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Research Review: Using Whole Food Phytonutrients to Modulate Detoxification Pathways

Prevailing scientific thought indicates that specific foods may upregulate or help balance the metabolic pathways that assist the body with toxin biotransformation and subsequent elimination. Studies have identified whole foods such as cruciferous vegetables, berries, soy, garlic and even spices like turmeric as beneficial in aiding the detoxification process.*[1] However, as science on this important subject evolves, new research is now pointing to how food-based nutrients might further affect these processes.

The following is an excerpt of a March 2015 review article by detoxification experts Deanna M. Minich, Ph.D., of the Institute of Functional Medicine and the University of Western States, and Romilly E. Hodges of the University of Bridgeport. Published in the Journal of Nutrition and Metabolism, the paper offers an overview of the most recent science directed toward phytonutrients and other food-based components and their influence on 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 concludes with clinical recommendations that may be applied in a personalized manner for patients through a qualified health professional.

Metabolic Pathways of Detoxification

The phases of detoxification were initially described as functionalization (phase 1), 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 defence employed by the body to biotransform xenobiotics, steroid hormones and pharmaceuticals.

It is accepted that variability in the number of CYP450 enzymes could have a benefit or consequence in how an individual responds to the effects of a toxin, The ability of an individual to metabolize drugs will depend on genetic expression of these enzymes. In addition, many of these CYP450 genes are subject to genetic polymorphisms, resulting in 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 phytonutrients, especially in the case of dietary supplements and functional foods, could be worthwhile as clinicians consider patients, particularly those who are taking a polypharmacy approach. Furthermore, as nutritional strategies become more personalized, this information could be interfaced with a patient’s known CYP450 polymorphisms to determine how to best optimize health outcomes.

The CYP1A enzymes are involved in metabolizing procarcinogens, hormones and pharmaceuticals. CYPI activity has been linked to higher risk of certain diseases, and, it has been suggested that genetic polymorphisms in this cytochrome family, may be useful markers of certain cancers. Various foods and phytonutrients affect this activity including cruciferous vegetables, resveratrol containing foods, and berries.

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 foods. Curcumin, for example, at 0.1 percent of the diet has been shown in animals to induce CYP1A1, yet a diet of 1 percent turmeric was inhibitory*. Varied effects may also occur from different members of the same food group. For example, seemingly contradictory research indicates that cruciferous vegetables activate CYP1 enzymes, while kale (another member of the cruciferous family) appears to inhibit CYP1A2.

The CYP2 family of enzymes is involved in metabolism of drugs, xenobiotics, hormones and other endogenous compounds, such as ketones, glycerol and fatty acids. Notable polymorphisms in this group occur in CYP2C and CYP2D subgroups and lead to poor metabolization of pharmaceuticals such as warfarin and CYP2C9, antiarrhythmia agents, metoprolol and propafenone, and CYP2C19, among others.

Watercress and garlic are CYP2E1 inhibitors in humans and in vivo evidence also suggests that N-acetyl cysteine, ellagic acid, green tea, black tea, dandelion, chrysin and medium chain triglycerides may down regulate CYP2E1 activity.

CYP3A enzymes occur in specific tissues. Rooibos tea, garlic, and fish oil appear to induce activity of these enzymes, while foods like green tea, black tea and those containing quercetin are possible inhibitors.* The most clinically relevant enzyme of this family is the CYP3A4, which is expressed mainly in the liver and to a lesser extent in the kidney. To date, the principal driver of research on CYP3A4 has been due to its role in metabolism of more than 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 appear to have similar effects on humans, albeit at intakes above what would be expected without high dose supplementation. Curcumin also may upregulate 3A4 activity.*

Less is known about the CYP4 family of enzymes as it is thought to play a smaller role in drug metabolism. These enzymes are understood to be an extrahepatic family of cytochromes inducible by hypolipidemic drugs, NSAIDS, prostaglandin and toxicants, such as phthalate esters.

Phase II Conjugation Enzymes

After a xenobiotic has gone through the process of becoming hydrophilic through reactions overseen by the 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-methytransferases). 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 various health issues.

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

One of the key players in phase II metabolic pathways is UDP-Glucuronosyltransferases, a class of enzymes comprising multiple proteins and even subfamilies, which 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, which occurs primarily in the liver, but also in other tissues such as the small intestine.

It has been estimated that 40 percent to 70 percent 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 down regulated enzyme activity; flavonoids are conjugated with glucuronide and sulfate; therefore, UGT or sulfotransferase (SULT) polymorphisms may produce variability in phytochemical clearance and efficacy.

Clinical observational studies point to cruciferous vegetables, resveratrol and citrus foods as bioactive compounds that induce UGT enzymes. Animal studies also suggest the potential for other foods and nutrients, including dandelion, rooibus tea, honeybush tea, rosemary, soy, ellagic acid, ferulic acid, curcumin and astaxanthin to enhance UGT activity, although studies have shown mixed results based on variables including gender and genotype.

Similar to the aforementioned categories of conjugating enzymes, glutathione S-transferases (GSTs) include a complex set 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 (ZRE), which will be subsequently discussed in this paper.

Cruciferous and allium vegetables and resveratrol demonstrate ability to induce GSTs in humans.* Observational research also associates citrus consumption with increased GST activity. In vivo data suggests many food and food constituents to be upregulators of these enzymes, including garlic, fish oil, black soybean, purple sweet potato, curcumin, green tea, rooibus 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 food and bioactive compounds may be due to their upregulation of the Nrf2 signaling pathway.

Genetic variances, gender and possibly even body weight may play a role in the effects of the dietary factors on GST enzymes. There is also some evidence that some foods and phytonutrients may exert modulatory rather than absolute inductive/inhibitory effects. For example, a study in 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 vegetable consumption on other mechanisms, such as glutathione peroxidase and superoxide dismutase.

N-Acetyl Transferases (NAT) is a class of enzymes 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, hydralizine, and sulphonamide. Polymorphisms in genes for this category of enzymes, leading to slow metabolism, have been been associated with hepatotoxicity during drug treatment. One study, for example, showed that 500 mg of quercetin daily enhanced NAT activity.*[2] However, more research is needed to understand the relationship between dietary nutrients and NAT function.

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, Keapl (Kelch-like ECH associated protein 1), it translocates to the nucleus to bind to AREs in the promoter enhancer portion of genes associated with phase II detoxification and antioxidant enzyme genes. 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 is considered protective against various oxidative stress-related conditions, such as cancer, kidney dysfunction, pulmonary disorders, arthritis, neurological disease, and cardiovascular disease.

The research demonstrates that dietary components, especially phytochemicals not only scavenge reactive oxygen species, thereby acting as direct antioxidants, but also regulate Nrf2 activity. There is in vivo evidence for Nrf2 modulation by curcumin, broccoli constituents, garlic, epicatechins, resveratrol, ginger, sweet purple potato, isoflavones, coffee, rosemary, blueberry, pomegranate, narigenin, ellagic acid, astaxanthin, and y-tocopherol.*

Various studies also point to the advantageous effects of whole foods, and food combinations, versus specific bioactive compounds. A 2014 study from Zhou et al, for example, illustrated how organosulfur compounds are not the only Nrf2 enhancing bioactive compounds in garlic; garlic carbohydrate derivatives also show Nrf2-modulatory activity.

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 to 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-kB signaling.

Dietary patterns and nutrients may result in changes in metallothionein production. For example, Lamb et al., in a 2011 study, reported a 54 percent increase in metallothionein mRNA production in a small clinical trial in women with fibromyalgia following an elimination diet in conjunction with phytonutrient-rich medical food consisting of hops, pomegranate, prune skin and watercress.

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. Below are some of the key concepts for translation into the clinical setting:

Nonclinical versus Clinical Studies

One of the limitations that comes to the forefront in this collection of studies is how the information is constrained to in vivo or animal studies. It remains questionable as to whether similar effects would be seen in humans at moderate reasonable doses. Given the limitations of these studies, 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 clinical studies that have been published to date in making more firm recommendations.

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. A dietary pattern favoring whole, unprocessed plant-based foods and the removal or reduction of toxic substances in one’s environment is a two-pronged approach that would seem to have the best overarching scientific underpinning.

Modulating versus Inhibiting/Inducing Effects.

Given that some foods are “bifunctional modulators, (those that have a particular activity on an enzyme, but at higher doses may produce the opposite effect), it may be best to recommend a mixed, varied diet, full of plant-based whole foods. Smaller amounts of many compounds might be more therapeutic and supportive to biochemical pathways rather than high concentrations.

Polypharmacy

For patients 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.

Dietary Supplement 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 full understanding of a patient’s SNPs (single nucleotide polymorphisms), it becomes difficult to make accurate assessments about nutrients and dosing.

Conclusions

Dietary intake may have a large bearing on incidence of chronic disease and also may have an influence for several generations due to transgenerational inheritance of epigenetic changes. As such, it would seem that designing clinical recommendations to maximize the effects of food and reduce the impacts of toxins is essential. However, these protocols should be designed for patients with caution and critical thinking by trained clinicians as there remain many unresolved issues in how and what foods modulate these detoxification pathways.

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

[1] Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Food and Food-Derived COmponents: A Scientific Review with Clinical Application. Jrnl Nutr Metab. 2015. Jan.

[2] Chen Y, Xiao P, Ou-Yang DS, et al. Simultaneous action of the flavonoid quercetin on cytochrom p450 (cyp) la2, cyp2a6, n-acetyltransferace and xanthine oxidase activity in healthy volunteers. Clinical and Experimental Pharamcology. 2009:36(8):828-833;l as shown in Hodges RE, Minich D<. Modulation of Metabolix Detoxification Pathways Using Food-Derived Component: A scientific Review with Clinical Application. Jrnl Nutr Metab. 2015.

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