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Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application

Romilly E. Hodges, Deanna M. Minich

Journal of Nutrition and Metabolism · 2015 · Review

doi:10.1155/2015/760689

Abstract

Research into human biotransformation and elimination systems continues to evolve. Various clinical and in vivo studies have been undertaken to evaluate the effects of foods and food-derived components on the activity of detoxification pathways, including phase I cytochrome P450 enzymes, phase II conjugation enzymes, Nrf2 signaling, and metallothionein. This review summarizes the research in this area to date, highlighting the potential for foods and nutrients to support and/or modulate detoxification functions. Clinical applications to alter detoxification pathway activity and improve patient outcomes are considered, drawing on the growing understanding 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 indications that many nutrients exert biphasic, dose-dependent effects and that genetic polymorphisms may alter outcomes. A whole-foods approach may, therefore, be prudent.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Food-based nutrients have been and continue to be investigated for their role in the modulation of metabolic pathways involved in detoxification processes. Several publications to date have leveraged cell, animal, and clinical studies to demonstrate that food-derived components and nutrients can modulate processes of conversion and eventual excretion of toxins from the body. In general, the nature of these findings indicates that specific foods may upregulate or favorably balance metabolic pathways to assist with toxin biotransformation and subsequent elimination. Various whole foods such as cruciferous vegetables, berries, soy, garlic, and even spices like turmeric have been suggested to be beneficial and commonly prescribed as part of naturopathic-oriented and functional medicine-based therapies.

While these foods are important to note, the science in this active area of inquiry continues to evolve to reveal new findings about food-based nutrients and their effect on health. Thus, the purpose of this review article is to summarize the science to date on the influence of whole foods, with a special focus directed towards phytonutrients and other food-based components, on influencing specific metabolic detoxification pathways, including phase I cytochrome enzymes, phase II conjugation enzymes, antioxidant support systems, and metallothionein upregulation for heavy metal metabolism. Based on this current science, the paper will conclude with clinical recommendations that may be applied in a personalized manner for patients via the discretion of a qualified health professional.

2. The Metabolic Pathways of Detoxification

Discussion of physiological pathways for detoxification has been mainly centered around phase I and phase II enzyme systems. This review will cover phase I cytochrome P450 enzymes as well as phase II enzymes, specifically UDP-glucuronosyl transferases, glutathione S-transferases, amino acid transferases, N-acetyl transferases, and methyltransferases. Note that there are other important classes of phase I enzymes, namely, hydroxylation and reduction, which are not covered in this review. While these important enzymes are pivotal to consider, this review of the effect of food on detoxification will also extend into other pathways, including ways to promote gene expression of antioxidant-related enzymes and of metallothionein, an endogenous protein carrier for heavy metals. Each of these four classes of detoxification-related pathways will be discussed within the context of nutrients.

2.1. Phase I Cytochrome P450 Enzymes

Initially, the “phases” of detoxification were described as functionalization (or phase I), or the addition of oxygen to form a reactive site on the toxic compound, and conjugation (phase II), or the process of adding a water-soluble group to this now reactive site. The “Phase I” cytochrome P450 superfamily of enzymes (CYP450) is generally the first defense employed by the body to biotransform xenobiotics, steroid hormones, and pharmaceuticals. These microsomal membrane-bound, heme-thiolate proteins, located mainly in the liver, but also in enterocytes, kidneys, lung, and even the brain, are responsible for the oxidation, peroxidation, and reduction of several endogenous and exogenous substrates. Specifically, the function of CYP450 enzymes is to add a reactive group such as a hydroxyl, carboxyl, or an amino group through oxidation, reduction, and/or hydrolysis reactions. These initial reactions have the potential to create oxidative damage within cell systems because of the resulting formation of reactive electrophilic species.

It is accepted that any variability in the number of CYP450 enzymes could have benefit(s) and/or consequence(s) for how an individual responds to the effect(s) of (a) toxin(s). Clinical application of the knowledge of these phase I CYP450 enzymes has been primarily addressed within pharmacology to understand the nature of drug interactions, side effects, and interindividual variability in drug metabolism. The ability of an individual to metabolize 90% of currently used drugs will largely depend on the genetic expression of these enzymes. It is established that many of these CYP450 genes are subject to genetic polymorphisms, resulting in an altered expression and function of individual enzymes. Currently, there exist some laboratory tests to identify the presence of these genetic variants. It is conceivable that having knowledge about foods and their individual (phyto)nutrients, especially in the case of dietary supplements and functional foods, could be worthwhile for clinicians to consider for patients who are taking a polypharmacy approach. Furthermore, as nutritional strategies become more personalized, it would seem that this information could be interfaced with a patient's known CYP450 polymorphisms to determine how to best optimize health outcomes.

2.1.1. CYP1 Enzymes

The CYP1A family is involved in metabolizing procarcinogens, hormones, and pharmaceuticals. It is well-known for its role in the carcinogenic bioactivation of polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines/amides, polychlorinated biphenyls (PCBs), and other environmental toxins. Low CYP1A2 activity, for example, has been linked to higher risk of testicular cancer. However, due to their rapid conversion to highly reactive intermediates, excessive activity of CYP1A enzymes without adequate phase II support may enhance the destructive effects of environmental procarcinogens. Indeed, genetic polymorphisms in this cytochrome family have been suggested as useful markers for predisposition to certain cancers. CYP1 enzymes are also involved in the formation of clinically relevant estrogen metabolites: CYP1A1/1A2 and CYP1B1 catalyze the 2-hydroxylation and 4-hydroxylation of estrogens, respectively. The potential role of 4-hydroxyestradiol in estrogen-related carcinogenesis, via the production of free radicals and related cellular damage, has prompted investigation into factors that modulate CYP1 enzymes.

Various foods and phytonutrients alter CYP1 activity (Tables 1(a) and 1(b)). Cruciferous vegetables have been shown, in humans, to act as inducers of CYP1A1 and 1A2, and animal studies also suggest an upregulation of CYP1B1. The inductory effect of crucifers on CYP1A2 seems especially well established. Clinical studies also indicate that resveratrol and resveratrol-containing foods are CYP1A1 enhancers. Conversely, berries and their constituent polyphenol, ellagic acid, may reduce CYP1A1 overactivity, and apiaceous vegetables and quercetin may attenuate excessive CYP1A2 action. Cruciferous vegetables and berries have been suggested as possible modulators of estrogen metabolites: berries for their reducing effect on CYP1A1 and cruciferous vegetables for their stronger induction of CYP1A versus 1B1 enzymes. Chrysoeriol, present in rooibos tea and celery, acts selectively to inhibit CYP1B1 in vitro and may be especially relevant to patients with CYP1B1 overactivity. However, further research is needed to confirm this finding.

Many foods appear to act as both inducers and inhibitors of CYP1 enzymes, an effect which may be dose dependent or altered by the isolation of bioactive compounds derived from food. Curcumin at 0.1% of the diet has been shown, in animals, to induce CYP1A1, for example,, yet a diet of 1% turmeric was inhibitory. Black tea at 54 mL/d induced both CYP1A1 and 1A2, yet 20 mg/kg of theaflavins was inhibitory to CYP1A1. Soybean intake at 100 mg/kg upregulated CYP1A1 activity, yet at 1 g/kg black soybean extract and 200 mg daidzein twice daily, its effect was inhibitory. Further research is needed to confirm different dose effects and impact in humans.

Varied effects may also occur from different members of the same food group. Seemingly contradictory to research showing that cruciferous vegetables activate CYP1 enzymes, kale (another member of the cruciferous family) appears to inhibit CYP1A2 (as well as 2C19, 2D6, and 3A4) in animals. The dose used, at 2 g/kg per day, is 15-fold higher than the typical level of human consumption, and more research would be required to determine whether lower intake levels would also have a similar effect. The same authors also tested the effects of an equivalent volume of cabbage consumption and found no such inhibitory effect, pointing to the possibility that different cruciferous vegetables may have distinct effects on cytochrome activity.

2.1.2. CYP2A-E Enzymes

The large CYP2 family of enzymes is involved in the metabolism of drugs, xenobiotics, hormones, and other endogenous compounds such as ketones, glycerol, and fatty acids. Some notable polymorphisms occur in the CYP2C and CYP2D subgroups, leading to the classification of patients as “poor metabolizers” of various pharmaceuticals: warfarin and CYP2C9, antiarrhythmia agents, metoprolol and propafenone, and CYP2D6, phenytoin, cyclobarbital, omeprazole, and CYP2C19, for example,. CYP2D polymorphisms may be associated with Parkinson's disease and lung cancer. Clinical evidence exists for the induction of CYP2A6 by quercetin and broccoli (Table 2(a)). In animals, chicory appears to induce CYP2A enzymes and rosemary and garlic may upregulate CYP2B activity. Clinical studies using resveratrol and garden cress indicate CYP2D6 inhibition (Table 2(b)). Ellagic acid, green tea, black tea, and cruciferous vegetables also appear to inhibit various CYP2 enzymes.

CYP2E1 enzymes have also attracted particular interest for their role in various diseases. 2E1 metabolizes nervous system agents such as halothane, isoflurane, chlorzoxazone, and ethanol and bioactivates procarcinogenic nitrosamines and aflatoxin B1. It produces free radicals regardless of substrate, and CYP2E1 polymorphisms have been associated with altered risk for coronary artery disease and gastric cancer. CYP2E1-induced oxidative stress has also been shown to lead to impaired insulin action via the suppression of GLUT4 expression. Attenuation of 2E1 overactivity may therefore be an important consideration in high-risk patients.

Watercress and garlic are CYP2E1 inhibitors in humans. In vivo evidence also suggests that N-acetyl cysteine, ellagic acid, green tea, black tea, dandelion, chrysin, and medium chain triglycerides (MCTs) may downregulate CYP2E1. MCT oil may specifically attenuate the ethanol-induced upregulation of CYP2E1 and production of mitochondrial 4-hydroxynonenal, a marker of oxidative stress.

2.1.3. CYP3A Enzymes

The occurrence of the different CYP3A isoforms is tissue-specific. Rooibos tea, garlic, and fish oil appear to induce the activity of CYP3A, 3A1, and 3A2 (Table 3(a)). Possible inhibitory foods include green tea, black tea, and quercetin (Table 3(b)). The most clinically relevant of the enzymes is CYP3A4, which is expressed mainly in the liver and to a lesser extent in the kidney. Caffeine, testosterone, progesterone, and androstenedione are substrates of the CYP3A4 enzyme system, as are various procarcinogens including PAHs and aflatoxin B1. To date, however, the principal driver for research on CYP3A4 has been due to its role in the metabolism of over 50 percent of all pharmaceuticals. The potential for drug interaction with this single enzyme, coupled with the wide interindividual differences in enzymatic activity, generates some level of risk in administration of high doses and multiple drugs as well as food-drug and herb-drug interactions. Grapefruit juice is perhaps the most well-known food inhibitor of this enzyme, though resveratrol and garden cress, a member of the cruciferous vegetable family, appear to have similar effects in humans, albeit at intakes above what would be expected without high-dose supplementation. Curcumin may upregulate 3A4 activity.

Once again, there are indications that a biphasic effect may be seen from dietary bioactive compounds; Davenport and Wargovich (2005) found that shorter-term or lower dosing with garlic organosulfur compounds produced potentially anticarcinogenic effects but that longer-term higher doses (200 mg/kg) of allyl sulfides led to minor hepatic toxicity. One garlic clove contains only 2,500–4,500 μg of the allyl sulfide precursor, allicin, so the higher dose is much more than would be consumed in a typical human diet. In another example, two components of cruciferous vegetables, sulforaphanes and indole-3-carbinol, inhibited and increased activity, respectively, highlighting the potential for human studies using whole foods to clarify the outcome of consumption.

2.1.4. CYP4 Enzymes

Less is known about this family of enzymes, since it is thought to play a smaller role in drug metabolism. It is, however, understood to be a primarily extrahepatic family of cytochromes, inducible by clofibrate and ciprofibrate (hypolipidemic drugs), NSAIDs, prostaglandins, and toxicants such as phthalate esters. The CYP4B1 isoform is involved in the metabolism of MCTs (medium chain triglycerides), as well as the bioactivation of pneumotoxic and carcinogenic compounds.

Polymorphisms and overexpression of this subgroup may be associated with bladder cancer and colitis. A report by Ye et al. (2009) which examined the link between colitis and CYP4B1 activity found that the promotion of CYP4B1 activity by caffeic acid (found in caffeine-containing foods) (Table 4) correlated with reduced inflammation and disease activity. Green tea may act to induce CYP4A1, as suggested by animal studies. More research is needed to clearly identify food influences on this enzyme family.

2.2. Phase II Conjugation Enzymes

After a xenobiotic has gone through the process of becoming hydrophilic through reactions overseen by CYP450 enzymes, its reactive site can be conjugated with an endogenous hydrophilic substance. This reaction is often referred to as “phase II detoxification.” Conjugation involves the transfer of a number of hydrophilic compounds (via their corresponding enzymes), including glucuronic acid (glucuronyl transferases), sulfate (sulfotransferases), glutathione (glutathione transferases), amino acids (amino acid transferases), an acetyl group (N-acetyl transferases), and a methyl group (N- and O-methyltransferases). The result of the collective activity of these enzymes is an increase in the hydrophilicity of the metabolite, theoretically leading to enhanced excretion in the bile and/or urine. Similar to the CYP450 enzymes, genetic polymorphisms can have profound influence on the function of these conjugating enzymes, with potential implication in the development of several forms of cancer.

It is conceivable that modulation of phase II enzymes by food-based bioactive compounds may be advantageous in patients who have altered enzyme activity due to genetic polymorphisms or who have a high toxic burden due to chronic exposure to environmental pollutants, overactive phase I activity, or hormonal imbalance. For example, James et al. (2008) suggest that upregulation of glucuronidation and sulfonation by certain bioactive compounds may be a useful consideration for the elimination of environmental PCBs.

2.2.1. UDP-Glucuronosyltransferases

This class of enzymes, comprising multiple proteins and even subfamilies, plays an essential role in enhancing the elimination of biotransformed toxins in urine and feces, as well as metabolizing steroid hormones and bilirubin. Their function is to catalyze the covalent linkage of glucuronic acid from UDP-glucuronic acid to an accepting functional group on the molecule, a process referred to as glucuronidation. Glucuronidation occurs primarily in the liver but can occur in other tissues, such as the small intestine. Bilirubin, specifically, is principally conjugated by UGT1A1 in hepatocytes and then excreted with bile into the intestinal tract. It has been estimated that 40–70% of all medications are subject to glucuronidation reactions in humans, thereby suggesting the significance of this conjugation enzyme family. Since UDP-glucuronosyltransferases (UGTs) also metabolize phytochemicals, alterations in their effects may be seen with genetically downregulated enzyme activity; flavonoids are conjugated with glucuronide and sulfate; therefore, UGT or sulfotransferase (SULT) polymorphisms may produce variability in phytochemical clearance and efficacy.

Clinical and observational studies point to cruciferous vegetables, resveratrol, and citrus as foods and bioactive compounds that induce UGT enzymes (Table 5(a)). Animal studies also suggest the potential for other foods and nutrients, including dandelion, rooibos tea, honeybush tea, rosemary, soy, ellagic acid, ferulic acid, curcumin, and astaxanthin, to enhance UGT activity. Interestingly, the effect of resveratrol was seen only in individuals with low baseline enzyme levels/activity, suggesting that some phytochemicals may modulate, rather than outright induce, enzymatic activity. In addition, many studies note that effects are variable depending on gender and genotype; for example, women with the UGT1A1 ∗28 polymorphism (7/7) were responsive to citrus intervention, whereas those with other genetic variants were not.

Meaningful interpretations of these studies may still be elusive, however: in one combined dietary trial, the consumption of 10 servings per day of a combination of cruciferous vegetables, soy foods, and citrus fruits did not have a significant effect on UGT enzyme activity compared with a diet devoid of fruits and vegetables. The authors hypothesize that these results may be due to their choice of specific foods within those groups or due to Nrf2 activation (discussed in subsequent sections) when fruits and vegetables were avoided.

The effects of UGT activity may also be enhanced by D-glucaric acid by theoretical inhibition of beta-glucuronidase enzymes. Beta-glucuronidase enzymes act to reverse UGT conjugation reactions. D-glucaric acid is found in many fruits, vegetables and legumes (Table 5(b)). When tested in humans, however, a diet supplemented with cruciferous vegetables (2/3 cup broccoli, 1/2 cup cabbage, and 1/2 cup radish sprouts), citrus fruits (1 cup grapefruit juice, 1/2 cup orange juice, 1 cup orange/grapefruit segments, and 1 orange peel), and soy foods was found to have no effect on beta-glucuronidase activity (amounts standardized for 55 kg body weight), indicating that the clinical effects of D-glucaric acid consumption still need further clarification.

In vivo research suggests that polyphenol extracts of certain berries, specifically strawberries and blackcurrant, may inhibit beta-glucuronidase activity in the intestinal lumen; Kosmala et al. (2014) observed this effect using both strawberry pomace water extract and water-alcohol extract containing 5.1% and 17.1% ellagic acid, and 0.2% and 10.9% proanthocyanidins, respectively. Jurgoński et al. (2014) found a similar inhibitory effect using a diet of 1.5% blackcurrant extract (total polyphenolic content 66.8 g/100 g extract). Interestingly, the highest levels of beta-glucuronidase activity were seen in rabbits fed a high fat diet (32% calories from fat, including 10% from lard), without blackcurrant extract supplementation, suggesting that dietary fat may also alter enzyme activity.

Inhibition of UGT enzymatic activity may be a consideration for modulation of hormone levels and the risk of certain cancers, such as prostate cancer. In vitro studies suggest that various foods and food-based components may inhibit UGT activity, including green and black tea, quercetin, rutin, naringenin, allspice, peppermint oil, cacao, and silymarin, although further research is needed to evaluate their in vivo and clinical effects.

2.2.2. Sulfotransferases

As the name of this superfamily of enzymes might suggest, SULTs are responsible for the transfer of a sulfuryl group donated by 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to hydroxyl or amine groups, particularly in the areas of liver, intestine, adrenal gland, brain, and skin tissues. This process is often referred to as sulfation but is more accurately termed sulfonation or sulfurylation. Decreased function of these enzymes, through genetic variability or presence of environmental chemicals, can lead to eventual interference with thyroid hormone, estrogen, and androgen levels, as well as variable polyphenol effects, since the active forms of these compounds can be degraded via sulfonation. Typically, once compounds have been conjugated with sulfate, there is less reactivity and toxicity incurred from the precursor molecule.

Few in vivo studies have examined the effects of dietary components on SULT activity, although caffeine and retinoic acid are possible SULT inducers according to animal studies (Table 6(a)). Although it is uncertain how their outcomes will translate in vivo, various in vitro studies have indicated the possibility of sulfotransferase inhibition (including competitive inhibition) by wine anthocyanins and flavonols, synthetic food colors (especially red colors), apple and grape juice, catechins including epigallocatechin gallate, quercetin, curcumin, resveratrol, flavonoids (apigenin, chrysin, fisetin, galangin, kaempferol, quercetin, myricetin, naringenin, and naringin), and certain phytoestrogens (daidzein, genistein). Pyridoxal-6-phosphate, the active form of vitamin B6 (which is widely distributed in foods), may also be a competitive SULT inhibitor, according to one in vitro study, although human tissue concentrations and clinical effects may be vastly different. Of note, caffeic acid demonstrates in vitro SULT-inhibitory properties. This finding conflicts with its in vivo ability to induce SULT enzymes, as described by Zhou et al. (2012), highlighting the difficulty of extrapolating meaningful conclusions from in vitro data.

SULT enzyme activity is dependent on a depletable reserve of inorganic sulfate. Dietary sources of sulfur-containing compounds may therefore play an essential role in SULT function, by providing the substrate for enzyme action (Table 6(b)).

2.2.3. Glutathione S-Transferases

Similar to the aforementioned categories of conjugating enzymes, glutathione S-transferases (GSTs) include a complex of enzymes, whose main function is to attach a glutathione group to a biotransformed metabolite. The production of these enzymes can be induced through the production of reactive oxygen species and via gene transcription involving the antioxidant-responsive element (ARE) and the xenobiotic-responsive element (XRE), which will be subsequently discussed in this paper.

Cruciferous and allium vegetables and resveratrol demonstrate ability to induce GSTs in humans (Table 7(a)). Observational research also associates citrus consumption with increased GST activity. In vivo data also suggest many foods and food constituents to be upregulators of these enzymes, including garlic, fish oil, black soybean, purple sweet potato, curcumin, green tea, rooibos tea, honeybush tea, ellagic acid, rosemary, ghee, and genistein. Conjugated linoleic acid has been shown to be at least partly responsible for the effect of ghee. It is possible that the effects of at least some of these foods and bioactive compounds may be due to their upregulation of the Nrf2 signaling pathway.

Genetic variances, gender, and even possibly body weight appear to play a role in the effects of dietary factors on GST enzymes. Clinical investigation of cruciferous and allium vegetables by Lampe et al. (2000) found that an upregulated effect was most marked in women, indicating gender variability, and that the effect was also genotype-dependent, occurring only in GSTM1-null individuals. The same investigators also found that apiaceous vegetables inhibited GST activity, but only in GSTM1+ men (Table 7(b)). High doses of quercetin and genistein have also shown inhibitory effects.

There is evidence that at least some of these foods and phytonutrients may exert modulatory rather than absolute inductive/inhibitory effects; Chow et al. (2010) found that resveratrol increased GST only in those with low baseline enzyme levels or activity. It is also noteworthy that bioactive components of crucifers, including isothiocyanates, are substrates for GST enzymes and that GST genotype may therefore alter the response to cruciferous vegetables consumption on other mechanisms such as glutathione peroxidase and superoxide dismutase. GSTM1-null genotype is associated with a more rapid excretion of isothiocyanates, leading some researchers to conclude that the benefits of cruciferous vegetable consumption may be lessened in individuals with this genetic variation.

Support for glutathione conjugation also involves enhancing reduced glutathione (GSH) status. Glutathione is a low-molecular weight tripeptide containing residues of cysteine, glutamate, and glycine. Most glutathione from foods and supplements is poorly absorbed, so liposomal delivery has been used. The sulfur-containing amino acids methionine and cystine are important precursors to glutathione formation; their depletion leads to depressed GSH levels. N-acetyl cysteine has also been used to restore depleted GSH levels in a clinical setting.

Various nutrients may also enhance endogenous glutathione synthesis, including vitamin B6, magnesium, and selenium. Curcuminoids (from turmeric), silymarin (from milk thistle), folic acid, and alpha-lipoic acid have been shown, in humans, to restore depleted GSH. In animal studies, cruciferous vegetables and artichoke have also demonstrated a GSH-protective effect. There is therefore the potential to improve glutathione status via diet or supplementation (Table 7(c)).

2.2.4. Amino Acid Transferases

Amino acids of various types (e.g., taurine, glycine), whether endogenous or exogenous (from dietary sources) in origin, can be utilized for attaching to molecules for their excretion. For the benefit of providing a substrate to these enzymes, it is generally thought that dietary protein is required for an effective detoxification protocol. Table 8 lists amino acids used in phase II conjugation reactions and selected food sources.

2.2.5. N-Acetyl Transferases (NAT)

This class of enzymes is responsible for the transfer of an acetyl group to convert aromatic amines or hydrazines to aromatic amides and hydrazides, which is significant for those taking pharmaceuticals such as isoniazid, hydralazine, and sulphonamides. Polymorphisms in genes for this category of enzymes, leading to slow metabolism, have been shown to be associated with hepatoxicity during drug treatment. One small human study found that 500 mg quercetin daily enhanced NAT activity. However, more research is needed to understand the relationship between dietary nutrients and NAT function.

2.2.6. Methyltransferases

Relatively significant attention has been given in various medical communities to this class of phase II enzymes due to the increasing importance of methylation for reducing disease risk. The conjugating donor compound in methyltransferase reactions is a methionine group from S-adenosyl-L-methionine (SAMe). Catechol O-methyltransferase (COMT) is one of the prominent methyltransferases that has received wide attention due to its role in estrogen detoxification.

Support for methylation consists of nutrient cofactors and methyl donors, such as methionine, vitamin B12, vitamin B6, betaine, folate, and magnesium. Various foods can provide these nutrients (Table 9). Conversely, a high sucrose diet may inhibit methylation enzymes such as COMT.

3. Gene Induction of Phase II Detoxification and Antioxidant Enzymes through Nrf2

The transcription factor, Nrf2 [nuclear factor erythroid 2 (NF-E2) p45-related factor 2], is key to regulating the body's detoxification and antioxidant system. When activated, Nrf2 dissociates from the cytosolic protein, Keap1 (Kelch-like ECH associated protein 1), and translocates to the nucleus to bind to AREs in the promoter/enhancer portion of genes associated with phase II detoxification and antioxidant enzyme genes (Figure 1). Nrf2-deficient animals experience increased toxicity from drugs, carcinogens, allergens, and environmental pollutants and do not respond as well to the anti-inflammatory effects of phytochemicals, indicating the essentiality of these enzymes. Conversely, Nrf2 induction is considered protective against various oxidative stress-related conditions such as cancer, kidney dysfunction, pulmonary disorders, arthritis, neurological disease, and cardiovascular disease.

Research demonstrates that dietary components, especially phytochemicals, not only scavenge reactive oxygen species, thereby acting as direct antioxidants, but also regulate Nrf2 activity. In vivo evidence exists for Nrf2-modulation by curcumin, broccoli constituents, garlic, epicatechins, resveratrol, ginger, purple sweet potato, isoflavones, coffee, rosemary, blueberry, pomegranate, naringenin, ellagic acid, astaxanthin, and γ-tocopherol (Table 10(a)). A clinical trial by Magbanua et al. (2011), investigating the Nrf2 modulation effects of fish oil and lycopene in the context of prostate cancer risk, also demonstrated that these dietary compounds can upregulate Nrf2 signaling and response to oxidative stress in humans. Direct comparison of the magnitude of effect between these compounds can be difficult to gauge. Some information on their relative effects is provided by Kavitha et al. (2013), who ranked the order of potency of the compounds they tested (from highest to lowest) as chlorophyllin (a semisynthetic compound derived from chlorophyll), blueberry, ellagic acid, astaxanthin, and EGCG.

Various studies point to the advantageous effects of whole foods, and food combinations, versus specific bioactive compounds. Zhou et al. (2014), for example, illustrate how organosulfur compounds are not the only Nrf2-enhancing bioactive compounds in garlic; garlic carbohydrate derivatives also show Nrf2-modulatory activity. Balstad et al. (2011), in testing the effects of a combination of food extracts on Nrf2 activity in mice, found that the combination produced a larger-than-expected effect, indicating an additive or synergistic effect. By their calculations, the food extract they used equated to a human (70 kg) dose of 14–23 g each of turmeric, rosemary, and thyme, which is clearly not practical for clinical application, as well as 140–233 g each of coffee, red onion, and broccoli. Calabrese et al. (2010) and Houghton et al. (2013) have also argued that Nrf2 inducers exhibit biphasic effects, with lower doses demonstrating stimulatory effects and higher doses exhibiting Nrf2-interference. These data suggest that the doses found in whole foods may be more beneficial than supplements at supraphysiological doses. In fact, it may well be their weak prooxidant effects that stimulate Nrf2 inducers' favorable antioxidant responses.

Nonuniform activities of different foods within the same food group should, once again, be considered; in their recent review of the effects of plant-derived compounds on Nrf2 activation, Stefanson and Bakovic (2014) noted that pak choi, via presumed Nrf2 activation, was more effective at reducing inflammation in the colon than broccoli and that broccoli upregulated some additional Nrf2-related antioxidant enzymes compared with pak choi. Interestingly, this effect was only apparent when steamed, rather than cooked, broccoli was used, indicating that food preparation may be an important consideration.

Conversely to its role in cancer prevention, overexpression of Nrf2 is found in many cancer cells and has been shown to promote tumor growth and resistance to anticancer therapy. Consequently, the inhibition of Nrf2 signaling may be clinically relevant for patients receiving cancer chemotherapy. Overexpression of Nrf2 and CYP2E1 has also been associated with impaired GLUT4 activity and insulin resistance. As noted above, supplementation (above levels normally consumed through diet) with certain phytochemicals may have inhibitory effects on Nrf2 activation, including luteolin and quercetin (Table 10(b)). Vitamins A, C, and E and N-acetyl cysteine have also been implicated as Nrf2 inhibitors at high doses. These findings point to the need for further research to clarify outcomes as they relate to specific disease states as well as potential biphasic dose effects.

4. Metallothionein

Metallothionein, a cysteine-rich protein with the ability to bind divalent cations, including toxic metals such as mercury, cadmium, lead, and arsenic, is gaining recognition as an important component in heavy metal detoxification. Similar to the upregulation of phase II and antioxidant enzymes, metallothionein can be induced at specific promoter regions of genes by stimuli such as heavy metals, oxidative stress, glucocorticoids, and even zinc. In addition to sequestering heavy metals, it is capable of scavenging free radicals and reducing injury from oxidative stress, as well as inhibiting NF-κB signaling.

Dietary patterns and nutrients may result in changes in metallothionein production. Lamb et al. (2011) reported a 54% increase in metallothionein mRNA production in a small clinical trial in women with fibromyalgia following an elimination diet in conjunction with a phytonutrient-rich medical food consisting of hops, pomegranate, prune skin, and watercress. Zinc supplementation (15 mg/day) to healthy men over 10 days led to significantly increased metallothionein mRNA, up to 2-fold in leukocytes and up to 4-fold from dried blood spots. Metallothionein has been shown to be decreased in the intestinal mucosa of patients with inflammatory bowel disease (IBD); however, zinc supplementation (300 mg zinc aspartate, equal to 60 mg elemental zinc per day for 4 weeks) in 14 zinc-deficient patients with IBD resulted in slightly higher metallothionein concentration in the intestinal mucosa. Cruciferous phytonutrients may also modulate metallothionein expression, as suggested by a 10-fold increase following a single oral dose of 50 μmol sulforaphane to rats. Chromium may inhibit zinc-induced metallothionein expression, according to animal studies by Kimura et al. (2011). Early-stage, in vitro studies also suggest that quercetin and Cordyceps sinensis, a mushroom native to the Himalayan region, may upregulate metallothionein expression.

5. Clinical Applications

With the continued emergence of data supporting the role of toxins in chronic disease processes, it is becoming increasingly necessary for clinicians to understand how to provide therapeutic modalities to reduce toxin load in patients. In this paper, several studies regarding the influence of foods and food-based nutrients on the systems of detoxification were presented. From the current information presented, listed below are some key concepts for translation into the clinical setting.

5.1. Nonclinical versus Clinical Studies

One of the limitations that comes to the forefront in this collection of studies is how the information, in many cases, is constrained primarily to studies in cells or animals. It remains questionable as to whether similar effects would be seen in humans at moderate, reasonable doses. In the cell studies, it is difficult to anticipate findings due to the lack of pleiotropic activity that occurs in a complex, living system with multiple detoxification systems working simultaneously. Along similar lines, animal studies are often difficult to extrapolate to individuals due to the degree of variability in genotype and environmental phenotype seen in the diverse human population. Therefore, at this time, it is best to take precaution in firmly advocating foods or food-based nutrients that only have cell or animal data as support. It is best to rely on the clinical studies that have been published to date in making more firm recommendations.

5.2. Single Agent versus Lifestyle

While this paper focuses on isolated nutrients and foods that contain those nutrients, it might be optimal from a clinical perspective to consider how an entire lifestyle might induce or inhibit the array of detoxification enzymes. For example, this paper has not addressed behaviors like smoking, physical activity, or stress. The modern clinician needs to weigh all these variables against each other. Yet, science has not fully demonstrated the individual impacts of these factors, along with all of them together. Therefore, at this time, a dietary pattern favoring whole, unprocessed, plant-based foods and the removal or reduction of toxic substances in one's environment is a two-prong approach that would seem to have the best overarching scientific underpinning.

5.3. Modulating versus Inhibiting/Inducing Effects

In several instances, certain foods exhibited a particular activity on an enzyme, while, at higher doses, they had another, opposite effect. Essentially, many foods serve as what is commonly referred to as being “bifunctional modulators,” possessing the ability to effectively induce or inhibit detoxification enzyme activity based on the dose response. Therefore, the resulting clinical takeaway might be to encourage patients to follow a mixed, varied diet, full of different plant-based, whole foods. Smaller amounts of many compounds might be more therapeutic and supportive for biochemical pathways rather than overriding signals derived from high concentrations of nutrients through high-dose supplementation or the repeat, daily ingestion of large quantities of the same food.

5.4. Polypharmacy

For patients who are taking multiple pharmaceuticals, it is important to know which detoxification systems will be influenced by nutrients and foods so that side effects are minimized or avoided.

5.5. Dietary Supplements versus Foods

Since there can be potent effects of food-based nutrients on detoxification pathways, it would be best for the average patient to follow, as indicated above, a mixed, complex, and whole-foods diet. Additionally, dietary supplements may be a helpful adjunct in patients in which the practitioner has information about the patient's genetic variability, so that nutrients can be tailored accordingly. Without a full understanding of a patient's SNPs (single nucleotide polymorphisms), it becomes difficult to make accurate assessments about nutrients and dosing.

5.6. Duration of Dosing

Another factor to consider in therapeutic intervention is the timing and duration of the dose of nutrient or the food. In some of the research presented here, effects on detoxification enzymes were seen after several days of food intake or supplementation, while, in other cases, induction of an enzyme might be fairly rapid, followed by efficient adaptability. This variable needs to be considered in further clinical research and requires close monitoring in clinical practice.

5.7. Foods Known to Impact Detoxification

Based on the four systems examined in this paper, there are several foods which seem to have demonstrated an influence on detoxification systems. Many of them have been acknowledged as part of naturopathic medicine. Hence, it would be useful to have a knowledge base of this cumulative set of foods as patients embark upon detoxification protocols. This recent scientific update notes clinical evidence of effects from cruciferous vegetables (in combination, and specifically watercress, garden cress, and broccoli), allium vegetables, apiaceous vegetables, grapefruit, resveratrol, fish oil, quercetin, daidzein, and lycopene. Many other foods, beverages, and nutrient bioactive compounds, based on this review of scientific literature, are also suggested as modulators of detoxification enzymes in vivo (Table 11).

6. Conclusions

Over the past decade, there has been investigation into nutrigenomic and epigenetic influences of food constituents on chronic diseases. Similarly, studies have revealed that exposure to and accumulation of toxins play a significant role in cardiovascular disease, type 2 diabetes, and obesity. Thus, one's dietary intake and environmental influences may have large bearing on the incidence of chronic disease. In fact, these influences may be significant not just for the individual, but for several generations due to the transgenerational inheritance of epigenetic changes. Therefore, it would seem that designing clinical recommendations to maximize the effects of food and reduce the impact of toxins is essential. However, it is not without caution and critical thinking that a detoxification protocol should be assembled for patients by trained clinicians. There remain many unresolved issues regarding knowing how and what foods modulate detoxification pathways.

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    Not in our library10.1016/j.biocel.2013.02.019

  87. 87.

    Strassburg C. P., Kneip S., Topp J., et al. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. The Journal of Biological Chemistry. 2000;275(46):36164-36171.

    Not in our library10.1074/jbc.m002180200

  88. 88.

    Wells P. G., Mackenzie P. I., Chowdhury J. R., et al. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metabolism and Disposition. 2004;32(3):281-290.

    Not in our library10.1124/dmd.32.3.281

  89. 89.

    Lampe J. W. Interindividual differences in response to plant-based diets: Implications for cancer risk. The American Journal of Clinical Nutrition. 2009;89(5):1553S-1557S.

    Not in our library10.3945/ajcn.2009.26736d

  90. 90.

    Navarro S. L., Peterson S., Chen C., et al. Cruciferous vegetable feeding alters UGT1A1 activity: diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial. Cancer Prevention Research (Phila). 2009;2(4):345-352.

    Not in our library10.1158/1940-6207.capr-08-0178

  91. 91.

    Hecht S. S., Carmella S. G., Murphy S. E. Effects of watercress consumption on urinary metabolites of nicotine in smokers. Cancer Epidemiology Biomarkers and Prevention. 1999;8(10):907-913.

    Not in our library

  92. 92.

    Saracino M. R., Bigler J., Schwarz Y., et al. Citrus fruit intake is associated with lower serum bilirubin concentration among women with the UGT1A1*28 polymorphism. Journal of Nutrition. 2009;139(3):555-560.

    Not in our library10.3945/jn.108.097279

  93. 93.

    Marnewick J. L., Joubert E., Swart P., van der Westhuizen F., Gelderblom W. C. Modulation of hepatic drug metabolizing enzymes and oxidative status by rooibos (Aspalathus linearis) and Honeybush (Cyclopia intermedia), green and black (Camellia sinensis) teas in rats. Journal of Agricultural and Food Chemistry. 2003;51(27):8113-8119.

    Not in our library10.1021/jf0344643

  94. 94.

    Marahatta A., Bhandary B., Jeong S.-K., Kim H.-R., Chae H.-J. Soybean greatly reduces valproic acid plasma concentrations: a food-drug interaction study. Scientific Reports. 2014;4, article 4362.

    Not in our library10.1038/srep04362

  95. 95.

    van der Logt E. M. J., Roelofs H. M. J., Nagengast F. M., Peters W. H. M. Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens. Carcinogenesis. 2003;24(10):1651-1656.

    Not in our library10.1093/carcin/bgg117

  96. 96.

    Graf E. Antioxidant potential of ferulic acid. Free Radical Biology and Medicine. 1992;13(4):435-448.

    Not in our library10.1016/0891-5849(92)90184-i

  97. 97.

    Simone C. B., Simone N. L., Pallante M., Simone C. B. Cancer, lifestyle modification and glucarate. Journal of Orthomolecular Medicine. 2001;16(2):83-90.

    Not in our library

  98. 98.

    Zółtaszek R., Hanausek M., Kiliańska Z. M., Walaszek Z. The biological role of D-glucaric acid and its derivatives: potential use in medicine. Postpy Higieny i Medycyny Doświadczalnej. 2008;62:451-462.

    Not in our library

  99. 99.

    Dwivedi C., Heck W. J., Downie A. A., Larroya S., Webb T. E. Effect of calcium glucarate on beta-glucoronidase activity and glucarate content of certain vegetable and fruits. Biochemical Medicine and Metabolic Biology. 1990;43(2):83-92.

    Not in our library10.1016/0885-4505(90)90012-p

  100. 100.

    Kosmala M., Zduńczyk Z., Kołodziejczyk K., Klimczak E., Jukiewicz J., Zduńczyk P. Chemical composition of polyphenols extracted from strawberry pomace and their effect on physiological properties of diets supplemented with different types of dietary fibre in rats. European Journal of Nutrition. 2014;53(2):521-532.

    Not in our library10.1007/s00394-013-0557-z

  101. 101.

    Maruti S. S., Chang J. L., Prunty J. A., et al. Serum β-glucuronidase activity in response to fruit and vegetable supplementation: a controlled feeding study. Cancer Epidemiology Biomarkers and Prevention. 2008;17(7):1808-1812.

    Not in our library10.1158/1055-9965.epi-07-2660

  102. 102.

    Jurgoński A., Juśkiewicz J., Zduńczyk Z., Matusevicius P., Kołodziejczyk K. Polyphenol-rich extract from blackcurrant pomace attenuates the intestinal tract and serum lipid changes induced by a high-fat diet in rabbits. European Journal of Nutrition. 2014;53(8):1603-1613.

    Not in our library10.1007/s00394-014-0665-4

  103. 103.

    James M. O., Ambadapadi S. Interactions of cytosolic sulfotransferases with xenobiotics. Drug Metabolism Reviews. 2013;45(4):401-414.

    Not in our library10.3109/03602532.2013.835613

  104. 104.

    Kodama S., Negishi M. Sulfotransferase genes: regulation by nuclear receptors in response to xeno/endo-biotics. Drug Metabolism Reviews. 2013;45(4):441-449.

    Not in our library10.3109/03602532.2013.835630

  105. 105.

    Wang L.-Q., James M. O. Inhibition of sulfotransferases by xenobiotics. Current Drug Metabolism. 2006;7(1):83-104.

    Not in our library10.2174/138920006774832596

  106. 106.

    Ung D., Nagar S. Variable sulfation of dietary polyphenols by recombinant human sulfotransferase (SULT) 1A1 genetic variants and SULT1E1. Drug Metabolism and Disposition. 2007;35(5):740-746.

    Not in our library10.1124/dmd.106.013987

  107. 107.

    Zhou T., Chen Y., Huang C., Chen G. Caffeine induction of sulfotransferases in rat liver and intestine. Journal of Applied Toxicology. 2012;32(10):804-809.

    Not in our library10.1002/jat.1698

  108. 108.

    Maiti S., Chen X., Chen G. All-trans retinoic acid induction of sulfotransferases. Basic and Clinical Pharmacology and Toxicology. 2005;96(1):44-53.

    Not in our library10.1111/j.1742-7843.2005.pto960107.x

  109. 109.

    Kamio K., Honke K., Makita A. Pyridoxal 5'-phosphate binds to a lysine residue in the adenosine 3′-phosphate 5′-phosphosulfate recognition site of glycolipid sulfotransferase from human renal cancer cells. Glycoconjugate Journal. 1995;12(6):762-766.

    Not in our library10.1007/bf00731236

  110. 110.

    Masters M., McCance R. A. The sulfur content of foods. Biochemical Journal. 1939;33(8):1304-1312.

    Not in our library10.1042/bj0331304

  111. 111.

    Nutrient Data Laboratory. Release 27. 2011.

    Not in our library

  112. 112.

    McFadden S. A. Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. Toxicology. 1996;111(1–3):43-65.

    Not in our library10.1016/0300-483x(96)03392-6

  113. 113.

    Hayes J. D., Pulford D. J. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Critical Reviews in Biochemistry and Molecular Biology. 1995;30(6):445-600.

    Not in our library10.3109/10409239509083491

  114. 114.

    Navarro S. L., Chang J. L., Peterson S., et al. Modulation of human serum glutathione S-transferase A1/2 concentration by cruciferous vegetables in a controlled feeding study is influenced by GSTM1 and GSTT1 genotypes. Cancer Epidemiology Biomarkers and Prevention. 2009;18(11):2974-2978.

    Not in our library10.1158/1055-9965.epi-09-0701

  115. 115.

    Wark P. A., Grubben M. J. A. L., Peters W. H. M., et al. Habitual consumption of fruits and vegetables: associations with human rectal glutathione S-transferase. Carcinogenesis. 2004;25(11):2135-2142.

    Not in our library10.1093/carcin/bgh238

  116. 116.

    Lampe J. W., Chen C., Li S., et al. Modulation of human glutathione S-transferases by botanically defined vegetable diets. Cancer Epidemiology Biomarkers and Prevention. 2000;9(8):787-793.

    Not in our library

  117. 117.

    Nijhoff W. A., Mulder T. P. J., Verhagen H., van Poppel G., Peters W. H. M. Effects of consumption of brussels sprouts on plasma and urinary glutathione S-transferase class-alpha and -pi in humans. Carcinogenesis. 1995;16(4):955-957.

    Not in our library10.1093/carcin/16.4.955

  118. 118.

    Hwang Y. P., Choi J. H., Yun H. J., et al. Anthocyanins from purple sweet potato attenuate dimethylnitrosamine-induced liver injury in rats by inducing Nrf2-mediated antioxidant enzymes and reducing COX-2 and iNOS expression. Food and Chemical Toxicology. 2011;49(1):93-99.

    Not in our library10.1016/j.fct.2010.10.002

  119. 119.

    Iqbal M., Sharma S. D., Okazaki Y., Fujisawa M., Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacology and Toxicology. 2003;92(1):33-38.

    Not in our library10.1034/j.1600-0773.2003.920106.x

  120. 120.

    Newsome B. J., Petriello M. C., Han S. G., et al. Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes. Journal of Nutritional Biochemistry. 2014;25(2):126-135.

    Not in our library10.1016/j.jnutbio.2013.10.003

  121. 121.

    Lin C. Y., Chen J. H., Fu R. H., Tsai C. W. Induction of Pi form of glutathione S-transferase by carnosic acid is mediated through PI3K/Akt/NF-κB pathway and protects against neurotoxicity. Chemical Research in Toxicology. 2014;27(11):1958-1966.

    Not in our library10.1021/tx5003063

  122. 122.

    Chinnadurai K., Kanwal H. K., Tyagi A. K., Stanton C., Ross P. High conjugated linoleic acid enriched ghee (clarified butter) increases the antioxidant and antiatherogenic potency in female Wistar rats. Lipids in Health and Disease. 2013;12(1, article 121).

    Not in our library10.1186/1476-511x-12-121

  123. 123.

    Froyen E. B., Reeves J. L. R., Mitchell A. E., Steinberg F. M. Regulation of phase II enzymes by Genistein and daidzein in male and female Swiss Webster mice. Journal of Medicinal Food. 2009;12(6):1227-1237.

    Not in our library10.1089/jmf.2009.0084

  124. 124.

    Perez J. L., Jayaprakasha G. K., Cadena A., Martinez E., Ahmad H., Patil B. S. In vivo induction of phase II detoxifying enzymes, glutathione transferase and quinone reductase by citrus triterpenoids. BMC Complementary and Alternative Medicine. 2010;10, article 51.

    Not in our library10.1186/1472-6882-10-51

  125. 125.

    Barrett J. R. The science of soy: what do we really know? Environmental Health Perspectives. 2006;114(6):A352-A358.

    Not in our library10.1289/ehp.114-a352

  126. 126.

    Wiegand H., Boesch-Saadatmandi C., Regos I., Treutter D., Wolffram S., Rimbach G. Effects of quercetin and catechin on hepatic glutathione-s transferase (GST), NAD(P)H quinone oxidoreductase 1 (NQO1), and antioxidant enzyme activity levels in rats. Nutrition and Cancer. 2009;61(5):717-722.

    Not in our library10.1080/01635580902825621

  127. 127.
    Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases · 2014
    No notice
  128. 128.

    Lipoic Acid. 2012.

    Not in our library

  129. 129.

    Kalpravidh R. W., Siritanaratkul N., Insain P., et al. Improvement in oxidative stress and antioxidant parameters in beta-thalassemia/Hb E patients treated with curcuminoids. Clinical Biochemistry. 2010;43(4-5):424-429.

    Not in our library10.1016/j.clinbiochem.2009.10.057

  130. 130.

    Lucena M. I., Andrade R. J., de la Cruz J. P., Rodriguez-Mendizabal M., Blanco E., Sánchez de la Cuesta F. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. International Journal of Clinical Pharmacology and Therapeutics. 2002;40(1):2-8.

    Not in our library10.5414/cpp40002

  131. 131.

    Santana-Martínez R. A., Galván-Arzáte S., Hernández-Pando R., et al. Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels. Neuroscience. 2014;272:188-198.

    Not in our library10.1016/j.neuroscience.2014.04.043

  132. 132.

    Chen M. F., Chen L. T., Boyce H. W. Cruciferous vegetables and glutathione: their effects on colon mucosal glutathione level and colon tumor development in rats induced by DMH. Nutrition and Cancer. 1995;23(1):77-83.

    Not in our library10.1080/01635589509514363

  133. 133.

    El Morsy E. M., Kamel R. Protective effect of artichoke leaf extract against paracetamol-induced hepatotoxicity in rats. Pharmaceutical Biology. 2015;53(2):167-173.

    Not in our library10.3109/13880209.2014.913066

  134. 134.

    Brauer H. A., Libby T. E., Mitchell B. L., et al. Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner. Nutrition Journal. 2011;10(1, article 11).

    Not in our library10.1186/1475-2891-10-11

  135. 135.

    Hofmann T., Kuhnert A., Schubert A., et al. Modulation of detoxification enzymes by watercress: in vitro and in vivo investigations in human peripheral blood cells. European Journal of Nutrition. 2009;48(8):483-491.

    Not in our library10.1007/s00394-009-0039-5

  136. 136.

    Forman H. J., Zhang H., Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Molecular Aspects of Medicine. 2009;30(1-2):1-12.

    Not in our library10.1016/j.mam.2008.08.006

  137. 137.

    Kern J. K., Geier D. A., Adams J. B., Garver C. R., Audhya T., Geier M. R. A clinical trial of glutathione supplementation in autism spectrum disorders. Medical Science Monitor. 2011;17(12):CR677-CR682.

    Not in our library10.12659/msm.882125

  138. 138.

    Paterson P. G., Lyon A. W., Kamencic H., Andersen L. B., Juurlink B. H. J. Sulfur amino acid deficiency depresses brain glutathione concentration. Nutritional Neuroscience. 2001;4(3):213-222.

    Not in our library10.1080/1028415x.2001.11747364

  139. 139.

    Treweeke A. T., Winterburn T. J., Mackenzie I., et al. N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial. Diabetologia. 2012;55(11):2920-2928.

    Not in our library10.1007/s00125-012-2685-z

  140. 140.

    Galluzzi L., Vitale I., Senovilla L., et al. Prognostic impact of vitamin B6 metabolism in lung cancer. Cell Reports. 2012;2(2):257-269.

    Not in our library10.1016/j.celrep.2012.06.017

  141. 141.

    Howard J. M., Davies S., Hunnisett A. Red cell magnesium and glutathione peroxidase in infertile women—effects of oral supplementation with magnesium and selenium. Magnesium Research. 1994;7(1):49-57.

    Not in our library

  142. 142.

    Child D. F., Hudson P. R., Jones H., et al. The effect of oral folic acid on glutathione, glycaemia and lipids in type 2 diabetes. Diabetes, Nutrition and Metabolism—Clinical and Experimental. 2004;17(2):95-102.

    Not in our library

  143. 143.

    Ansar H., Mazloom Z., Kazemi F., Hejazi N. Effect of alpha-lipoic acid on blood glucose, insulin resistance, and glutathione peroxidase of type 2 diabetic patients. Saudi Medical Journal. 2011;32(6):584-588.

    Not in our library

  144. 144.

    Lord R. S., Bralley J. A. Laboratory Evaluations for Integrative and Functional Medicine. 2012.

    Not in our library

  145. 145.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

  146. 146.

    Makarova S. I. Human N-acetyltransferases and drug-induced hepatotoxicity. Current Drug Metabolism. 2008;9(6):538-545.

    Not in our library10.2174/138920008784892047

  147. 147.

    Kohalmy K., Vrzal R. Regulation of phase II biotransformation enzymes by steroid hormones. Current Drug Metabolism. 2011;12(2):104-123.

    Not in our library10.2174/138920011795016872

  148. 148.

    Yager J. D. Mechanisms of estrogen carcinogenesis: the role of E2/E1-quinone metabolites suggests new approaches to preventive intervention—a review. Steroids. 2014.

    Not in our library10.1016/j.steroids.2014.08.006

  149. 149.

    Busserolles J., Zimowska W., Rock E., Rayssiguier Y., Mazur A. Rats fed a high sucrose diet have altered heart antioxidant enzyme activity and gene expression. Life Sciences. 2002;71(11):1303-1312.

    Not in our library10.1016/s0024-3205(02)01846-5

  150. 150.

    Su Z. Y., Shu L., Khor T. O., Lee J. H., Fuentes F., Kong A. N. T. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, Nrf2, and epigenomics. Topics in Current Chemistry. 2013;329:133-162.

    Not in our library10.1007/128-2012-340

  151. 151.

    Chan K., Han X. D., Kan Y. W. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(8):4611-4616.

    Not in our library10.1073/pnas.081082098

  152. 152.

    Calabrese V., Cornelius C., Mancuso C., et al. Cellular stress response: A novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochemical Research. 2008;33(12):2444-2471.

    Not in our library10.1007/s11064-008-9775-9

  153. 153.

    Boyanapalli S. S., Paredes-Gonzalez X., Fuentes F., et al. Nrf2 knockout attenuates the anti-inflammatory effects of phenethyl isothiocyanate and curcumin. Chemical Research in Toxicology. 2014;27(12):2036-2043.

    Not in our library10.1021/tx500234h

  154. 154.

    Niture S. K., Khatri R., Jaiswal A. K. Regulation of Nrf2—an update. Free Radical Biology and Medicine. 2014;66:36-44.

    Not in our library10.1016/j.freeradbiomed.2013.02.008

  155. 155.

    Xie Y., Zhao Q. Y., Li H. Y., Zhou X., Liu Y., Zhang H. Curcumin ameliorates cognitive deficits heavy ion irradiation-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Pharmacology Biochemistry and Behavior. 2014.

    Not in our library10.1016/j.pbb.2014.08.005

  156. 156.

    Soetikno V., Sari F. R., Lakshmanan A. P., et al. Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway. Molecular Nutrition & Food Research. 2013;57(9):1649-1659.

    Not in our library10.1002/mnfr.201200540

  157. 157.

    He H. J., Wang G. Y., Gao Y., Ling W. H., Yu Z. W., Jin T. R. Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World Journal of Diabetes. 2012;3(5):94-104.

    Not in our library10.4239/wjd.v3.i5.94

  158. 158.

    Farombi E. O., Shrotriya S., Na H. K., Kim S. H., Surh Y. J. Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food and Chemical Toxicology. 2008;46(4):1279-1287.

    Not in our library10.1016/j.fct.2007.09.095

  159. 159.

    Zhang Z., Wang S., Zhou S., et al. Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. Journal of Molecular and Cellular Cardiology. 2014;77:42-52.

    Not in our library10.1016/j.yjmcc.2014.09.022

  160. 160.

    McWalter G. K., Higgins L. G., McLellan L. I., et al. Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. Journal of Nutrition. 2004;134(12, supplement):3499S-3506S.

    Not in our library10.1093/jn/134.12.3499s

  161. 161.

    Lee I. C., Kim S. H., Baek H. S., et al. The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats. Food and Chemical Toxicology. 2014;63:174-185.

    Not in our library10.1016/j.fct.2013.11.006

  162. 162.

    Padiya R., Chowdhury D., Borkar R., Srinivas R., Pal Bhadra M., Banerjee S. K. Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat. PLoS ONE. 2014;9(5).

    Not in our library10.1371/journal.pone.0094228

  163. 163.

    Gómez-Sierra T., Molina-Jijón E., Tapia E., et al. S-allylcysteine prevents cisplatin-induced nephrotoxicity and oxidative stress. Journal of Pharmacy and Pharmacology. 2014;66(9):1271-1281.

    Not in our library10.1111/jphp.12263

  164. 164.

    Chang C. F., Cho S., Wang J. (-)-Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways. Annals of Clinical and Translational Neurology. 2014;1(4):258-271.

    Not in our library10.1002/acn3.54

  165. 165.

    Leonardo C. C., Agrawal M., Singh N., Moore J. R., Biswal S., Doré S. Oral administration of the flavanol (-)-epicatechin bolsters endogenous protection against focal ischemia through the Nrf2 cytoprotective pathway. European Journal of Neuroscience. 2013;38(11):3659-3668.

    Not in our library10.1111/ejn.12362

  166. 166.

    Kavitha K., Thiyagarajan P., Rathna J., Mishra R., Nagini S. Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification, and DNA repair enzymes. Biochimie. 2013;95(8):1629-1639.

    Not in our library10.1016/j.biochi.2013.05.004

  167. 167.

    Shah Z. A., Li R.-C., Ahmad A. S., et al. The flavanol (−)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. Journal of Cerebral Blood Flow and Metabolism. 2010;30(12):1951-1961.

    Not in our library10.1038/jcbfm.2010.53

  168. 168.

    Tamaki N., Cristina Orihuela-Campos R., Inagaki Y., Fukui M., Nagata T., Ito H. Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model. Free Radical Biology and Medicine. 2014;75:222-229.

    Not in our library10.1016/j.freeradbiomed.2014.07.034

  169. 169.

    Sadi G., Bozan D., Yildiz H. B. Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver. Molecular and Cellular Biochemistry. 2014;393(1-2):111-122.

    Not in our library10.1007/s11010-014-2051-1

  170. 170.

    Chen H., Fu J., Hu Y., et al. Ginger compound [6]-shogaol and its cysteine-conjugated metabolite (M2) activate Nrf2 in colon epithelial cells in vitro and in vivo. Chemical Research in Toxicology. 2014;27(9):1575-1585.

    Not in our library10.1021/tx500211x

  171. 171.

    Bak M. J., Ok S., Jun M., Jeong W. S. 6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice. Molecules. 2012;17(7):8037-8055.

    Not in our library10.3390/molecules17078037

  172. 172.

    Xi Y. D., Li X. Y., Yu H. L., et al. Soy isoflavone antagonizes the oxidative cerebrovascular injury induced by β-Amyloid Peptides 1–42 in Rats. Neurochemical Research. 2014;39(7):1374-1381.

    Not in our library10.1007/s11064-014-1319-x

  173. 173.

    Li R., Liang T., Xu L., Zheng N., Zhang K., Duan X. Puerarin attenuates neuronal degeneration in the substantia nigra of 6-OHDA-lesioned rats through regulating BDNF expression and activating the Nrf2/ARE signaling pathway. Brain Research. 2013;1523:1-9.

    Not in our library10.1016/j.brainres.2013.05.046

  174. 174.

    Vicente S. J. V., Ishimoto E. Y., Torres E. A. F. S. Coffee modulates transcription factor Nrf2 and highly increases the activity of antioxidant enzymes in rats. Journal of Agricultural and Food Chemistry. 2014;62(1):116-122.

    Not in our library10.1021/jf401777m

  175. 175.

    Sahu B. D., Putcha U. K., Kuncha M., Rachamalla S. S., Sistla R. Carnosic acid promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress and apoptosis in mice. Molecular and Cellular Biochemistry. 2014;394(1-2):163-176.

    Not in our library10.1007/s11010-014-2092-5

  176. 176.

    Balstad T. R., Carlsen H., Myhrstad M. C. W., et al. Coffee, broccoli and spices are strong inducers of electrophile response element-dependent transcription in vitro and in vivo—studies in electrophile response element transgenic mice. Molecular Nutrition and Food Research. 2011;55(2):185-197.

    Not in our library10.1002/mnfr.201000204

  177. 177.

    Wang Y. P., Cheng M. L., Zhang B. F., et al. Effect of blueberry on hepatic and immunological functions in mice. Hepatobiliary and Pancreatic Diseases International. 2010;9(2):164-168.

    Not in our library

  178. 178.

    Bishayee A., Bhatia D., Thoppil R. J., Darvesh A. S., Nevo E., Lansky E. P. Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis. 2011;32(6):888-896.

    Not in our library10.1093/carcin/bgr045

  179. 179.

    Esmaeili M. A., Alilou M. Naringenin attenuates CCl4-induced hepatic inflammation by the activation of an Nrf2-mediated pathway in rats. Clinical and Experimental Pharmacology and Physiology. 2014;41(6):416-422.

    Not in our library10.1111/1440-1681.12230

  180. 180.

    Singh C. K., Ndiaye M. A., Siddiqui I. A., et al. Methaneseleninic acid and γ-tocopherol combination inhibits prostate tumor growth in vivo in a xenograft mouse model. Oncotarget. 2014;5(11):3651-3661.

    Not in our library10.18632/oncotarget.1979

  181. 181.

    Magbanua M. J. M., Roy R., Sosa E. V., et al. Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS ONE. 2011;6(9).

    Not in our library10.1371/journal.pone.0024004

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    Manach C., Scalbert A., Morand C., Rémésy C., Jiménez L. Polyphenols: food sources and bioavailability. The American Journal of Clinical Nutrition. 2004;79(5):727-747.

    Not in our library10.1093/ajcn/79.5.727

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    Delmonte P., Rader J. I. Analysis of isoflavones in foods and dietary supplements. Journal of AOAC International. 2006;89(4):1138-1146.

    Not in our library

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    Chian S., Thapa R., Chi Z., Wang X. J., Tang X. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochemical and Biophysical Research Communications. 2014;447(4):602-608.

    Not in our library10.1016/j.bbrc.2014.04.039

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    Marina R., González P., Ferreras M. C., Costilla S., Barrio J. P. Hepatic Nrf2 expression is altered by quercetin supplementation in Xirradiated rats. Molecular Medicine Reports. 2015;11(1):539-546.

    Not in our library10.3892/mmr.2014.2741

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    Zhou H., Qu Z., Mossine V. V., et al. Proteomic analysis of the effects of aged garlic extract and its fruarg component on lipopolysaccharide-induced neuroinflammatory response in microglial cells. PLoS ONE. 2014;9(11).

    Not in our library10.1371/journal.pone.0113531

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    Calabrese V., Cornelius C., Dinkova-Kostova A. T., Calabrese E. J., Mattson M. P. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxidants & Redox Signaling. 2010;13(11):1763-1811.

    Not in our library10.1089/ars.2009.3074

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    Houghton C. A., Fassett R. G., Coombes J. S. Sulforaphane: translational research from laboratory bench to clinic. Nutrition Reviews. 2013;71(11):709-726.

    Not in our library10.1111/nure.12060

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    Dietary Regulation of Keap1/Nrf2/ARE Pathway: Focus on Plant-Derived Compounds and Trace Minerals · 2014
    No notice
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    Andrews G. K. Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochemical Pharmacology. 2000;59(1):95-104.

    Not in our library10.1016/s0006-2952(99)00301-9

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    Lichtlen P., Schaffner W. Putting its fingers on stressful situations: the heavy metal-regulatory transcription factor MTF-1. BioEssays. 2001;23(11):1010-1017.

    Not in our library10.1002/bies.1146

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    Sato M., Kondoh M. Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku Journal of Experimental Medicine. 2002;196(1):9-22.

    Not in our library10.1620/tjem.196.9

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    Pan Y., Huang J., Xing R., et al. Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection. Journal of Translational Medicine. 2013;11(1, article 173).

    Not in our library10.1186/1479-5876-11-173

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    Lamb J. J., Konda V. R., Quig D. W., et al. A program consisting of a phytonutrient-rich medical food and an elimination diet ameliorated fibromyalgia symptoms and promoted toxic-element detoxification in a pilot trial. Alternative Therapies in Health and Medicine. 2011;17(2):36-44.

    Not in our library

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    Aydemir T. B., Blanchard R. K., Cousins R. J. Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(6):1699-1704.

    Not in our library10.1073/pnas.0510407103

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    Mulder T. P. J., van der Sluys Veer A., Verspaget H. W., et al. Effect of oral zinc supplementation on metallothionein and superoxide dismutase concentrations in patients with inflammatory bowel disease. Journal of Gastroenterology and Hepatology. 1994;9(5):472-477.

    Not in our library10.1111/j.1440-1746.1994.tb01277.x

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    Hu R., Hebbar V., Kim B. R., et al. In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat. Journal of Pharmacology and Experimental Therapeutics. 2004;310(1):263-271.

    Not in our library10.1124/jpet.103.064261

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    Kimura T., Okumura F., Onodera A., Nakanishi T., Itoh N., Isobe M. Chromium (VI) inhibits mouse metallothionein-I gene transcription by modifying the transcription potential of the co-activator p300. The Journal of Toxicological Sciences. 2011;36(2):173-180.

    Not in our library10.2131/jts.36.173

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    Weng C. J., Chen M. J., Yeh C. T., Yen G. C. Hepatoprotection of quercetin against oxidative stress by induction of metallothionein expression through activating MAPK and PI3K pathways and enhancing Nrf2 DNA-binding activity. New Biotechnology. 2011;28(6):767-777.

    Not in our library10.1016/j.nbt.2011.05.003

  200. 200.

    Singh M., Tulsawani R., Koganti P., Chauhan A., Manickam M., Misra K. Cordyceps sinensis increases hypoxia tolerance by inducing heme oxygenase-1 and metallothionein via Nrf2 activation in human lung epithelial cells. BioMed Research International. 2013;2013:13.

    Not in our library10.1155/2013/569206

  201. 201.

    Sales N. M. R., Pelegrini P. B., Goersch M. C. Nutrigenomics: definitions and advances of this new science. Journal of Nutrition and Metabolism. 2014;2014:6.

    Not in our library10.1155/2014/202759

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    Lim U., Song M. A. Dietary and lifestyle factors of DNA methylation. Methods in Molecular Biology. 2012;863:359-376.

    Not in our library10.1007/978-1-61779-612-8_23

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    Lang I. A., Galloway T. S., Scarlett A., et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. The Journal of the American Medical Association. 2008;300(11):1303-1310.

    Not in our library10.1001/jama.300.11.1303

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    Bisphenol A and human chronic diseases: Current evidences, possible mechanisms, and future perspectives · 2014
    Not checked
  205. 205.

    Mostafalou S., Abdollahi M. Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Toxicology and Applied Pharmacology. 2013;268(2):157-177.

    Not in our library10.1016/j.taap.2013.01.025

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    Magliano D. J., Loh V. H. Y., Harding J. L., Botton J., Shaw J. E. Persistent organic pollutants and diabetes: a review of the epidemiological evidence. Diabetes & Metabolism. 2014;40(1):1-14.

    Not in our library10.1016/j.diabet.2013.09.006

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    Agarwal S., Zaman T., Tuzcu E. M., Kapadia S. R. Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999–2006. Angiology. 2011;62(5):422-429.

    Not in our library10.1177/0003319710395562

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    Rissman E. F., Adli M. Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds. Endocrinology. 2014;155(8):2770-2780.

    Not in our library10.1210/en.2014-1123

  209. 209.

    Walker D. M., Gore A. C. Transgenerational neuroendocrine disruption of reproduction. Nature Reviews Endocrinology. 2011;7(4):197-207.

    Not in our library10.1038/nrendo.2010.215

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