Nutritional Management of Chemical Sensitivity and its Role in Autoimmunity

In the last segment, we reviewed how our bodies eliminate the toxic chemicals we are exposed to on a daily basis and introduced the concept of “toxicant-induced loss of tolerance”.  We also discussed some of the mechanisms that lead to this condition, which is becoming more and more common, as well as common signs and symptoms of this condition.  In this final segment of this series, we discuss the role chemical sensitivity plays in the development of autoimmunity and laboratory evaluation of immune-chemical tolerance.  We also consider other factors besides chemical exposure that impact chemical sensitivity.  Then we discuss nutritional management of loss of chemical tolerance from a functional medicine perspective.

Key concepts for this issue:

• The Role Chemical Sensitivity Plays in the Development of Autoimmunity
• Why Does Chemical Tolerance Vary From Person to Person?
• Laboratory Evaluation of Immune-Chemical Tolerance
• Other Factors Besides Chemical Exposure That Impact Chemical Sensitivity
• Nutritional Management of Loss of Chemical Tolerance

The Role Chemical Sensitivity Plays in the Development of Autoimmunity

As discussed in previous segments, the prevalence of autoimmunity is increasing at an alarming rate.

“Currently 1 in 12 women and 1 in 25 men have autoimmune disease.  Over 50 million Americans now have autoimmune disease”[47]

Additionally, the research points to chemicals as contributing factors to autoimmunity, cancer and neurological conditions:

 “There are increasing rates of autoimmunity, cancer, neurological disorders, and inflammatory conditions evoked by chemicals”[48]

“Autoimmune diseases may be induced by physical and/or chemical environmental factors”[49]

Somewhere along the way after the depletion of glutathione, we turn on autoimmunity causing destruction of various tissues, including the brain, gut, thyroid and a number of other tissues.  When we lose this glutathione system, we lose our capacity to handle environmental compounds and self-tolerance to our own tissue.  But how does this happen?

Prevailing theory of how chemical sensitivity leads to autoimmunity:

When environmental compounds enter the body, they often bind to proteins of human tissue such as albumin because this is how the body eliminates these compounds.  A hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein.  In some individuals, the immune system responds to this protein-bound hapten. When the immune system responds to this foreign antigen complex, it usually produces antibodies to the human tissue portion, rather than the hapten so the immune response continues even after the hapten is removed.  Depending on the human tissue that becomes targeted by the immune system, various autoimmune conditions can result.

“Epidemic clustering of some autoimmune diseases following xenobiotic exposure reinforces the thesis that autoimmune disease is secondary to genetic and environmental factors”[50]

“Basic science and epidemiological research suggests that oxidative stress and inflammation may play a role in autoimmune disease”[51]

Why Does Chemical Tolerance Vary From Person to Person?

Why are most people living relatively normal, healthy lives despite all these toxic exposures while other people succumb to toxin-induced illness?  If you tested random people in the U.S., including healthy people, chances are all of them would show contamination from heavy metals and environmental chemicals.  Being completely free of heavy metals and environmental chemicals these days is impossible.  Anthropological studies show even mummies were contaminated with heavy metals.  Our bodies have the capacity to deal with chemical and heavy metal exposure by either eliminating these from the body following transformation via the liver and excretion via the urine or stool, or in some cases, sequestering heavy metals in tissue, such as bone.

Some people seem to have immune responses to these environmental compounds, while others do not.  In fact, one person can have very high levels of toxicity and be symptom-free, while another person who has low levels of contamination reacts severely.  The issue is not how many toxins are in your system but whether your immune system reacts to them.  This can cause severe reactions and symptoms and lead to chronic inflammation. This is the mechanism behind toxicant-induced loss of chemical tolerance (TILT), multiple chemical sensitivities, and toxin-induced brain degeneration mechanisms that are becoming so common today.  How do we evaluate loss of chemical tolerance?

Laboratory Evaluation of Environmental Chemical Tolerance

Evaluating chemical immune tolerance can be done objectively with Cyrex Labs Array 11—Chemical Immune Reactivity Screen.  Chemical immunoreactivity testing evaluates for immunological reactivity to environmental compounds by evaluating antigen-antibody reactivity to these compounds.  The presence of elevated antibodies to common environmental compounds indicates overzealous immune reactions to chemicals and loss of immune tolerance.  Chemical antibody testing has several advantages.  First, it allows for a diverse array of common chemicals to be evaluated, in addition to heavy metals.  Second, it measures immune responses to these chemicals, unrelated to their quantitative load, that result in immunological and inflammatory responses from these environmental chemicals.  Elevated chemical antibodies indicate an exaggerated immune response to these common chemicals leading to the promotion of systemic inflammation and can occur with trace exposures of chemicals when immune integrity is compromised.  Any elevation in chemical antibodies indicate loss of chemical tolerance and risk of abnormal immune reactions to everyday environmental compounds. 

Are There Factors Besides Chemical Exposure That Impact Chemical Sensitivity?

Unrelated to environmental loads, you can lose chemical tolerance from the following immunological imbalances:

• Chronic stress
• Intestinal permeability
• Chronic infections
• Chronic inflammation
• Autoimmunity
• Poor sleep
• Malnutrition

Chemical sensitivity can be impacted by all of these factors unrelated to toxin exposures. For example, patients exposed to chronic stress may lose the integrity of their barrier systems and develop insufficiency of their immune regulatory T-cells as a result.  They may then start to react immunologically to daily chemical exposures such as cigarette smoke or gasoline fumes.  The exposure may cause them to suffer migraines, skin outbreaks, sinus reactions, etc.  In this case, addressing the person’s internal stress response with stress management and nutritional compounds (ie: adaptogens, etc.) is critical to minimizing the factors promoting the person’s stress physiology and chemical sensitivity.

Another example of a condition that can affect chemical sensitivity is chronic infection.  Chronic infection can lead to chronic inflammation and compromised immune regulatory T-cell function as well as loss of barrier system integrity.  When your immune system is constantly working 24/7 to eliminate a pathogen but is unsuccessful, it is at risk of loss of regulatory T-cell function and dysfunctional immune responses.  This is what happens in certain chronic infections such as chronic Lyme disease when the instigating pathogen (a bacteria called borellia burgdorferi and other concomitant co-infections) cannot be eliminated by the immune system.  The individual eventually becomes at risk for chemical intolerance and autoimmune reactions.   Autoimmune conditions always involve a certain degree of chronic inflammation and T-regulatory cell dysfunction as well which can then lead to loss of chemical tolerance.  These types of issues must be identified and addressed in order to have a chance at improving tolerance to environmental chemicals.  Otherwise, progress will be very limited and palliative at best.  It is important the practitioner consider all of the potential contributors that may play a role in loss of chemical tolerance. 

Management of Loss of Chemical Tolerance

Management of loss of chemical tolerance involves:

• Identification of offending chemicals/heavy metals (through laboratory evaluation)
• Avoidance or minimization of exposures to these offending chemicals/heavy metals from one’s environment (as much as possible)
• Nutritional support of the physiologic systems involved in loss of chemical tolerance
• Targeted nutritional support for phase I and phase II biotransformation pathways for transformation and elimination of offending chemicals (when applicable)

Avoiding Exposures

Knowing common environmental sources of exposure of these chemical compounds that initiate immune responses is a critical first step in order to minimize these exposures and resultant “flareups” of symptoms.  Avoiding these compounds completely cannot always be done in all cases but many of these compounds can often be avoided and avoidance alone can sometimes lead to significant improvement in symptoms.  For example, common sources of mercury exposures include amalgam fillings and medical implants, vaccinations and contaminated fish and shellfish and contaminated fish oils.  Consideration should be given to removal of dental amalgums (by a qualified dentist in an appropriate way) and vaccination schedules.  Decreased frequency or decreased regularity of vaccinations can minimize impact of exposures.  Fish consumption can be a source of exposure as well, as discussed earlier.  Limiting fish consumption to twice a week and consuming only wild fish rather than farm-raised fish can significantly decrease risk of mercury exposures.  Quality fish oils produced by a reputable company that tests for mercury levels (which tend to cost a little more than some of the cheaper supplements) are recommended.  Look for levels of detectability of heavy metals, such as mercury, lead, PCBs and dioxins in ppb (parts per billion) and ppt (parts per trillion).

Nutritional Support for Chemical Tolerance

Immune-chemical tolerance is dependent upon many overlapping physiological factors that include the glutathione system, regulatory T-cell function, barrier system integrity, NF-kB dysregulation and chronic inflammation and impaired hepatic biotransformation.

• Depletion of glutathione and inadequate glutathione system
• Regulatory T-cell failure
• Breakdown of barrier systems
• NF-kB dysregulation/chronic inflammation
• Impaired hepatic biotransformation

All of these systems are compromised to some degree in loss of chemical tolerance and management of this condition must include assessment of all these areas and address all physiological imbalances that are identified or suspected.  There are various natural compounds that have been shown in the scientific literature to address each of these physiologic imbalances which can have powerful effects.  These are the compounds we use in functional medicine to improve chemical tolerance.  Here are the primary strategies we use and a brief list of the main compounds used to support each of these systems.

Optimize Glutathione and Glutathione System

Glutathione helps support regulatory T cells, and differentiation of T-cells into their specific types by reducing damage from oxidative stress.  This system is absolutely critical for overall modulation of immune responses.  There are several compounds that have been identified in the literature to help raise intracellular glutathione, activate the glutathione peroxidase and reductase enzymes, and support the glutathione system.

N-acetyl-cysteine

N-acetyl-cysteine is a metabolite of the sulfur-containing amino acid, cysteine.  It plays a role in the sulfation cycle, acting as a sulfur donor in phase II detoxification and as a methyl donor in the conversion of homocysteine to methionine.  N-acetyl cysteine is rapidly metabolized to intracellular glutathione.  It is used for acetaminophen overdose and as a nephroprotective agent for radiocontrast. [52-58]

Alpha lipoic acid

Alpha lipoic acid is an antioxidant that is made by the body and is found in every cell, where it helps turn glucose into energy. Unlike other antioxidants, which work only in water (such as vitamin C) or fatty tissues (such as vitamin E), alpha lipoic acid is both fat- and water-soluble.  This means it can work throughout the body. Alpha lipoic acid also plays an important role in the synergism of antioxidants.  It directly recycles and extends the metabolic life spans of vitamin C, glutathione, and coenzyme Q10, and it indirectly renews vitamin E, all of which are necessary for glutathione recycling. [59-68]

L-glutamine

L-glutamine is important for the generation of glutathione stores since glutamate is unable to be transported into cells. Glutamine is efficiently transported into the cell, converted to glutamate, and readily available for glutathione synthesis. Research has demonstrated that glutamine is important for the generation of glutathione. [69-82]

Selenium

Selenium is a trace element nutrient that serves as the essential cofactor for the enzyme glutathione peroxidase. Selenium-deficient humans and animals are known to be deficient in glutathione peroxidase activity in their cells and plasma. [83-94]

Cordyceps

Cordyceps (used in Chinese medicine for thousands of years) has been shown to activate glutathione peroxidase synthesis in the body (the enzymes that increase glutathione) and raise glutathione levels within minutes.  Research has demonstrated cordyceps helps protect cells by engaging the glutathione enzyme cycle. [95-98]

Centella asiatica (Gotu Kola)

Research has clearly demonstrated that oral intake of gotu kola very rapidly and dramatically increases the activity and amount of glutathione peroxidase and quantity of glutathione. [99-109]

Silybum marianum

Administration of Silybum marianum has shown to significantly increase glutathione, increase superoxide dismutase activity, and have positive influence in the ratios of reduced and oxidized glutathione. [110-126]

Broccoli extract

Broccoli has a high content of glucosinolates, which are metabolized into isothiocyanates and sulforaphane [127]. These compounds exhibit chemoprotective activity through a mechanism involving inhibition of cytochrome P450 and induction of GST and other enzymes. [128,129]

Optimize Regulatory T-Cell Function and TH-3 System

The two most powerful ways known to support regulatory T-cell function and coordinate TH-1 and TH-2 balance involve glutathione and vitamin D.

Glutathione

Glutathione (GSH) is one of the most critical immune-modulating substances that we know of.   Like a conductor of an orchestra, glutathione regulates various aspects of immune balance.  As previously discussed, studies show that GSH has a significant impact on the immune system’s ability to activate the appropriate T-helper cell response. [130,131]  Because GSH is so important in the immune system’s activation of the appropriate T-helper response, altering its levels may have significant implications in TH1/TH2-related diseases. [132]

“Accumulation of evidence suggests that intracellular GSH (glutathione) levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response pattern. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to support immune modulation.” [133]

“These data indicate that glutathione peroxidase-dependent control of intracellular reactive oxygen species accumulation is important not only for regulation of TH-cell proliferation, but also for modulation of differentiation into TH1, TH2 and TH17 cells.”[134]

See the clinical strategies described above for strategies for increasing glutathione levels.

Vitamin D

Numerous studies have been published establishing the critical immunoregulatory role that vitamin D plays in the prevention of immune dysfunction and the development of autoimmune disease. [135-142] Vitamin D appears to act on a number of different immune cells to promote various regulatory responses by the immune system.  Vitamin D deficiency has been associated with many autoimmune disorders including multiple sclerosis, Type 1 diabetes, Crohn’s disease, rheumatoid arthritis as well as others. [143]

Studies have shown a significant relation between vitamin D deficiency and allergy and an important role of vitamin D in the pathogenesis and severity of allergic disease, and its capacity to control allergic disease. [144,145]  Vitamin D supplementation has been shown to reduce the occurrence of asthma in most related studies and may be useful in the prevention or adjunct treatment of chronic obstructive pulmonary disease. [146,147]

Here are a few selections from the literature on the role vitamin D plays in immune health:

“Increasing evidence demonstrates a strong association between vitamin D signaling and many biological processes that regulate immune responses. The discovery of the vitamin D receptor in multiple immune cell lineages, such as monocytes, dendritic cells, and activated T cells credits vitamin D with a novel role in modulating immunological functions and its subsequent role in the development or prevention of autoimmune diseases.”[148]

“It is apparent that vitamin D has significant effects on the immune system and as such may contribute to the pathogenesis of autoimmune disease. Low vitamin D status is reported in many inflammatory rheumatic conditions. In some this extends to an association with disease activity. Vitamin D acts on a number of cells involved in both innate and acquired immunity biasing the adaptive immune system away from Th17 and Th1, towards Th2 and T-regs (T3). Deficiency accordingly could encourage autoimmunity.  Vitamin D deficiency may well be an important factor in autoimmune rheumatic disease, including initial disease development and worsening the disease once present.”[149]

Optimize Protective Barrier Systems

Most people with loss of chemical tolerance have a compromised intestinal barrier. Improving the integrity of this barrier is critical to minimizing inflammatory responses.  There are a number of compounds which have been shown to improve the integrity of the body’s intestinal barrier system.

L-Glutamine

L-glutamine is the preferred fuel source for the cells of the small intestine and has been shown in numerous studies to support the regeneration and repair of the intestinal lining. It has also been shown to increase the number of cells in the small intestine, the number of villi on those cells, as well as the height of the villi. Glutamine-reduced permeability of the lining may accompany “leaky gut” patterns that promote intestinal inflammation and the development of delayed food intolerances. [150-171]

Deglycyrrhizinated Licorice

Deglycyrrhizinated licorice is a popular and substantially studied natural compound that provides flavonoids that help heal the gastric and intestinal lining. Many different mechanisms have been shown with regard to its restorative properties including stimulation and differentiation of glandulars cells, protective mucous formation, protective mucous secretion, increased intestinal blood flow, and growth and regeneration of intestinal lining cells. [172-189]

N-Acetyl Glucosamine

N-acetyl glucosamine is a monosaccharide derivative of glucose that is used to support the intestinal glycoprotein cover of the mucosa called mucin. It is also a precursor substrate for the repair of the intestinal mucosal cells and provides support of mucosa membrane irritation. [190-193]

Aloe Leaf Extract

Aloe leaf extract contains natural phytochemicals and powerful antioxidant properties that reduce intestinal inflammation, soothe the intestines, aid in intestinal wound healing, and have an anti-ulcer effect. It also appears to have antifungal properties, supports cholinergic intestinal motility, and reduces intestinal pain and discomfort. [194-203]

Spanish Moss

Spanish moss is also known as Tillandsia and it has historically been used for intestinal irritation and allergies. Research on the plant has identified rich sources of flavonoids and other phytochemicals that provide antimicrobial activity and free radical scavenging properties. [204-209]

Marshmallow Extract

Marshmallow extract has high content of mucilage that can soothe and help heal compromised intestinal barrier tissue. It is also rich in antioxidants that can support healing of tissue. It also has properties that inhibit hyaluronidase, which is the enzyme involved in the production of hyaluronic acid that is involved with intestinal tissue destruction. [210-213]

Methylsulfonylmethane (MSM)

Methylsulfonylmethane (MSM) is a rich source of natural sulfur which helps as a substrate for antioxidant defense systems as well as support substrates for hepatic phase II sulfation pathways.  It has antifungal and anti-inflammatory properties that help support the compromised liver-gut axis. [214-218]

Gamma Oryzanol

Gamma oryzanol is a mixture of plant sterols and ferulic acid esters from rice. It has demonstrated to be a powerful antioxidant.  Numerous papers have demonstrated its effectiveness in gastrointestinal complaints, ulcers, irritable bowel syndrome and non-specific gastrointestinal conditions. It has also been shown to modulate and support the enteric nervous system in its ability to activate intestinal motility and secrete digestive enzymes. [219-226]

Slippery Elm Bark

Slippery elm bark is very high in natural mucilage and helpful in soothing the inflamed intestinal cells. It reduces contact of inflammatory proteins with the intestinal mucosa, thereby enhancing recovery from intestinal barrier compromise and inflammation. [227-230]

German Chamomile

The chief constituents of German chamomile have been shown to enhance wound-healing time, modulate prostaglandins and nitric oxide activity to provide gastric and intestinal protection. [231-238]

Marigold Flower Extract

Marigold flower extract constituents include saponins, carotenoids, flavonoids, mucilage, bitter principle, phytosterols, polysaccharides, and resin. It has been used historically for varied gastrointestinal complaints. It provides substrates for digestive enzyme production, helps during inflammation and provides antibacterial activity. [239-246]

Glutathione

When a person loses their ability to recycle glutathione and glutathione levels become depleted, they are at risk for intestinal lining inflammation which then leads to leaky gut. The glutathione recycling system is one of the main systems that prevents leaky gut onset.  Glutathione is suggested to play an important role in gut barrier function and prevention of intestinal inflammation. [247-252]

Zinc Carnosine

“Regarding intestinal permeability, zinc carnosine caused an approximate threefold increase in gut integrity and repair”[253]

Vitamin D

“VDR (vitamin D receptor) plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium. Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD (inflammatory bowel disease).”[254]

“There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity” [255]

“1,25(OH)2D3 (vitamin D) may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH)2D3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD (inflammatory bowel disease).”[256]

Intestinal Permeability Dietary Restrictions

It is important to avoid certain types of food that tend to aggravate or worsen intestinal permeability when trying to repair the gut barrier and decrease autoimmune responses.  These self-promoting vicious cycles become difficult to unwind unless aggressive dietary and nutritional strategies are employed.  See Intestinal Permeability Dietary Restrictions at the end of Successful Aging Part 6b for a complete list of these foods.

Optimize NF-kB Activity and Minimize Chronic Inflammation

NF-kB signaling needs to be downregulated in order to maintain tissue homeostasis.  Overall, it appears that the two most potent natural NF-kB minimizers that researchers have discovered are curcumin and resveratrol.  Curcumin is the alkaloid derived from turmeric, a spice used in Indian   cooking.  Resveratrol is a compound found in the skin of red grapes, peanuts and some berries.  In recent studies, both curcumin and resveratrol have shown to support healthy numbers of T-cell cytokines (inflammatory messengers).  These results suggest the potential use of these phytochemicals for supporting healthy immune responses.  Here is what some recent literature is saying about these compounds:

Curcumin

“Curcumin, a dietary spice from turmeric, has outstanding anti-inflammation and neuroprotective effects.  Herein, we review key features of curcumin involved in biology, pharmacology, and medicinal chemistry and discuss its potential relevance to pathophysiological progress of multiple sclerosis”[257]

“Curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFkB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS)”[258]

“In a larger, randomized, double-blind, multicenter trial involving patients with quiescent ulcerative colitis, administration of 1 g of curcumin twice daily resulted in both clinical improvement and a statistically significant decrease in the rate of relapse”[259]

“Our results indicate that curcumin has the potential to protect against cardiac inflammation… and may provide a novel therapeutic strategy for autoimmune myocarditis” [260]

“In various chronic illnesses in which inflammation is known to play a major role, curcumin has been shown to exhibit therapeutic potential. These diseases include Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy, asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and AIDS”[261]

“…curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses.  The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB)…”[262]

Resveratrol

Resveratrol has been shown in the literature to have powerful anti-inflammatory effects which involve multiple pathways including inhibiting NF-kB, inhibiting iNOS (inducible-nitric oxide synthase) expression and inhibiting inflammatory cytokines such as IL-6 in various inflammatory conditions, including multiple sclerosis [263], diabetic neuropathy [264], arthritis [265], autoimmune myocarditis [266], colitis [267], and exerts immunomodulatory effects both in vitro and in vivo in lymphocytic leukemia. [268]

“These studies demonstrate that SRT501 (a pharmaceutical grade formulation of resveratrol) attenuates neuronal damage and neurological dysfunction in experimental autoimmune encephalomyelitis (the animal model of multiple sclerosis) by a mechanism involving SIRT1 activation”[269]

“This study confirms the NF-kB inhibitory activity and anti-inflammatory activity of resveratrol, which may contribute to neuroprotection in diabetic neuropathy apart from its antioxidant effect”[270]

“In summary, our results suggest that resveratrol suppresses apoptosis and inflammatory signaling through its actions on the NF-kB pathway in human chondrocytes”[271]

“Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis” [272]

In addition, both curcumin and resveratrol have been shown to reduce the inflammatory mediators that contribute to the low-level, chronic inflammation found in obese individuals and have been linked to the onset of cardiovascular disorders, insulin resistance and type 2 diabetes mellitus.

“Curcumin and resveratrol are able to inhibit TNFalpha-activated NF-kappaB signaling in adipocytes and as a result significantly reduce cytokine expression. These data suggest that curcumin and resveratrol may provide a novel and safe approach to reduce or inhibit the chronic inflammatory properties of adipose tissue.”[273]

Optimize Targeted Phase I and Phase II Hepatic Biotransformation Pathways

As discussed above, both phase I and phase II hepatic biotransformation pathways are involved in transformation and elimination of environmental chemicals.  Phase I reactions involve the cytochrome P450 enzyme which is responsible for converting lipophilic (fat-loving) toxins into biotransformed intermediates that are more water-soluble.  In phase II, these biotransformed intermediates undergo further biotransformation in a second series of enzymes called conjugases.  Each chemical we are exposed to is eliminated from the body via specific phase II pathways.  This means it is most efficient to support those specific detox pathways that are involved in the elimination of the particular chemicals that are responsible for the immune reactions and increase of symptoms as identified by laboratory testing.  It is important to note that heavy metals do not enter phase I and phase II biotransformation pathways. 

Phase I pathways are primarily dependent on the glutathione system as well as the cytochrome P450 enzyme system, therefore, the glutathione system is always supported in all chemical exposures.  Phase II pathways rely on different enzymes with various coenzymes and cofactors needed to function properly.  There are a number of key compounds that have been identified to support each of these specific pathways, including sulfation, methylation, glutathione conjugation, acetylation, glucoronidation and glycine (amino acid) conjugation.  In addition, there are a number of natural compounds that have been shown to support bile formation and secretion and excretion of toxic compounds through the biliary system, known as phase III pathways.

Dandelion (Taraxacum officinale)

Dandelion root has physiologic impacts on both the liver and gallbladder. It impacts the liver by promoting the production of bile and its delivery to the gallbladder. It impacts the gallbladder by causing contraction and release of stored bile.[274-276]

Milk Thistle (Silybum marianum)

Milk thistle has the ability to increase the solubility of bile and its use has been shown to significantly reduce biliary cholesterol concentrations and bile saturation index.[277] It has potent antioxidant activity which supports phase I detoxification and prevents the depletion of hepatic glutathione which is important for phase II detoxification.[278-280] Silybum marianum has anti-inflammatory chemical properties that are inhibitors of inflammatory prostaglandins and leukotrienes as well as chemical properties that promote protein synthesis to replace damaged liver cells. [281-284]

Gotu Kola (Centella asiatica)

Gotu kola has active constituents known as triterpenoid compounds that have impacts on cells and tissues that are important in detoxification. It has shown the ability to improve histological findings of liver cirrhosis.[285,286] It also supports hepatic detoxification due to its physiological impact on enhancing venous circulation. Centella asiatica has shown the ability to improve venous disorders such as chronic venous insufficiency and venous hypertension.[287,288] Improved venous circulation has influential roles in optimizing detoxification that are generally overlooked.

Panax Ginseng

Panax ginseng has shown in several studies to have numerous positive impacts on hepatic function. It has shown to reverse fatty liver in animals, and demonstrate profound anti-hepatotoxic properties.[289,290]  It has shown the ability to promote Kupffer cells and shown to increase nuclear, ribosomal, and messenger RNA biosynthesis. [291-293]

Glutathione Conjugation Support

Glutathione is a tripeptide amino acid that depends upon adequate levels of essential nutrients such as B6, riboflavin, choline, methionine, cysteine or n-acetyl-cysteine (NAC), vitamin C, betaine, glycine, glutamic acid, potassium, copper, zinc, and selenium. Numerous studies have shown that taking these essential nutrients will enhance glutathione levels. [294,295]

Methylation Conjugation Support

Methylation involves conjugating phase I end-products with single-carbon compounds. Methylation requires methionine, betaine, ascorbic acid, alpha tocopherol (vitamin E), choline, pyradoxyl-5-phosphate (vitamin B6), trimethlyglycine, magnesium, methylcobalamin (vitamin B12), and folic acid.

Acetylation Conjugation Support

Acetylation pathways conjugate toxins with acetyl-CoA and two carbon compounds. Acetylation pathways are dependent on pantothenic acid, thiamin, and vitamin C.[296]

Glucuronidation Conjugation Support

Glucuronidation involves combining toxins and end-products with glucuronic acid. This pathway is supported by B-vitamins, magnesium, and glycine, which help support the uronic acid pathway that synthesizes glucuronic acid.

Sulfation Conjugation Support

Sulfation involves combining toxins and end products with sulfur-containing amino acids.  An important step in sulfation is the conversion of sulfites to sulfates by the molybdenum-dependent enzyme sulfite oxidase. Therefore, the mineral molybdenum and the sulfur-containing amino acids such as N-acetyl-cysteine, glycine, and methionine are important for sulfation conjugation support.

Heavy Metal Exposure and Elimination

Heavy metals are eliminated by the body via different mechanisms, which rely heavily on our body’s metallothionein and glutathione systems.  Metal binding proteins, including metallothioneins, are potent chelators for heavy metals and are central to the natural response of the body to these toxic elements.[297-299]  Glutathione is another potent chelator involved in cellular response, transport, and excretion of metals and is a biomarker for toxic metal overload. [300-303] But it is a type of chelator that does not redistribute to other tissues, which is a big risk in many chelation therapies.[304-308]  Natural compounds such as N-acetyl L-cysteine, alpha lipoic acid and glutathione all contribute to chelation and excretion of metals in the human body with much less risk of displacement into other tissues, such as the brain, than synthetic chelating agents.[309,310]

These compounds  also serve as antioxidants in the tissue to protect the tissue from damage caused by interaction with heavy metals.[311-313]  Oxidative stress may be considered as one of the prime contributing mechanisms in metal toxicity and thus provide a strong rationale for including antioxidants during chelation therapy.[314]  Antioxidant supplementation with chelating agents has been found beneficial in increasing metal mobilization and providing improved recovery from problems associated with chelation therapy [315-317]. Combination therapies with antioxidants like N-acetylcysteine (NAC), alpha-lipoic acid (ALA), and melatonin have shown considerable promise in improving clinical recoveries in animal models.[318] Antioxidant therapy should be considered and utilized in any protocol to support elimination of heavy metals.

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