ndash799 1996

[27] T L Horn M A Reichert R L Bliss and D Malejka-GigantildquoModulations of P450 mRNA in liver and mammary gland andP450 activities andmetabolism of estrogen in liver by treatmentof rats with indole-3-carbinolrdquo Biochemical Pharmacology vol64 no 3 pp 393ndash404 2002

[28] 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

[29] Y Chen P Xiao D S Ou-Yang et al ldquoSimultaneous actionof the flavonoid quercetin on cytochrome p450 (cyp) 1a2cyp2a6 n-acetyltransferase and xanthine oxidase activity inhealthy volunteersrdquo Clinical and Experimental Pharmacologyand Physiology vol 36 no 8 pp 828ndash833 2009

[30] R S Lord B Bongiovanni and J A Bralley ldquoEstrogenmetabolism and the diet-cancer connection rationale forassessing the ratio of urinary hydroxylated estrogen metabo-litesrdquo Alternative Medicine Review vol 7 no 2 pp 112ndash1292002


[31] H Takemura H Sakakibara S Yamazaki and K ShimoildquoBreast cancer and flavonoidsmdasha role in preventionrdquo CurrentPharmaceutical Design vol 19 no 34 pp 6125ndash6132 2013

[32] J Burns T Yokota H Ashihara M E J Lean and A CrozierldquoPlant foods and herbal sources of resveratrolrdquo Journal ofAgricultural and Food Chemistry vol 50 no 11 pp 3337ndash33402002

[33] H T Yao Y R Hsu C K Lii A H Lin K H Chang and HT Yang ldquoEffect of commercially available green and black teabeverages on drug-metabolizing enzymes and oxidative stressin Wistar ratsrdquo Food and Chemical Toxicology vol 70 pp 120ndash127 2014

[34] R F Tayyem D D Heath W K Al-Delaimy and C L RockldquoCurcumin content of turmeric and curry powdersrdquo Nutritionand Cancer vol 55 no 2 pp 126ndash131 2006

[35] S S Bansal H Kausar M V Vadhanam et al ldquoCurcuminimplants not curcumin diet inhibit estrogen-induced mam-mary carcinogenesis in ACI ratsrdquo Cancer Prevention Researchvol 7 no 4 pp 456ndash465 2014

[36] H W Chen C W Tsai J J Yang C T Liu W W Kuo andC K Lii ldquoThe combined effects of garlic oil and fish oil onthe hepatic antioxidant anddrug-metabolizing enzymes of ratsrdquoBritish Journal of Nutrition vol 89 no 2 pp 189ndash200 2003

[37] P Debersac J M Heydel M J Amiot et al ldquoInductionof cytochrome P450 andor detoxication enzymes by variousextracts of rosemary Description of specific patternsrdquo Food andChemical Toxicology vol 39 no 9 pp 907ndash918 2001

[38] R R Ambati P S Moi S Ravi and R G AswathanarayanaldquoAstaxanthin sources extraction stability biological activitiesand its commercial applicationsmdasha reviewrdquoMarine Drugs vol12 no 1 pp 128ndash152 2014

[39] S Gradelet P Astorg J Leclerc J Chevalier M-F Vernevautand M-H Siess ldquoEffects of canthaxanthin astaxanthinlycopene and lutein on liver xenobiotic-metabolizing enzymesin the ratrdquo Xenobiotica vol 26 no 1 pp 49ndash63 1996

[40] A Bu-Abbas M N Clifford R Walker and C IoannidesldquoSelective induction of rat hepatic CYP1 and CYP4 proteins andof peroxisomal proliferation by green teardquo Carcinogenesis vol15 no 11 pp 2575ndash2579 1994

[41] M K Rasmussen C Brunius G Zamaratskaia and BEkstrand ldquoFeeding dried chicory root to pigs decrease andro-stenone accumulation in fat by increasing hepatic 3120573 hydroxys-teroid dehydrogenase expressionrdquo Journal of Steroid Biochem-istry and Molecular Biology vol 130 no 1-2 pp 90ndash95 2012

[42] C Usta S Ozdemir M Schiariti and P E Puddu ldquoThepharmacological use of ellagic acid-rich pomegranate fruitrdquoInternational Journal of Food Sciences and Nutrition vol 64 no7 pp 907ndash913 2013

[43] G Celik A Semiz S Karakurt S Arslan O Adali and A SenldquoA comparative study for the evaluation of two doses of ellagicacid on hepatic drug metabolizing and antioxidant enzymes inthe ratrdquo BioMed Research International vol 2013 Article ID358945 9 pages 2013

[44] T Zhang S Jiang C He Y Kimura Y Yamashita and HAshida ldquoBlack soybean seed coat polyphenols prevent B(a)P-induced DNA damage through modulating drug-metabolizingenzymes in HepG2 cells and ICRmicerdquoMutation Research vol752 no 1-2 pp 34ndash41 2013

[45] F Catterall N J McArdle L Mitchell A Papayanni M NClifford and C Ioannides ldquoHepatic and intestinal cytochromeP450 and conjugase activities in rats treated with black tea

theafulvins and theaflavinsrdquo Food and Chemical Toxicology vol41 no 8 pp 1141ndash1147 2003

[46] R Thapliyal and G B Maru ldquoInhibition of cytochrome P450isozymes by curcumins in vitro and in vivordquo Food and ChemicalToxicology vol 39 no 6 pp 541ndash547 2001

[47] L Sampson E Rimm P C H Hollman J H M de Vriesand M B Katan ldquoFlavonol and flavone intakes in US healthprofessionalsrdquo Journal of the American Dietetic Association vol102 no 10 pp 1414ndash1420 2002

[48] M G L Hertog E J M Feskens P C H Hollman et al ldquoCon-tent of potentially anticarcinogenic flavonoids of 28 vegetablesand 9 fruits commonly consumed in the Netherlandsrdquo Journalof Agricultural and Food Chemistry vol 40 no 12 pp 2379ndash2383 1992

[49] W X Peng H D Li and H H Zhou ldquoEffect of daidzeinon CYP1A2 activity and pharmacokinetics of theophylline inhealthy volunteersrdquo European Journal of Clinical Pharmacologyvol 59 no 3 pp 237ndash241 2003

[50] U Fuhr K Klittich and A H Staib ldquoInhibitory effect ofgrapefruit juice and its bitter principal naringenin on CYP1A2dependent metabolism of caffeine in manrdquo British Journal ofClinical Pharmacology vol 35 no 4 pp 431ndash436 1993

[51] I Yamasaki M Yamada N Uotsu S Teramoto R Takayanagiand Y Yamada ldquoInhibitory effects of kale ingestion onmetabolism by cytochrome P450 enzymes in ratsrdquo BiomedicalResearch vol 33 no 4 pp 235ndash242 2012

[52] T Zeng C L Zhang F Y Song X Y Han and K Q Xie ldquoThemodulatory effects of garlic oil on hepatic cytochrome P450s inmicerdquo Human and Experimental Toxicology vol 28 no 12 pp777ndash783 2009

[53] P P Maliakal and S Wanwimolruk ldquoEffect of herbal teason hepatic drug metabolizing enzymes in ratsrdquo Journal ofPharmacy andPharmacology vol 53 no 10 pp 1323ndash1329 2001

[54] A U Nissar M R Farrukh P J Kaiser et al ldquoEffect of N-acetyl cysteine (NAC) an organosulfur compound fromAlliumplants on experimentally induced hepatic prefibrogenic eventsin wistar ratrdquo Phytomedicine vol 20 no 10 pp 828ndash833 2013

[55] F I Al-Jenoobi A A Al-Thukair M A Alam et al ldquoEffectof garden cress seeds powder and its alcoholic extract on themetabolic activity of CYP2D6 and CYP3A4rdquo Evidence-BasedComplementary and Alternative Medicine vol 2014 Article ID634592 6 pages 2014

[56] D Park J H Jeon S Shin et al ldquoGreen tea extract increasescyclophosphamide-induced teratogenesis by modulating theexpression of cytochrome P-450 mRNArdquo Reproductive Toxicol-ogy vol 27 no 1 pp 79ndash84 2009

[57] V Yoxall P Kentish N Coldham N Kuhnert M J Sauerand C Ioannides ldquoModulation of hepatic cytochromes P450and phase II enzymes by dietary doses of sulforaphane inrats implications for its chemopreventive activityrdquo InternationalJournal of Cancer vol 117 no 3 pp 356ndash362 2005

[58] C Li S C Lim J Kim and J S Choi ldquoEffects ofmyricetin an anticancer compound on the bioavailability andpharmacokinetics of tamoxifen and its main metabolite 4-hydroxytamoxifen in ratsrdquo European Journal of Drug Meta-bolism and Pharmacokinetics vol 36 no 3 pp 175ndash182 2011

[59] I Leclercq J P Desager and Y Horsmans ldquoInhibition ofchlorzoxazone metabolism a clinical probe for CYP2E1 bya single ingestion of watercressrdquo Clinical Pharmacology andTherapeutics vol 64 no 2 pp 144ndash149 1998

[60] G D Loizou and J Cocker ldquoThe effects of alcohol and diallylsulphide on CYP2E1 activity in humans a phenotyping study


using chlorzoxazonerdquoHuman andExperimental Toxicology vol20 no 7 pp 321ndash327 2001

[61] K A Park S Kweon and H Choi ldquoAnticarcinogenic effect andmodification of cytochrome P450 2E1 by dietary garlic powderin diethylnitrosamine-initiated rat hepatocarcinogenesisrdquo Jour-nal of Biochemistry andMolecular Biology vol 35 no 6 pp 615ndash622 2002

[62] C M Park Y S Cha H J Youn C W Cho and Y SSong ldquoAmelioration of oxidative stress by dandelion extractthrough CYP2E1 suppression against acute liver injury inducedby carbon tetrachloride in sprague-dawley ratsrdquo PhytotherapyResearch vol 24 no 9 pp 1347ndash1353 2010

[63] M Tahir and S Sultana ldquoChrysin modulates ethanol meta-bolism inWistar rats a promising role against organ toxicitiesrdquoAlcohol and Alcoholism vol 46 no 4 Article ID agr038 pp383ndash392 2011

[64] C S Lieber Q Cao L M Decarli et al ldquoRole of medium-chain triglycerides in the alcohol-mediated cytochrome P4502E1 induction ofmitochondriardquoAlcoholism Clinical and Exper-imental Research vol 31 no 10 pp 1660ndash1668 2007

[65] S A Sheweita ldquoDrug-metabolizing enzymes mechanisms andfunctionsrdquo Current Drug Metabolism vol 1 no 2 pp 107ndash1322000

[66] N K Zgheib Z Mitri E Geryess and P Noutsi ldquoCytochromeP4502E1 (CYP2E1) genetic polymorphisms in a Lebanese pop-ulation frequency distribution and association with morbiddiseasesrdquo Genetic Testing and Molecular Biomarkers vol 14 no3 pp 393ndash397 2010

[67] C A Gonzalez N Sala and G Capella ldquoGenetic susceptibilityand gastric cancer riskrdquo International Journal of Cancer vol 100no 3 pp 249ndash260 2002

[68] M Armoni C Harel M Ramdas and E Karnieli ldquoCYP2E1impairs GLUT4 gene expression and function NRF2 as apossible mediatorrdquo Hormone and Metabolic Research vol 46no 7 pp 477ndash483 2014

[69] K Matsuda Y Nishimura N Kurata M Iwase and HYasuhara ldquoEffects of continuous ingestion of herbal teas onintestinal CYP3A in the ratrdquo Journal of Pharmacological Sci-ences vol 103 no 2 pp 214ndash221 2007

[70] C C Wu L Y Sheen H W Chen W W Kuo S J Tsai andC K Lii ldquoDifferential effects of garlic oil and its three majororganosulfur components on the hepatic detoxification systemin ratsrdquo Journal of Agricultural and Food Chemistry vol 50 no2 pp 378ndash383 2002

[71] 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

[72] S N Umathe P V Dixit V Kumar K U Bansod and M MWanjari ldquoQuercetin pretreatment increases the bioavailabilityof pioglitazone in rats involvement of CYP3A inhibitionrdquoBiochemical Pharmacology vol 75 no 8 pp 1670ndash1676 2008

[73] J Liu G J Tawa and A Wallqvist ldquoIdentifying cytochromeP450 functional networks and their allosteric regulatory ele-mentsrdquo PLoS ONE vol 8 no 12 Article ID e81980 2013

[74] S Tanaka S Uchida S Miyakawa et al ldquoComparison ofinhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4rdquoBiologicaland Pharmaceutical Bulletin vol 36 no 12 pp 1936ndash1941 2013

[75] D A Leibelt O R Hedstrom K A Fisher C B Pereira and DE Williams ldquoEvaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 331015840-diidolylmethane in

Sprague-Dawley ratsrdquo Toxicological Sciences vol 74 no 1 pp10ndash21 2003

[76] Linus Pauling Institute Garlic and Organosulfur CompoundsMicronutrient Information Center Corvallis Ore USA 2008httplpioregonstateeduinfocenterphytochemicalsgarlic

[77] C Ioannides ldquoEffect of diet and nutrition on the expression ofcytochromes P450rdquoXenobiotica vol 29 no 2 pp 109ndash154 1999

[78] B Baer and A Rettie ldquoCYP4B1 an enigmatic P450 at theinterface between xenobiotic and endobioticmetabolismrdquoDrugMetabolism Reviews vol 38 no 3 pp 451ndash476 2006

[79] Z Ye Z Liu A Henderson et al ldquoIncreased CYP4B1 mRNAis associated with the inhibition of dextran sulfate sodium-induced colitis by caffeic acid in micerdquo Experimental Biologyand Medicine (Maywood) vol 234 no 6 pp 606ndash616 2009

[80] S Lafay C Morand C Manach C Besson and A ScalbertldquoAbsorption and metabolism of caffeic acid and chlorogenicacid in the small intestine of ratsrdquo British Journal of Nutritionvol 96 no 1 pp 39ndash46 2006

[81] C Xu C Y Li and A T Kong ldquoInduction of phase I IIand III drug metabolismtransport by xenobioticsrdquo Archives ofPharmacal Research vol 28 no 3 pp 249ndash268 2005

[82] G Ginsberg K Guyton D Johns J Schimek K Angleand B Sonawane ldquoGenetic polymorphism in metabolism andhost defense enzymes implications for human health riskassessmentrdquo Critical Reviews in Toxicology vol 40 no 7 pp575ndash619 2010

[83] P Jancova P Anzenbacher and E Anzenbacherova ldquoPhase IIdrug metabolizing enzymesrdquo Biomedical Papers vol 154 no 2pp 103ndash116 2010

[84] C Jenkinson A Petroczi and D P Naughton ldquoEffects ofdietary components on testosterone metabolism via UDP-glucuronosyltransferaserdquo Frontiers in Endocrinology vol 4article 80 2013

[85] J L Chang J Bigler Y Schwarz et al ldquoUGT1A1 polymorphismis associated with serum bilirubin concentrations in a random-ized controlled fruit and vegetable feeding trialrdquo Journal ofNutrition vol 137 no 4 pp 890ndash897 2007

[86] A Rowland J O Miners and P I Mackenzie ldquoThe UDP-glucuronosyltransferases their role in drug metabolism anddetoxificationrdquo International Journal of Biochemistry and CellBiology vol 45 no 6 pp 1121ndash1132 2013

[87] C P Strassburg S Kneip J Topp et al ldquoPolymorphic generegulation and interindividual variation of UDP-glucurono-syltransferase activity in human small intestinerdquoThe Journal ofBiological Chemistry vol 275 no 46 pp 36164ndash36171 2000

[88] P G Wells P I Mackenzie J R Chowdhury et al ldquoGlucu-ronidation and theUDP-glucuronosyltransferases in health anddiseaserdquo Drug Metabolism and Disposition vol 32 no 3 pp281ndash290 2004

[89] 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

[90] S L Navarro S Peterson C Chen et al ldquoCruciferous vegetablefeeding alters UGT1A1 activity diet- and genotype-dependentchanges in serum bilirubin in a controlled feeding trialrdquo CancerPrevention Research (Phila) vol 2 no 4 pp 345ndash352 2009

[91] S S Hecht S G Carmella and S E Murphy ldquoEffects ofwatercress consumption on urinary metabolites of nicotine insmokersrdquo Cancer Epidemiology Biomarkers and Prevention vol8 no 10 pp 907ndash913 1999


[92] M R Saracino J Bigler Y Schwarz et al ldquoCitrus fruitintake is associated with lower serum bilirubin concentrationamong women with the UGT1A128 polymorphismrdquo Journal ofNutrition vol 139 no 3 pp 555ndash560 2009

[93] J L Marnewick E Joubert P Swart F van der Westhuizenand W C Gelderblom ldquoModulation of hepatic drug metab-olizing enzymes and oxidative status by rooibos (Aspalathuslinearis) andHoneybush (Cyclopia intermedia) green and black(Camellia sinensis) teas in ratsrdquo Journal of Agricultural and FoodChemistry vol 51 no 27 pp 8113ndash8119 2003

[94] A Marahatta B Bhandary S-K Jeong H-R Kim and H-JChae ldquoSoybean greatly reduces valproic acid plasma concen-trations a food-drug interaction studyrdquo Scientific Reports vol4 article 4362 2014

[95] E M J van der Logt H M J Roelofs F M Nagengastand W H M Peters ldquoInduction of rat hepatic and intestinalUDP-glucuronosyltransferases by naturally occurring dietaryanticarcinogensrdquo Carcinogenesis vol 24 no 10 pp 1651ndash16562003

[96] E Graf ldquoAntioxidant potential of ferulic acidrdquo Free RadicalBiology and Medicine vol 13 no 4 pp 435ndash448 1992

[97] C B Simone II N L Simone M Pallante and C B SimoneldquoCancer lifestyle modification and glucaraterdquo Journal of Ortho-molecular Medicine vol 16 no 2 pp 83ndash90 2001

[98] R Zołtaszek M Hanausek Z M Kilianska and Z WalaszekldquoThe biological role of D-glucaric acid and its deriva-tives potential use in medicinerdquo Postpy Higieny i MedycynyDoswiadczalnej vol 62 pp 451ndash462 2008

[99] C Dwivedi W J Heck A A Downie S Larroya and TE Webb ldquoEffect of calcium glucarate on beta-glucoronidaseactivity and glucarate content of certain vegetable and fruitsrdquoBiochemical Medicine and Metabolic Biology vol 43 no 2 pp83ndash92 1990

[100] M Kosmala Z Zdunczyk K Kołodziejczyk E KlimczakJ Jukiewicz and P Zdunczyk ldquoChemical composition ofpolyphenols extracted from strawberry pomace and their effecton physiological properties of diets supplementedwith differenttypes of dietary fibre in ratsrdquo European Journal of Nutrition vol53 no 2 pp 521ndash532 2014

[101] S S Maruti J L Chang J A Prunty et al ldquoSerum 120573-glucuronidase activity in response to fruit and vegetable sup-plementation a controlled feeding studyrdquo Cancer EpidemiologyBiomarkers and Prevention vol 17 no 7 pp 1808ndash1812 2008

[102] A Jurgonski J Juskiewicz Z Zdunczyk P Matusevicius andK Kołodziejczyk ldquoPolyphenol-rich extract from blackcurrantpomace attenuates the intestinal tract and serum lipid changesinduced by a high-fat diet in rabbitsrdquo European Journal ofNutrition vol 53 no 8 pp 1603ndash1613 2014

[103] M O James and S Ambadapadi ldquoInteractions of cytosolicsulfotransferases with xenobioticsrdquo Drug Metabolism Reviewsvol 45 no 4 pp 401ndash414 2013

[104] S Kodama and M Negishi ldquoSulfotransferase genes regulationby nuclear receptors in response to xenoendo-bioticsrdquo DrugMetabolism Reviews vol 45 no 4 pp 441ndash449 2013

[105] L-QWang andM O James ldquoInhibition of sulfotransferases byxenobioticsrdquo Current Drug Metabolism vol 7 no 1 pp 83ndash1042006

[106] D Ung and S Nagar ldquoVariable sulfation of dietary polyphenolsby recombinant human sulfotransferase (SULT) 1A1 geneticvariants and SULT1E1rdquo Drug Metabolism and Disposition vol35 no 5 pp 740ndash746 2007

[107] T Zhou Y Chen C Huang and G Chen ldquoCaffeine inductionof sulfotransferases in rat liver and intestinerdquo Journal of AppliedToxicology vol 32 no 10 pp 804ndash809 2012

[108] S Maiti X Chen and G Chen ldquoAll-trans retinoic acid induc-tion of sulfotransferasesrdquo Basic and Clinical Pharmacology andToxicology vol 96 no 1 pp 44ndash53 2005

[109] K Kamio K Honke and A Makita ldquoPyridoxal 5rsquo-phosphatebinds to a lysine residue in the adenosine 31015840-phosphate 51015840-phosphosulfate recognition site of glycolipid sulfotransferasefrom human renal cancer cellsrdquo Glycoconjugate Journal vol 12no 6 pp 762ndash766 1995

[110] M Masters and R A McCance ldquoThe sulfur content of foodsrdquoBiochemical Journal vol 33 no 8 pp 1304ndash1312 1939

[111] USDA National Nutrient Database for Standard ReferenceNutrient Data Laboratory Release 27 Agriculture Research Ser-viceWashingtonDCUSA 2011 httpndbnalusdagovndb

[112] S A McFadden ldquoPhenotypic variation in xenobiotic meta-bolism and adverse environmental response focus on sulfur-dependent detoxification pathwaysrdquo Toxicology vol 111 no 1ndash3pp 43ndash65 1996

[113] J D Hayes and D J Pulford ldquoThe glutathione S-transferasesupergene family regulation of GST and the contribution of theisoenzymes to cancer chemoprotection and drug resistancerdquoCritical Reviews in Biochemistry and Molecular Biology vol 30no 6 pp 445ndash600 1995

[114] S L Navarro J L Chang S Peterson et al ldquoModulation ofhuman serum glutathione S-transferase A12 concentration bycruciferous vegetables in a controlled feeding study is influ-enced by GSTM1 and GSTT1 genotypesrdquo Cancer EpidemiologyBiomarkers and Prevention vol 18 no 11 pp 2974ndash2978 2009

[115] P AWarkM J A L GrubbenW HM Peters et al ldquoHabitualconsumption of fruits and vegetables associations with humanrectal glutathione S-transferaserdquo Carcinogenesis vol 25 no 11pp 2135ndash2142 2004

[116] J W Lampe C Chen S Li et al ldquoModulation of human glu-tathione S-transferases by botanically defined vegetable dietsrdquoCancer Epidemiology Biomarkers and Prevention vol 9 no 8pp 787ndash793 2000

[117] W A Nijhoff T P J Mulder H Verhagen G van Poppel andW H M Peters ldquoEffects of consumption of brussels sprouts onplasma and urinary glutathione S-transferase class-alpha and -pi in humansrdquo Carcinogenesis vol 16 no 4 pp 955ndash957 1995

[118] Y P Hwang J H Choi H J Yun et al ldquoAnthocyanins frompurple sweet potato attenuate dimethylnitrosamine-inducedliver injury in rats by inducing Nrf2-mediated antioxidantenzymes and reducing COX-2 and iNOS expressionrdquo Food andChemical Toxicology vol 49 no 1 pp 93ndash99 2011

[119] M Iqbal S D Sharma Y Okazaki M Fujisawa and S OkadaldquoDietary supplementation of curcumin enhances antioxidantand phase II metabolizing enzymes in ddY male mice possiblerole in protection against chemical carcinogenesis and toxicityrdquoPharmacology and Toxicology vol 92 no 1 pp 33ndash38 2003

[120] B J Newsome M C Petriello S G Han et al ldquoGreentea diet decreases PCB 126-induced oxidative stress in miceby up-regulating antioxidant enzymesrdquo Journal of NutritionalBiochemistry vol 25 no 2 pp 126ndash135 2014

[121] C Y Lin J H Chen R H Fu and C W Tsai ldquoInduction of Piform of glutathione S-transferase by carnosic acid is mediatedthrough PI3KAktNF-120581B pathway and protects against neu-rotoxicityrdquo Chemical Research in Toxicology vol 27 no 11 pp1958ndash1966 2014


[122] K Chinnadurai H K Kanwal A K Tyagi C Stanton and PRoss ldquoHigh conjugated linoleic acid enriched ghee (clarifiedbutter) increases the antioxidant and antiatherogenic potencyin female Wistar ratsrdquo Lipids in Health and Disease vol 12 no1 article 121 2013

[123] E B Froyen J L R Reeves A E Mitchell and F M SteinbergldquoRegulation of phase II enzymes by Genistein and daidzein inmale and female SwissWebstermicerdquo Journal ofMedicinal Foodvol 12 no 6 pp 1227ndash1237 2009

[124] J L Perez G K Jayaprakasha A Cadena E Martinez HAhmad and B S Patil ldquoIn vivo induction of phase II detoxi-fying enzymes glutathione transferase and quinone reductaseby citrus triterpenoidsrdquo BMC Complementary and AlternativeMedicine vol 10 article 51 2010

[125] J R Barrett ldquoThe science of soy what do we really knowrdquoEnvironmental Health Perspectives vol 114 no 6 pp A352ndashA358 2006

[126] H Wiegand C Boesch-Saadatmandi I Regos D Treutter SWolffram and G Rimbach ldquoEffects of quercetin and catechinon hepatic glutathione-s transferase (GST) NAD(P)H quinoneoxidoreductase 1 (NQO1) and antioxidant enzyme activitylevels in ratsrdquo Nutrition and Cancer vol 61 no 5 pp 717ndash7222009

[127] M B Gomes and C A Negrato ldquoAlpha-lipoic acid as apleiotropic compound with potential therapeutic use in dia-betes and other chronic diseasesrdquo Diabetology amp MetabolicSyndrome vol 6 no 1 article 80 2014

[128] Linus Pauling Institute Lipoic Acid Micronutrient InformationCenter Corvalis Ore USA 2012 httplpioregonstateeduinfocenterothernutsla

[129] R W Kalpravidh N Siritanaratkul P Insain et al ldquoImprove-ment in oxidative stress and antioxidant parameters in beta-thalassemiaHb E patients treated with curcuminoidsrdquo ClinicalBiochemistry vol 43 no 4-5 pp 424ndash429 2010

[130] M I Lucena R J Andrade J P de la Cruz M Rodriguez-Mendizabal E Blanco and F Sanchez de la Cuesta ldquoEffects ofsilymarin MZ-80 on oxidative stress in patients with alcoholiccirrhosisrdquo International Journal of Clinical Pharmacology andTherapeutics vol 40 no 1 pp 2ndash8 2002

[131] R A Santana-Martınez S Galvan-Arzate R Hernandez-Pando et al ldquoSulforaphane reduces the alterations induced byquinolinic acidmodulation of glutathione levelsrdquoNeurosciencevol 272 pp 188ndash198 2014

[132] M F Chen L T Chen and H W Boyce Jr ldquoCruciferousvegetables and glutathione their effects on colon mucosalglutathione level and colon tumor development in rats inducedby DMHrdquo Nutrition and Cancer vol 23 no 1 pp 77ndash83 1995

[133] E M El Morsy and R Kamel ldquoProtective effect of artichokeleaf extract against paracetamol-induced hepatotoxicity in ratsrdquoPharmaceutical Biology vol 53 no 2 pp 167ndash173 2015

[134] H A Brauer T E Libby B L Mitchell et al ldquoCruciferousvegetable supplementation in a controlled diet study alters theserum peptidome in a GSTM1-genotype dependent mannerrdquoNutrition Journal vol 10 no 1 article 11 2011

[135] T Hofmann A Kuhnert A Schubert et al ldquoModulation ofdetoxification enzymes by watercress in vitro and in vivo inves-tigations in human peripheral blood cellsrdquo European Journal ofNutrition vol 48 no 8 pp 483ndash491 2009

[136] H J Forman H Zhang and A Rinna ldquoGlutathione overviewof its protective roles measurement and biosynthesisrdquoMolecu-lar Aspects of Medicine vol 30 no 1-2 pp 1ndash12 2009

[137] J K Kern D A Geier J B Adams C R Garver T Audhya andM R Geier ldquoA clinical trial of glutathione supplementation inautism spectrumdisordersrdquoMedical ScienceMonitor vol 17 no12 pp CR677ndashCR682 2011

[138] P G Paterson A W Lyon H Kamencic L B Andersen andB H J Juurlink ldquoSulfur amino acid deficiency depresses brainglutathione concentrationrdquoNutritional Neuroscience vol 4 no3 pp 213ndash222 2001

[139] A T Treweeke T J Winterburn I Mackenzie et alldquoN-Acetylcysteine inhibits platelet-monocyte conjugation inpatients with type 2 diabetes with depleted intraplatelet glu-tathione a randomised controlled trialrdquo Diabetologia vol 55no 11 pp 2920ndash2928 2012

[140] L Galluzzi I Vitale L Senovilla et al ldquoPrognostic impact ofvitamin B6 metabolism in lung cancerrdquo Cell Reports vol 2 no2 pp 257ndash269 2012

[141] JMHoward S Davies andAHunnisett ldquoRed cellmagnesiumand glutathione peroxidase in infertile womenmdasheffects of oralsupplementation with magnesium and seleniumrdquo MagnesiumResearch vol 7 no 1 pp 49ndash57 1994

[142] D F Child P R Hudson H Jones et al ldquoThe effect oforal folic acid on glutathione glycaemia and lipids in type2 diabetesrdquo Diabetes Nutrition and MetabolismmdashClinical andExperimental vol 17 no 2 pp 95ndash102 2004

[143] H Ansar Z Mazloom F Kazemi and N Hejazi ldquoEffect ofalpha-lipoic acid on blood glucose insulin resistance and glu-tathione peroxidase of type 2 diabetic patientsrdquo Saudi MedicalJournal vol 32 no 6 pp 584ndash588 2011

[144] R S Lord and J A Bralley Eds Laboratory Evaluationsfor Integrative and Functional Medicine Genova DiagnosticsDuluth Ga USA 2nd edition 2012

[145] University of Maryland Medical Center Glutamine Universityof Maryland Medical Center Baltimore Md USA 2014 httpummeduhealthmedicalaltmedsupplementglutamine

[146] S IMakarova ldquoHumanN-acetyltransferases and drug-inducedhepatotoxicityrdquo Current DrugMetabolism vol 9 no 6 pp 538ndash545 2008

[147] K Kohalmy and R Vrzal ldquoRegulation of phase II biotrans-formation enzymes by steroid hormonesrdquo Current DrugMetabolism vol 12 no 2 pp 104ndash123 2011

[148] J D Yager ldquoMechanisms of estrogen carcinogenesis the roleof E2E1-quinone metabolites suggests new approaches topreventive interventionmdasha reviewrdquo Steroids 2014

[149] J Busserolles W Zimowska E Rock Y Rayssiguier andA Mazur ldquoRats fed a high sucrose diet have altered heartantioxidant enzyme activity and gene expressionrdquo Life Sciencesvol 71 no 11 pp 1303ndash1312 2002

[150] Z Y Su L Shu T O Khor J H Lee F Fuentes and A NT Kong ldquoA perspective on dietary phytochemicals and cancerchemoprevention oxidative stress Nrf2 and epigenomicsrdquoTopics in Current Chemistry vol 329 pp 133ndash162 2013

[151] K Chan X D Han and Y W Kan ldquoAn important func-tion of Nrf2 in combating oxidative stress detoxification ofacetaminophenrdquo Proceedings of the National Academy of Sci-ences of theUnited States of America vol 98 no 8 pp 4611ndash46162001

[152] V Calabrese C Cornelius C Mancuso et al ldquoCellular stressresponse A novel target for chemoprevention and nutritionalneuroprotection in aging neurodegenerative disorders andlongevityrdquo Neurochemical Research vol 33 no 12 pp 2444ndash2471 2008


[153] S S Boyanapalli X Paredes-Gonzalez F Fuentes et al ldquoNrf2knockout attenuates the anti-inflammatory effects of phenethylisothiocyanate and curcuminrdquoChemical Research in Toxicologyvol 27 no 12 pp 2036ndash2043 2014

[154] S K Niture R Khatri and A K Jaiswal ldquoRegulation of Nrf2mdashan updaterdquo Free Radical Biology and Medicine vol 66 pp 36ndash44 2014

[155] Y Xie Q Y Zhao H Y Li X Zhou Y Liu and H ZhangldquoCurcumin ameliorates cognitive deficits heavy ion irradiation-induced learning and memory deficits through enhancing ofNrf2 antioxidant signaling pathwaysrdquo Pharmacology Biochem-istry and Behavior 2014

[156] V Soetikno F R Sari A P Lakshmanan et al ldquoCurcuminalleviates oxidative stress inflammation and renal fibrosis inremnant kidney through the Nrf2-keap1 pathwayrdquo MolecularNutrition amp Food Research vol 57 no 9 pp 1649ndash1659 2013

[157] H J He G Y Wang Y Gao W H Ling Z W Yu and T R JinldquoCurcumin attenuates Nrf2 signaling defect oxidative stress inmuscle and glucose intolerance in high fat diet-fedmicerdquoWorldJournal of Diabetes vol 3 no 5 pp 94ndash104 2012

[158] E O Farombi S Shrotriya H K Na S H Kim and YJ Surh ldquoCurcumin attenuates dimethylnitrosamine-inducedliver injury in rats through Nrf2-mediated induction of hemeoxygenase-1rdquo Food and Chemical Toxicology vol 46 no 4 pp1279ndash1287 2008

[159] Z Zhang S Wang S Zhou et al ldquoSulforaphane preventsthe development of cardiomyopathy in type 2 diabetic miceprobably by reversing oxidative stress-induced inhibition ofLKB1AMPK pathwayrdquo Journal of Molecular and Cellular Car-diology vol 77 pp 42ndash52 2014

[160] G K McWalter L G Higgins L I McLellan et al ldquoTranscrip-tion factor Nrf2 is essential for induction of NAD(P)Hquinoneoxidoreductase 1 glutathione S-transferases and glutamatecysteine ligase by broccoli seeds and isothiocyanatesrdquo Journal ofNutrition vol 134 no 12 supplement pp 3499Sndash3506S 2004

[161] I C Lee SHKimH S Baek et al ldquoThe involvement ofNrf2 inthe protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory responsein ratsrdquo Food andChemical Toxicology vol 63 pp 174ndash185 2014

[162] R Padiya D Chowdhury R Borkar R Srinivas M Pal Bhadraand S K Banerjee ldquoGarlic attenuates cardiac oxidative stressvia activation of PI3KAKTNrf2-Keap1 pathway in fructose-fed diabetic ratrdquoPLoSONE vol 9 no 5 Article ID e94228 2014

[163] T Gomez-Sierra EMolina-Jijon E Tapia et al ldquoS-allylcysteineprevents cisplatin-induced nephrotoxicity and oxidative stressrdquoJournal of Pharmacy and Pharmacology vol 66 no 9 pp 1271ndash1281 2014

[164] C F Chang S Cho and J Wang ldquo(-)-Epicatechin protectshemorrhagic brain via synergistic Nrf2 pathwaysrdquo Annals ofClinical and Translational Neurology vol 1 no 4 pp 258ndash2712014

[165] C C Leonardo M Agrawal N Singh J R Moore S Biswaland SDore ldquoOral administration of the flavanol (-)-epicatechinbolsters endogenous protection against focal ischemia throughthe Nrf2 cytoprotective pathwayrdquo European Journal of Neuro-science vol 38 no 11 pp 3659ndash3668 2013

[166] K Kavitha PThiyagarajan J Rathna R Mishra and S NaginildquoChemopreventive effects of diverse dietary phytochemicalsagainst DMBA-induced hamster buccal pouch carcinogenesisvia the induction of Nrf2-mediated cytoprotective antioxidantdetoxification andDNA repair enzymesrdquoBiochimie vol 95 no8 pp 1629ndash1639 2013

[167] Z A Shah R-C Li A S Ahmad et al ldquoThe flavanol (minus)-epicatechin prevents stroke damage through the Nrf2HO1pathwayrdquo Journal of Cerebral Blood Flow and Metabolism vol30 no 12 pp 1951ndash1961 2010

[168] N Tamaki R Cristina Orihuela-Campos Y Inagaki M FukuiT Nagata andH Ito ldquoResveratrol improves oxidative stress andprevents the progression of periodontitis via the activation ofthe Sirt1AMPK and the Nrf2antioxidant defense pathways ina rat periodontitis modelrdquo Free Radical Biology and Medicinevol 75 pp 222ndash229 2014

[169] G Sadi D Bozan and H B Yildiz ldquoRedox regulation ofantioxidant enzymes post-translational modulation of catalaseand glutathione peroxidase activity by resveratrol in diabetic ratliverrdquoMolecular and Cellular Biochemistry vol 393 no 1-2 pp111ndash122 2014

[170] H Chen J Fu Y Hu et al ldquoGinger compound [6]-shogaoland its cysteine-conjugated metabolite (M2) activate Nrf2 incolon epithelial cells in vitro and in vivordquo Chemical Research inToxicology vol 27 no 9 pp 1575ndash1585 2014

[171] M J Bak S OkM Jun andW S Jeong ldquo6-shogaol-rich extractfrom ginger up-regulates the antioxidant defense systems incells and micerdquoMolecules vol 17 no 7 pp 8037ndash8055 2012

[172] Y D Xi X Y Li H L Yu et al ldquoSoy isoflavone antagonizesthe oxidative cerebrovascular injury induced by 120573-AmyloidPeptides 1ndash42 in Ratsrdquo Neurochemical Research vol 39 no 7pp 1374ndash1381 2014

[173] R Li T Liang L Xu N Zheng K Zhang and X DuanldquoPuerarin attenuates neuronal degeneration in the substantianigra of 6-OHDA-lesioned rats through regulating BDNFexpression and activating the Nrf2ARE signaling pathwayrdquoBrain Research vol 1523 pp 1ndash9 2013

[174] S J V Vicente E Y Ishimoto and E A F S Torres ldquoCoffeemodulates transcription factor Nrf2 and highly increases theactivity of antioxidant enzymes in ratsrdquo Journal of Agriculturaland Food Chemistry vol 62 no 1 pp 116ndash122 2014

[175] B D Sahu U K Putcha M Kuncha S S Rachamallaand R Sistla ldquoCarnosic acid promotes myocardial antioxi-dant response and prevents isoproterenol-induced myocardialoxidative stress and apoptosis in micerdquo Molecular and CellularBiochemistry vol 394 no 1-2 pp 163ndash176 2014

[176] T R Balstad H Carlsen M C W Myhrstad et al ldquoCoffeebroccoli and spices are strong inducers of electrophile responseelement-dependent transcription in vitro and in vivomdashstudiesin electrophile response element transgenic micerdquo MolecularNutrition and Food Research vol 55 no 2 pp 185ndash197 2011

[177] Y P Wang M L Cheng B F Zhang et al ldquoEffect of blueberryonhepatic and immunological functions inmicerdquoHepatobiliaryand Pancreatic Diseases International vol 9 no 2 pp 164ndash1682010

[178] A Bishayee D Bhatia R J Thoppil A S Darvesh E Nevoand E P Lansky ldquoPomegranate-mediated chemopreventionof experimental hepatocarcinogenesis involves Nrf2-regulatedantioxidantmechanismsrdquoCarcinogenesis vol 32 no 6 pp 888ndash896 2011

[179] M A Esmaeili and M Alilou ldquoNaringenin attenuates CCl4-induced hepatic inflammation by the activation of an Nrf2-mediated pathway in ratsrdquo Clinical and Experimental Pharma-cology and Physiology vol 41 no 6 pp 416ndash422 2014

[180] C K Singh M A Ndiaye I A Siddiqui et al ldquoMethane-seleninic acid and 120574-tocopherol combination inhibits prostatetumor growth in vivo in a xenograft mouse modelrdquoOncotargetvol 5 no 11 pp 3651ndash3661 2014


[181] M J M Magbanua R Roy E V Sosa et al ldquoGene expressionand biological pathways in tissue of men with prostate cancer ina randomized clinical trial of lycopene and fish oil supplemen-tationrdquo PLoS ONE vol 6 no 9 Article ID e24004 2011

[182] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004

[183] P Delmonte and J I Rader ldquoAnalysis of isoflavones in foodsand dietary supplementsrdquo Journal of AOAC International vol89 no 4 pp 1138ndash1146 2006

[184] S Chian R Thapa Z Chi X J Wang and X Tang ldquoLuteolininhibits the Nrf2 signaling pathway and tumor growth in vivordquoBiochemical and Biophysical Research Communications vol 447no 4 pp 602ndash608 2014

[185] R Marina P Gonzalez M C Ferreras S Costilla and J PBarrio ldquoHepatic Nrf2 expression is altered by quercetin supple-mentation in Xirradiated ratsrdquoMolecular Medicine Reports vol11 no 1 pp 539ndash546 2015

[186] H Zhou Z Qu V V Mossine et al ldquoProteomic analysis ofthe effects of aged garlic extract and its fruarg componenton lipopolysaccharide-induced neuroinflammatory response inmicroglial cellsrdquo PLoS ONE vol 9 no 11 Article ID e1135312014

[187] V Calabrese C Cornelius A T Dinkova-Kostova E J Cal-abrese and M P Mattson ldquoCellular stress responses thehormesis paradigm and vitagenes novel targets for therapeuticintervention in neurodegenerative disordersrdquo Antioxidants ampRedox Signaling vol 13 no 11 pp 1763ndash1811 2010

[188] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013

[189] A L Stefanson and M Bakovic ldquoDietary regulation ofKeap1Nrf2ARE pathway focus on plant-derived compoundsand trace mineralsrdquoNutrients vol 6 no 9 pp 3777ndash3801 2014

[190] G K Andrews ldquoRegulation of metallothionein gene expressionby oxidative stress and metal ionsrdquo Biochemical Pharmacologyvol 59 no 1 pp 95ndash104 2000

[191] P Lichtlen andW Schaffner ldquoPutting its fingers on stressful sit-uations the heavy metal-regulatory transcription factor MTF-1rdquo BioEssays vol 23 no 11 pp 1010ndash1017 2001

[192] M Sato and M Kondoh ldquoRecent studies on metallothioneinprotection against toxicity of heavy metals and oxygen freeradicalsrdquo Tohoku Journal of Experimental Medicine vol 196 no1 pp 9ndash22 2002

[193] Y Pan JHuang R Xing et al ldquoMetallothionein 2A inhibitsNF-120581B pathway activation and predicts clinical outcome segregatedwith TNM stage in gastric cancer patients following radicalresectionrdquo Journal of TranslationalMedicine vol 11 no 1 article173 2013

[194] J J Lamb V R Konda D W Quig et al ldquoA program consist-ing of a phytonutrient-rich medical food and an eliminationdiet ameliorated fibromyalgia symptoms and promoted toxic-element detoxification in a pilot trialrdquo Alternative Therapies inHealth and Medicine vol 17 no 2 pp 36ndash44 2011

[195] T B Aydemir R K Blanchard and R J Cousins ldquoZincsupplementation of young men alters metallothionein zinctransporter and cytokine gene expression in leukocyte popu-lationsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 103 no 6 pp 1699ndash1704 2006

[196] T P J Mulder A van der Sluys Veer H W Verspaget etal ldquoEffect of oral zinc supplementation on metallothionein

and superoxide dismutase concentrations in patients withinflammatory bowel diseaserdquo Journal of Gastroenterology andHepatology vol 9 no 5 pp 472ndash477 1994

[197] R Hu V Hebbar B R Kim et al ldquoIn vivo pharmacokineticsand regulation of gene expression profiles by isothiocyanate sul-foraphane in the ratrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 310 no 1 pp 263ndash271 2004

[198] T Kimura F Okumura A Onodera T Nakanishi N ItohandM Isobe ldquoChromium (VI) inhibits mousemetallothionein-I gene transcription by modifying the transcription potential ofthe co-activator p300rdquoThe Journal of Toxicological Sciences vol36 no 2 pp 173ndash180 2011

[199] C J Weng M J Chen C T Yeh and G C Yen ldquoHepato-protection of quercetin against oxidative stress by inductionof metallothionein expression through activating MAPK andPI3Kpathways and enhancingNrf2DNA-binding activityrdquoNewBiotechnology vol 28 no 6 pp 767ndash777 2011

[200] M Singh R Tulsawani P Koganti A Chauhan MManickamand K Misra ldquoCordyceps sinensis increases hypoxia toleranceby inducing heme oxygenase-1 and metallothionein via Nrf2activation in human lung epithelial cellsrdquo BioMed ResearchInternational vol 2013 Article ID 569206 13 pages 2013

[201] N M R Sales P B Pelegrini and M C Goersch ldquoNutrige-nomics definitions and advances of this new sciencerdquo Journal ofNutrition andMetabolism vol 2014 Article ID 202759 6 pages2014

[202] U Lim and M A Song ldquoDietary and lifestyle factors of DNAmethylationrdquo Methods in Molecular Biology vol 863 pp 359ndash376 2012

[203] I A Lang T S Galloway A Scarlett et al ldquoAssociation ofurinary bisphenol A concentration with medical disorders andlaboratory abnormalities in adultsrdquoThe Journal of the AmericanMedical Association vol 300 no 11 pp 1303ndash1310 2008

[204] R Rezg S El-Fazaa N Gharbi and B Mornagui ldquoBisphenol Aand human chronic diseases current evidences possible mech-anisms and future perspectivesrdquo Environment Internationalvol 64 pp 83ndash90 2014

[205] SMostafalou andMAbdollahi ldquoPesticides and human chronicdiseases evidences mechanisms and perspectivesrdquo Toxicologyand Applied Pharmacology vol 268 no 2 pp 157ndash177 2013

[206] D J Magliano V H Y Loh J L Harding J Botton and J EShaw ldquoPersistent organic pollutants and diabetes a review ofthe epidemiological evidencerdquo Diabetes amp Metabolism vol 40no 1 pp 1ndash14 2014

[207] S Agarwal T Zaman E M Tuzcu and S R Kapadia ldquoHeavymetals and cardiovascular disease results from the NationalHealth and Nutrition Examination Survey (NHANES) 1999ndash2006rdquo Angiology vol 62 no 5 pp 422ndash429 2011

[208] E F Rissman and M Adli ldquoMinireview transgenerationalepigenetic inheritance focus on endocrine disrupting com-poundsrdquo Endocrinology vol 155 no 8 pp 2770ndash2780 2014

[209] D M Walker and A C Gore ldquoTransgenerational neu-roendocrine disruption of reproductionrdquo Nature ReviewsEndocrinology vol 7 no 4 pp 197ndash207 2011

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


enzymes as well as phase II enzymes specifically UDP-glucuronosyl transferases glutathione S-transferases aminoacid transferases N-acetyl transferases and methyltrans-ferases Note that there are other important classes of phase Ienzymes namely hydroxylation and reduction which are notcovered in this review While these important enzymes arepivotal to consider this review of the effect of food on detox-ification will also extend into other pathways including waysto promote gene expression of antioxidant-related enzymesand of metallothionein an endogenous protein carrier forheavy metals Each of these four classes of detoxification-related pathways will be discussed within the context ofnutrients

21 Phase I Cytochrome P450 Enzymes Initially the ldquophasesrdquoof detoxification were described as functionalization (orphase I) or the addition of oxygen to form a reactive siteon the toxic compound and conjugation (phase II) or theprocess of adding a water-soluble group to this now reactivesite [14 15] The ldquoPhase Irdquo cytochrome P450 superfamily ofenzymes (CYP450) is generally the first defense employedby the body to biotransform xenobiotics steroid hormonesand pharmaceuticals These microsomal membrane-boundheme-thiolate proteins locatedmainly in the liver but also inenterocytes kidneys lung and even the brain are responsiblefor the oxidation peroxidation and reduction of severalendogenous and exogenous substrates [13 15 16] Specificallythe function of CYP450 enzymes is to add a reactive groupsuch as a hydroxyl carboxyl or an amino group throughoxidation reduction andor hydrolysis reactions [15] Theseinitial reactions have the potential to create oxidative damagewithin cell systems because of the resulting formation ofreactive electrophilic species

It is accepted that any variability in the number ofCYP450enzymes could have benefit(s) andor consequence(s) forhow an individual responds to the effect(s) of (a) toxin(s)Clinical application of the knowledge of these phase ICYP450 enzymes has been primarily addressed within phar-macology to understand the nature of drug interactions sideeffects and interindividual variability in drug metabolism[15] The ability of an individual to metabolize 90 ofcurrently used drugs will largely depend on the geneticexpression of these enzymes [17] It is established that manyof these CYP450 genes are subject to genetic polymor-phisms resulting in an altered expression and function ofindividual enzymes Currently there exist some laboratorytests to identify the presence of these genetic variants It isconceivable that having knowledge about foods and theirindividual (phyto)nutrients especially in the case of dietarysupplements and functional foods could be worthwhilefor clinicians to consider for patients who are taking apolypharmacy approach Furthermore as nutritional strate-gies become more personalized it would seem that thisinformation could be interfaced with a patientrsquos knownCYP450 polymorphisms to determine how to best optimizehealth outcomes

211 CYP1 Enzymes TheCYP1A family is involved inmetab-olizing procarcinogens hormones and pharmaceuticals

It is well-known for its role in the carcinogenic bioactivationof polycyclic aromatic hydrocarbons (PAHs) heterocyclicaromatic aminesamides polychlorinated biphenyls (PCBs)and other environmental toxins [18 19] LowCYP1A2 activityfor example has been linked to higher risk of testicularcancer [20] However due to their rapid conversion tohighly reactive intermediates excessive activity of CYP1Aenzymes without adequate phase II support may enhancethe destructive effects of environmental procarcinogens [21]Indeed genetic polymorphisms in this cytochrome familyhave been suggested as useful markers for predispositionto certain cancers [15] CYP1 enzymes are also involvedin the formation of clinically relevant estrogen metabolitesCYP1A11A2 and CYP1B1 catalyze the 2-hydroxylation and4-hydroxylation of estrogens respectively [22] The potentialrole of 4-hydroxyestradiol in estrogen-related carcinogenesisvia the production of free radicals and related cellular damage[22] has prompted investigation into factors that modulateCYP1 enzymes

Various foods and phytonutrients alter CYP1 activity(Tables 1(a) and 1(b)) Cruciferous vegetables have beenshown in humans to act as inducers of CYP1A1 and 1A2and animal studies also suggest an upregulation of CYP1B1[4 23ndash27]The inductory effect of crucifers onCYP1A2 seemsespecially well established Clinical studies also indicatethat resveratrol and resveratrol-containing foods are CYP1A1enhancers [28] Conversely berries and their constituentpolyphenol ellagic acid may reduce CYP1A1 overactivity[6] and apiaceous vegetables and quercetin may attenuateexcessive CYP1A2 action [24 29] Cruciferous vegetables andberries have been suggested as possible modulators of estro-gen metabolites berries for their reducing effect on CYP1A1[6] and cruciferous vegetables for their stronger induction ofCYP1A versus 1B1 enzymes [25ndash27 30] Chrysoeriol presentin rooibos tea and celery acts selectively to inhibit CYP1B1in vitro [31] and may be especially relevant to patients withCYP1B1 overactivity However further research is needed toconfirm this finding

Many foods appear to act as both inducers and inhibitorsof CYP1 enzymes an effect which may be dose dependentor altered by the isolation of bioactive compounds derivedfrom food Curcumin at 01 of the diet has been shown inanimals to induce CYP1A1 for example [35] yet a diet of 1turmeric was inhibitory [46] Black tea at 54mLd inducedboth CYP1A1 and 1A2 [33] yet 20mgkg of theaflavins wasinhibitory to CYP1A1 [45] Soybean intake at 100mgkgupregulated CYP1A1 activity [7] yet at 1 gkg black soybeanextract [44] and 200mg daidzein twice daily [49] its effectwas inhibitory Further research is needed to confirm differ-ent dose effects and impact in humans

Varied effects may also occur from different members ofthe same food group Seemingly contradictory to researchshowing that cruciferous vegetables activate CYP1 enzymeskale (another member of the cruciferous family) appears toinhibit CYP1A2 (as well as 2C19 2D6 and 3A4) in animals[51]Thedose used at 2 gkg per day is 15-fold higher than thetypical level of human consumption [51] and more researchwould be required to determine whether lower intake levelswould also have a similar effect The same authors also tested



(a)






CYP1A1Curcumin







for 15 days [39]













for 15 days [39]

CYP1B1Curcumin



(b)



CYP1A1







(b) Continued






[47 48]


CYP1A2Daidzein




drink[51]














(a)



CYP2A6


powder [47 48]



CYP2B1






dose used


(b)




[43]








CYP2C6Ellagic acid



CYP2C9


dose usedMyricetin




dose used




(b) Continued









CYP2E1Ellagic acid
















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)






CYP1A1Curcumin







for 15 days [39]













for 15 days [39]

CYP1B1Curcumin



(b)



CYP1A1







(b) Continued






[47 48]


CYP1A2Daidzein




drink[51]














(a)



CYP2A6


powder [47 48]



CYP2B1






dose used


(b)




[43]








CYP2C6Ellagic acid



CYP2C9


dose usedMyricetin




dose used




(b) Continued









CYP2E1Ellagic acid
















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(b) Continued






[47 48]


CYP1A2Daidzein




drink[51]














(a)



CYP2A6


powder [47 48]



CYP2B1






dose used


(b)




[43]








CYP2C6Ellagic acid



CYP2C9


dose usedMyricetin




dose used




(b) Continued









CYP2E1Ellagic acid
















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)



CYP2A6


powder [47 48]



CYP2B1






dose used


(b)




[43]








CYP2C6Ellagic acid



CYP2C9


dose usedMyricetin




dose used




(b) Continued









CYP2E1Ellagic acid
















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(b) Continued









CYP2E1Ellagic acid
















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)





weekly [70]




(b)


CYP3A

Green tea In vivo



[56]



powder [47 48]





dose used





[58]







































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































(b)










(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)


SULTs





(b)













(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)












[124]



















(b)




carrots [116]


(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(b) Continued


GSTsQuercetin







(c)























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Keap1Keap1Nrf2Nrf2

ARE

Nrf2




Cytosol

Nucleus



































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































(b)








4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















4 Metallothionein

















6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























6 Conclusions







References

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

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Review Article Modulation of Metabolic Detoxification ...

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