Photo of Sharol Tilgner
Drawing of glutathione structure.
Glutathione Structure

Our Protector

Glutathione is our protector, and friend. It  tempers inflammation through its super hero antioxidant abilities. When it is depleted, inflammation can take over our body. Glutathione is found in nearly every compartment of our cells, including the nucleus. As the main antioxidant for mitochondria, glutathione is an absolute necessity for those little power-house mitochondrial factories who would otherwise become buried in reactive oxygen species.

What Glutathione Is, And Does - In A Nutshell

  • A tripeptide
  • Protects from reactive oxygen species
  • Protects from reactive nitrogen species
  • Cofactor for many antioxidant enzymes such as peroxidases and transferases
  • Storage form of cysteine
  • Storage form and transporter of nitric oxide
  • Metabolizes estrogens, leukotrienes, and prostaglandins
  • Involved in regulation of some transcription factors
  • Detoxifies many endogenous substances and  xenobiotics

Gluatathione protects us from from free radicals through it's antioxidant activity. Free radicals are unstable molecules that cause damage in your body. They cause much of the inflammation that takes place in your body, and are associated with premature aging. Glutathione protects you from nasty free radicals such as reactive oxygen species, reactive nitrogen species and advanced glycation end products.

A Few Details

Glutathione (γ-glutamyl-cysteinyl-glycine) is a tripeptide found in all cells where it is the major intracellular antioxidant. Composed of cysteine, glutamine and glycine, it is used as a major antioxidant, glutathione is the main nonprotein thiol (sulfhydryl/sulfur compound) responsible for the cellular redox balance. Glutathione is recycled to use it over, and over again. It is also synthesized anew by the body through combination of the three amino acids that is is composed of.

The organs that are highest in glutathione levels are the eye, the ears, the lung, the liver, the kidneys, and the skin. These organs have the highest concentrations of glutathione, for good reason, because these organs are subject to all of the toxins in the environment.


Glutathione as an Antioxidant and Redox Potential

Two Forms Of Glutathione

Glutathione exists in two forms. It is found in an oxidized form and a free or reduced form. Ony the free or reduced form has antioxidant activity. Once it is used and therefore oxidized, it needs to be recycled back to the reduced form again before it can continue with its antioxidant behavior. It is recycled back, and fourth, over, and, over again. The oxidized form is called glutathione disulfide (GSSG) and the reduced form is called glutathione (GSH). GSH is used by the body to neutralize reactive oxygen species which leads to its alteration into GSSG from GSH. (loses it's super hero antioxidant powers when it is oxidzed) The GSH needs the enzyme glutathione peroxidase to help it reduce free radicals. Glutathione is oxidized to GSSG in this process. Only GSH has the antioxidant activity. Think of the glutathione (GSH) as a super hero. It saves the body from damage by being oxidzed into (GSSG), rather than allowing free radicals to oxidize important cellular componants in our body (damaging mitochondria). Basically, it takes the hit to save our body from damage. However, to be able to continue functioning as an antioxidant, it has to change back into the reduced form and regaining it's super hero powers.



Changing Glutathione Back To The Reduced Form GSH (Regaining Super Hero Antioxidant Powers)

GSSG can be recycled to GSH again and regain it's super hero antioxidant powers. This recycling back to GSH needs the enzyme glutathione reductase to facilitate the reduction of GSSG to GSH. It requires NADPH, and forms two GSH molecules from the one GSSG molecule.

Remember, we are examining reduced glutathione(GSH) and oxidized glutathione(GSSG). The ratio of GSH to GSSG controls the "redox potential" in the cells. It is the reduced glutathione that is guarding our body. GSH is a part of our antioxidant system and protects us from "free radicals". Free radicals are molecules that are unstable because they have unpaired electrons and are looking for another electron to steal in order to become stable again. They can steal electrons from the mitochondria, thereby damaging the mitochondria, causing inflammation and degeneration.

Here is another way to examine this process: GSH will sacrifice themselves by giving an electron to a free radical. I mentioned that this happens with the help of an enzyme called glutathione peroxidase. This turns the glutathione (GSH) into glutathione disulfide (GSSG). The GSSG is now a free radical itself, but it can be turned back into its reduced state via an enzyme called glutathione reductase (GSR) using NADPH as an electron donor. This reinstates it back into its old GSH self again. Redox status (measure of reduced glutathione to oxidized glutathione) within the cells is reflected by the ratio of reduced GSH to oxidized GSSG (GSH/GSSG).This is used as a measure of cell toxicity. In healthy cells, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% in the disulfide form (GSSG).

You can see that these enzymes are a really important part of the process of glutathione's super hero abilities. We need enough glutathione, and we also need glutathione peroxidase, and glutathione reductase for this system to work effectively, and for us to stay healthy. Without this recycling process going smoothly we are in deep doo doo.


De Novo Synthesis Of Glutathione

New GSH can be made from scratch. This is called de novo synthesis. To make glutathione we need the amino acids L-glutamine, L-cysteine, and glycine. L-glutatmine, and L-cysteine are added together with the help of the rate limiting enzyme Glutamate-cysteine ligase (AKA γ-glutamylcysteine synthetase or glutamylcysteine ligase) and is dependant on ATP. You get L-γ-Glutamyl-L cysteine. This is the rate limiting step of making glutathione and the rate limiting amino acid is cysteine. Next, glycine is added to the the newly created L-γ-Glutamyl-L-cysteine with the enzymatic help of glutathione synthetase and powered by ATP. This produces reduced glutathione (GSH).

Mutations in the GSS gene develop glutathione synthetase deficiency. A moderate deficiency can cause hemolytic anemia, elevated acidity – metabolic acidosis.  Severe deficiency can cause neurological symptoms such as seizures, decreased physical reactions, movements and speech, intellectual disability and loss of coordination. Some people with severe deficiency experience recurrent bacterial infections.

Glutathione can be recycled back to its constitutive amino acids by γ-glutamyl-n-transferase and dipeptidase.

See the diagram below that depicts how glutathione is made anew as well as recycled.

Diagram of transulfuration and making glutathione.


Depletion Of Glutathione

It is synthesized in the body, but toxins, poor diet, as well as stress, aging, trauma, infections, and radiation all deplete glutathione levels. The sulfhydryl group (SH) of cysteine serves as a proton donor, and is responsible for the biological activity of glutathione. Cysteine is the rate-limiting factor in cellular glutathione synthesis, since this amino acid is relatively rare in foodstuffs. Normally glutathione is recycled in the body, except when the toxic load becomes too great and much of the glutathione is lost as it conjugates toxins, and is excreted from the body through the bile, or urine.

Since glutathione is the master detoxifier in our body, a deficiency creates a serious lack of anitoxidant status and promotes mitochondrial damage to cells all over the body, especially causing liver dysfunction, as well as liver damage. Exposure to high levels of toxins depletes glutathione faster than it can be produced, or absorbed from the diet. This results in increased susceptibility to toxin-induced diseases, such as cancer, especially if phase I detoxification system is highly active. Disease states due to glutathione deficiency are not uncommon. Health conditions like mold susceptibility (CFIDS), Parkinson's and Alzheimer's have been linked to glutathione deficiency. Autoimmune diseases are linked to low glutathione levels. Glutathione is needed to protect us from damage due to cigarette smoke, radiation exposure, and alcohol to name a few environmental toxins it protects us from.

Transforming Growth Factor - Beta (TGF-Beta)

It has been shown that decreased levels of GSH will stimulate production of TGF-β and that when GSH is replenished, the production of TGF-β will be decreased

Glutathione Conjugation

A primary phase II transformation route is conjugation with glutathione. Reduced glutathione, in coordination with glutathione reductase, glutathione peroxidase, and glutathione-S-transferase are involved in conjugation. Through direct conjugation with the toxin, glutathione detoxifies many xenobiotics (foreign compounds) and carcinogens, both organic and inorganic. The elimination of heavy metals such as mercury, lead, and arsenic is dependent upon adequate levels of glutathione, which in turn is dependent upon adequate levels of methionine and cysteine. When increased levels of toxic compounds are present, more methionine is utilized for cysteine and glutathione synthesis. Glutathione conjugation is probably the most important detoxification pathway for industrial toxins and carcinogens and 60% of toxins excreted in the bile are excreted in this way. Glutathione conjugation also produces water-soluble mercaptates which are excreted via the kidneys.

The Enzyme Glutathione S-transferase (GST) Needed For Glutathione Conjugation

Glutathione S-transferase is necessary for glutathione to conjugate with toxins. In humans, the glutathione S-transferase (GST) gene called hGSTM1-1 is absent in about 50% of individuals in most human populations. This means that in individuals lacking the assistance of hGSTM1-1, they may be at some elevated risk to some toxins.   The cells with the lower levels of GSTs, or lacking specific GST isoforms like the liver would have higher risk of toxicity.


Gene Control of Glutathione by Nrf2

Glutathione biosynthesis, glutathione peroxidases, glutathione S-transferases, glutathione reductase and glutathione S-conjugate efflux pumps function in a coordinated fashion to facilitate a coordinated response to oxidative stress. Regulation of this response is facilitated by the antioxidant responsive element (ARE) which is located in the promoters of many of the genes that are induced by oxidative and chemical stress.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that is released when there is an increase in oxidative stress. It translocates to the nucleus where it binds and activates ARE, and upregulates several genes associated with glutathione synthesis. Nrf2 is found in most types of cells. Nrf2 induces the rate-limiting enzyme for glutathione synthesis, γ-glutamyl-cysteine synthetase, as well as glutathione synthetase needed to make glutathione from scratch.

Even if Nrf2 is upregulated, research has shown that Nrf2 may be damaged after its production by excess oxidative stress. Without functioning Nrf2 the genes which make γ-glutamyl-cysteine synthetase, as well as glutathione synthetase can not be formed and new GSH is not made.

If the genes needed to produce glutathione are not functioning, supplying the building block of glutathione production, N-acetyl-cysteine (NAC) is much less efficient than supplying the whole molecule of glutathione using a liposomal encapsulation, acetyl glutathione, or other absorbable forms.

Nrf2 also controls the formation of the glutathione s-transferases (GSTs). These are necessary for glutathione conjugation which is a Phase II biotransformational process that detoxifies toxins.


Examples Of Glutathione's Bodily Activities

It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.

It is involved in numerous metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Every system in the body can be affected by the state of the glutathione system.

It regulates the nitric oxide cycle, which is critical for life but can be problematic if unregulated.

Regarding muscles, research has shown that raising glutathione levels decrease muscle damage, reduce recovery time, increase strength and endurance and shift metabolism from fat production to muscle development.

It is a necessary to support the immune system in its job of fighting infections and preventing cancer. e.g., (1) modulating antigen presentation to lymphocytes, thereby influencing cytokine production and type of response (cellular or humoral) that develops, (2) enhancing proliferation of lymphocytes, thereby increasing magnitude of response, (3) enhancing killing activity of cytotoxic T cells and NK cells, and (4) regulating apoptosis, thereby maintaining control of the immune response. Low glutathione is seen in autoimmune disease. GSH depletion in antigen presenting cells inhibits Th1-associated cytokine production and/or favors Th-2-associated responses. Multiple chemical sensitivities seen are associated with decreased Th-1, increased Th-2 response.


Glutathione Deficiency

A deficiency can be induced either by diseases that increase the need for glutathione, deficiencies of the nutrients needed for synthesis or for synthesis of glutathione reductase or glutathione peroxidase, or diseases that inhibit its formation. When glutathione becomes depleted and we can't get rid of toxins, we  head into downward spiral of chronic illness.

An example of how toxins can decrease glutathione is evident in research on mycotoxins that suggests they can decrease the formation of glutathione due to decreased gene expression of the enzymes needed to form glutathione. This is why oxidative damage is often sited as the cause of tissue damage from mycotoxins. Without the glutathione unchecked oxidative stress leads to tissue damage and systemic illness that those living or working in water-damaged buildings know all to well. This is why I tell clients I work with to start out with glutathione rather than n-acetyl cysteine (NAC). While NAC works well as the limiting amino acid to assist in making glutathione, this is not going to be helpful if you also don't have adeqaute enzymes to make glutathione. So, until they are no longer exposed and the mycotoxins are mostly out of their body, glutathione is the better first choice rather than NAC. This does not mean NAC can not be helpful, it is often beneficial for other reasons and mycotoxins don't usually stop glutathione creation, but decrease it. Therefore, some NAC will still help to build glutathione, just not as much as necessary in many cases and it can't be rellied on by itself initially.

Cellular consequences of decreased glutathione antioxidant potential
  • Reduced ability to detoxify environmental toxins and heavy metals, resulting in neurotoxicity
  • Oxidation of cysteine thiol (SH) groups in proteins, resulting in altered function of proteins.
  • Decreased liver GSH synthesis, resulting in reduced glutathione conjugation in the liver.
  • Degeneration of the lining of the intestinal tract, resulting in increased gut permeability and autoimmunity.
  • Increased Th2, altered thymic T cell subsets, resulting in autoimmune issues.
  • Reduced S-adenosylmethionine synthesis and increased S-adenosylhomocysteine accumulation, resulting inhibition of methyltransferase and reduced ability to methylate and excrete toxins from the body.


Interesting Factoids
  • Low levels of glutathione peroxidase are seen in vitiligo (H. Zedan, 2015), relapsing-remitting multiple sclerosis (k. Socha, 2014), and type 2 diabetes (O. Sedighi, 2014) and thought to be a contributing factor in these diseases.
  • Glutathione peroxidase genetic polymorphisms may also be associated with development of celiac disease. (M. Katar, 2014)
  • The liver toxic effects of acetaminophen, a drug responsible for considerable drug-induced liver injury are brought on with excessive doses of this common pain and fever drug. This is associated with rapidly depleted intracellular GSH reserves and can be treated with n-acetylcysteine (NAC) the first 48 hours after overdose.


How to Optimize Glutathione Levels


Anything that contains the sulfur amino acid called cysteine will be beneficial as it is the rate limiting amino acid necessary for making gluathione. Gluathione is made of the amino acids glycine, glutamine and cysteine.

Cysteine is an amino acid and can be found in most high protein foods such as meat,  eggs, dairy, also good amounts in nuts and seeds, high in sunflower seeds, high in oats, and also in fish, dairy foods, legumes, asparagus, avacado, spinach.

Whey from making cheese or concentrated whey products are rich in cysteine: The whey protein needs to be bioactive and made from non-denatured proteins ("denaturing" refers to the breakdown of the normal protein structure). Use non-pasteurized, organic, non-denatured  whey, or whey protein. I use to make cheese when I milked goats and had tons of whey. It can be added to smoothies, drank as is, or added to anything where you need moisture in a dish you are making.  What is on the market is a concentrated whey product. This study found whey protein isolate increased plasma glutathione and total antioxidant capacity.

The body can also make cysteine, but does not always make enough. It is considered a semi-essential amino acid. Sulfur-rich foods are needed to make cysteine. Sulfur rich foods are onions, garlic, leeks, all cruciferous vegetables such a broccoli, collards, cabbage, brussel sprouts, kale, cauliflower, kohlrabi, watercress, etc. The glucosinolates such as glucoraphanin in the cruciferous vegetables is changed by myorsinase (in the plant or made by colon bacteria) to sulforaphane that is then conjugated with our bodies glutathione and ultimately made into a sulforaphane N-acetlycysteine using our bodies glutathione,  and may exhibit goitrogenic or antithyroid activity. Although we are providing sulfurs by eating Cruciferae plants (mustard family), we are also using our glutathione in the metabolism of the plant materials. Is this an issue? I really can't say.

Many people on the web claim that Crucifereae plants give us cysteine or glutathione, but from the research studies I read, it is evident they give us sulfur to make cysteine, or in the process of conjugating with our glutathione, and undergoing more metabolic processes, that our glutathione is broken down to make cysteine. I can't find the data that shows these plants contain cysteine or glutathione.  If anyone has a research article showing glutathione, or cysteine are actually in Cruciferae plants, please send it to me at the contact email at the top of the page.

The Cruciferae And Glutathione-S-transferase.

The Cruciferae plants appear to ramp up production of glutathion-S-transferase. This is not unusual  when a plant uses a biotransformation pathway for that pathways activity to be increased if the plant is consumed on a continual basis, but usually not so much as to use the enzymes up as might happen with an environmental toxin (unless you are the sensitive person above in the "Tip"). Cruciferae plant metabolites are conjugated in the body by the use of  glutathione-S-transferase inducing glutathione conjugation to the plant substances, so they might  be inducers of glutathione-S-transferase production, and ultimately increase the ability of glutathione to conjugate with toxins. Studies in animals and humans appear to support this thought. This means that the net effect of eating the Cruciferous vegetables over time would be a beneficial one as far as glutathione conjugation and removal of mycotoxins.

Although cysteine is the rate limiting amino acid, remember that glutathione is also made from gluatamine and glycine. Additionally, selenium helps both produce and recycle glutathione. Selenium content in food depends on the soil that food is grown in. Some areas are high in selenium and some low. However, brazil nuts, sunflower seeds, oatmeal , tuna, turkey, beef, chicken breast, eggs and brown rice are possible sources of selenium.

Sulforaphanes (glucoraphanin-derived isothiocyanate) ability to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway. I think we will find these Cruciferous veggies have a modulating effect when eaten in some moderate amount.

Raising Nrf2

Nrf2 increases tissue glutathione levels and also controls the formation of the glutathione s-transferases. So, anything that enhance Nrf2 will be supportive of glutathione, glutathione conjugation and moving mycotoxins out of the body.

In a study comparing four NRF2 activators, it was found that R-α-Lipoic acid, tert-butylhydroquinone, sulforaphane and Polygonum cuspidatum extract containing 50% resveratrol increased astroglial release of glutathione.

Sulforaphane (Eat lots in fresh broccoli/sprouts) produced the best effect. It increased glutathione by up to 2.4-fold. Polygonum increased glutathione up to 1.6-fold, followed by tert-butylhydroquinone (1.5-fold) and lipoic acid (1.4-fold).

Eating to Raise Glutathione S-transferase (GST) - to enhance glutathione conjugation

Studies have found Cruciferous vegetables can enhance  Glutathione S-transferase (GST). One study found a significant increase in the amount of  serum GST and its GST activity when GSTM1-null individuals, especially women ate a moderate diet of Cruciferae plants. It appears that being a GSTM1-null or listed as AA on a "23 and Me" report (people who are thought to have low GST activity - although other genes may make up for it) means a Cruciferae diet might enhance your ability to  make GST. Yipee for those folks.

Whey (cheese making by-product) from non-pasteurized and organic animals contains globular protein precursors from whey such as, serum albumin, alpha lactoalbumin, lactoferin, and beta lactoglobulin that are high in cysteine. Cysteine residues, can be manufactured into glutathione. Additionally, sheep/goat whey protein was shown to enhance Nrf2 in endothelial cells. As we know increases in Nrf2 are associated with increases in GST and glutathione.

Anything that enhances Nrf2 will increase glutahtione and GST. In a study comparing four NRF2 activators, it was found that R-α-Lipoic acid,  sulforaphane and Polygonum cuspidatum extract containing 50% resveratrol increased astroglial release of glutathione.

Sulforaphane (lots in fresh broccoli/sprouts) produced the best effect. It increased glutathione by up to 2.4-fold. Polygonum increased glutathione up to 1.6-fold, and lipoic acid (1.4-fold).


Exercise will enhance glutathione levels.

Relaxation Techniques

Relaxation Techniques will also enhance glutathione levels. According to a study by Mahagita, meditation diminishes oxidative stress and therefore raises glutathione. The same results are seen in this yoga study. These studies are about meditation and yoga, however, I believe any technique such as controlled breathing, prayer, and biofeedback can reduce oxidative stress and increase glutathione.

Relaxation Techniques will change gene expression and enhance glutathione levels. This includes mediation, prayer, yoga and biofeedback. Research by Herbert Benson showed that genes that triggered inflammation and cell death were turned off in the research group that regularly practiced relaxation techniques. However, this deactivation did not appear to be permanent. The daily practice of relaxation techniques was necessary to sustain benefits.

When the control group was taught techniques to evoke the relaxation response, about 1,500 genes changed their expression within 8 weeks. These were many of the same genes seen in the group that have been practicing these relaxation techniques for years.

Supplements to Support glutathione formation And Recycling Of Glutathione
Forms Of Glutathione

Clinicians have found in the past that most glutathione supplements have not been useful. However, acetyl-Glutathione is a form of oral glutathione that is stable in the stomach and gastrointestinal tract, and well absorbed. Another type that is often used with good results is liposomal glutathione.

Research On Absorption

A research article studying the increase of glutathione in the body after consumption came up with the following data:

A 2015 published 6 month randomized, placebo-controlled trail with oral glutathione (250 or 1,000 mg/day) in healthy adults showed an increase of glutathione in blood after 1,3 and 6 months vs control. At 6 months there was a 30-35% increase in red blood cell levels,plasma and white blood cells. There was a 260% increase in buccal cell level in the high dose group and in the low dose group an increase of 17-29% in blood and red blood cells respectively. The results were time and dose dependent. They returned to baseline after a 1 month period of abstinance from glutatione. A reduced oxidative stress level was shown in both groups by the decrease in oxidized to reduced glutathione ratio in whole blood after 6 months. There was a two-fold increase in natural killer cell activity vs. the controls at 3 months.

Nebulized Glutathione

Nebulized (inhaled) glutathione is also used, but should only be used under the care of a trained practitioner. Bronchoconstriction has occured among patients who are thought to be sulfite-sensitive. Inhalation of GSH results in a mechanism of action that is thought to be confined to the upper airways and lungs and will not influence plasma levels to a significant degree. This is what most research has shown. However, there are people who claim to get cognitive effects from taking inhaled glutathione, so I am not sure research has the full picture yet. At least we do know GSH inhalation exerts its effects upon the lower respiratory tract and the upper respiratory tract. It may exert other yet unknown effects.

Research shows inhaled GSH is potentially indicated for the following clinical conditions: cystic fibrosis, chronic otitis media with effusion, HIV seropositive individuals, idiopathic pulmonary fibrosis and chronic rhinitis. These are just the conditions with good research. Of course inhalation of glutathione could be useful in many more conditions. Asthma is a condition where inhaled GSH cannot be recommended since this treatment caused notable side effects (e.g. breathlessness, bronchoconstriction and cough) in one study. These side effects were linked primarily to the production of sulfites that occurred when GSH was in solution. Anyone who has a sulfite sensitivity should not use nebulized/inhaled gluathione. More data on nebulilzed glutathione can be found in this research article.

Glutathione production can be supported by n-acetyl cysteine, glutamine,  glycine,  Vitamins C and E, selenium, magnesium, zinc, B vitamins, vitamin D and alpha-lipoic acid.

N-Acetyl Cysteine

Contains sulfur amino acids including a dimer of cysteine. N-acetyl cysteine is one of the three necessary amino acids necessary for glutathione production. It is a free radical scavenger on its own, effective at reducing oxidative stress, particularly due to heavy metal toxicity. Because it can directly replenish glutathione stores, NAC is more effective than methionine or SAMe at preventing liver damage, and is the current treatment for acetaminophen (Tylenol) toxicity. It is an effective treatment for acute liver failure due to non-acetaminophen drug toxicity as well. It is readily absorbed and boosts glutathione levels. It readily crosses the cell membrane and increases intracellular gluthatione levels. This has been used for years to help treat asthma, and lung disease, as well as treat people with life-threatening liver failure from acetaminophen overdose. It is given to prevent kidney damage from dyes used during x-ray studies.


Cysteine is generated from methionine catabolism via the transsulfuration pathway, so dietary methionine can be used to make cysteine to support glutathione synthesis. Check out the methylation and transulfuration pathways to understand how cysteine is made from this precursor.

SAMe - AKA S-adenosylmethionine

Cysteine is generated from S-Adenosyl Methionine, so SAMe can be used to ultimately make cysteine to support glutathione synthesis. Methionine is turned into SAMe with the help of the enzyme methionine adenosyl-transferase. It is simply one step closer to making glutathione than methionine is. Check out the methylation and transulfuration pathways to understand how cysteine is made from these precursors.

Alpha lipoic acid

Time released (I use alamax CR  600 mg alpha lipoic acid and Biotin 450 mcg per capsule) Start with 1 cap 2-3 times per day.
Side effects: little data, but skin rash possible. It will chelate heavy metals, so if you have a heavy metal issue, you might notice some detox activity from it and detoxing can create side effects. The most common symptom is nausea.


Herbs to increase Glutathione
  • Turmeric - Curcuma longa
  • Milk thistle - Silybum marianum
  • Cinnamonum - Cinnamon (human study did not specify species)
  • Cordyceps - Coryceps sinensis/militaris  (okay, a mushroom and not technically an herb)
  • Gotu kola - Centella asiatica

Milk thistle - Silybum marianum: 1 Tablespoon BID Milk thistle contains a mixture of several related polyphenolic compounds called silymarin. Silymarin is an antioxidant which lowers the liver's oxidative stress associated with toxin metabolism, particularly lipid peroxidation, which has the effect of conserving cellular glutathione levels. Like NAC, silymarin can protect against acetaminophen toxicity (possibly by the similar mechanism of preserving glutathione levels). Silymarin, however, may be a more effective antidote than NAC for acetaminophen toxicity if the treatment is delayed (in an animal model, it was effective when administered up to 24 hours after overdose).

Turmeric - Curcuma longa: Curcumin induces gstA gene expression and overall glutathione activity.

Cordyseps - Cordyseps sinensis research shows it increases glutathione peroxidase. Glutathione peroxidase is a necessary enzyme to help glutathione act as an antioxidant.


Eating to Raise Glutathione S-transferase (GST) - to enhance glutathione conjugation

Studies have found Cruciferous vegetables can enhance  Glutathione S-transferase (GST). One study found a significant increase in the amount of  serum GST and its GST activity when GSTM1-null individuals, especially women ate a moderate diet of Cruciferae plants. It appears that being a GSTM1-null or listed as AA on a "23 and Me" report (people who are thought to have low GST activity - although other genes may make up for it) means a Cruciferae diet might enhance your ability to  make GST. Yipee for those folks.

Whey (cheese making by-product) from non-pasteurized and organic animals. Want precursors from whey as follows: Serum albumin, alpha lactoalbumin, lactoferin, beta lactoglobulin. These globular proteins are high in cysteine and cysteine residues and can be manufactured into glutathione.

Anything that enhances Nrf2 will increase glutahtione and GST. In a study comparing four NRF2 activators, it was found that R-α-Lipoic acid,  sulforaphane and Polygonum cuspidatum extract containing 50% resveratrol increased astroglial release of glutathione.

Sulforaphane (lots in fresh broccoli/sprouts) produced the best effect. It increased glutathione by up to 2.4-fold. Polygonum increased glutathione up to 1.6-fold, and lipoic acid (1.4-fold).



Supplements to Raise Glutathione S-transferase - to enhance glutathione conjugation

S-Adenylsyl methionine (SamE or SAM) in studies with mice - Methionine feeds into a cycle that includes preliminary steps to make glutathione. I have an article on the methionine/methylation cycle on this website.

Cardamom - Elettaria cardamomum upregulated glutathione-S-transferase and glutathione peroxidase in mice.

Green Tea polyphenols significantly enhance GST levels and activity in human study.


Additional Methods to Support Glutathione or Glutathione Conjugation

Anything that reduces stress will help preserve glutathione. Studies have shown that relaxation techniques change gene expression and enhance glutathione levels.

  • Meditation and prayer enhance glutathione
  • Biofeedback practices enhance glutathione
  • Yoga enhances glutathione
  • Supporting restful sleep will help support glutathione levels

I think you get the picture, you choose your choice of relaxing activity.


Other Substances/Nutrients That Go Into Enhancing Production Of Glutathione
Methylation Cycle Nutrients

The methylaction cycle makes homoceysteine as part of the it's pathway, and homocysteine routes into the transulfuration cycle, that makes cysteine, and ultimately makes glutalthione. Active folate (a segment of the population needs active folate-L-5-methyltetrahydrofolate for folate dependent remethylation), vitamins B6(as Pyridoxal 5'-phosphate sodium) and B12(in the active form of methylcobalamin), and Betain Anhydrous (trimethylglycine).These are very critical to keep the body producing glutathione. Methylation and the production and recycling of glutathione are some of the most important biochemical functions in your body. many companies sell methylation products.

Interruption of the remethylation of the methionine cycle leads to decreased production of glutathione. The decreased availability of methylcobalamin is part of this defect and injections of methylcobalamin (b12) have been shown to restore the methionine cycle in situations where there is a deficiency of methylcobalamin. In a twist of biochemical irony, glutathione appears to be needed to maintain the production of methylcobalamin and the function of the methionine cycle.

Some people take S-adenosyl methionine or SAM to replace it in the cycle. Some people simply bypass the whole cycle to make cysteine and simply take N-acteyl cysteine (NAC).

Need Following Cofactors/Substrates To Metabolize Glutathione
  • Glycine
  • Selenium,
  • B. Vitamins
  • Vit C
  • Vit E,
  • Zinc,
  • Magnesium
  • Vitamin D

Magnesium - Much of our United States populace is deficient in magnesium. Glutathione requires magnesium for synthesis.

Selenium - Glutathione peroxidase is necessary for glutathione to act as an antioxidant. Glutathione peroxidase is a seleium-dependent enzyme. Selenium deficiency is common in malabsorption and gastrointestinal disease. Some people live in areas were there is no selenium in the soil and other people live in areas where the soil contains toxic levels of selenium.

Zinc - the rate limiting enzyme γ-glutamylcysteine synthetase that is necessary to make glutathione, depends on zinc for its activity.

Riboflavin (B2) - Glutathione reductase is necessary to change glutathione disulfide (Oixdized glutathione) back into the reduced state. Glutathione reductase is a riboflavin -dependent enzyme.

Amino Acids: Cysteine,Glutamine and Glycine are all necessary to make glutathione. The rate limiting aminio acid is usually cysteine. However, there are conditions which could deplete one of the other amino acids. For instance a stressful surgery has been shown to deplete glutatmine.

NADPH - Necessary for recycling of glultathione from glutathione disulfide to glutathione.

Vit C and E help the body recycle glutathione

In healthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to elevate and maintain good tissue glutathione levels. In one double-blind study, the average red blood cell glutathione concentration rose nearly 50% with 500 mg/day of vitamin C. Increasing the dosage to 2,000 mg only raised red blood cell (RBC) glutathione levels by another 5%. Vitamin C raises glutathione by increasing its rate of synthesis.

 Active vitamin D - 1,25-dihydroxyvitamin D3 has been shown to increase glutathione levels in the brain and may be a catalyst for glutathione production.

Vitamin B 6 - cystathionine B-synthase (CBS) and cystathionine lyase are both B6 dependent enzymes that are involved in transulfuration of homocysteine on its pathway to make glutathione.

Vitamin A was shown to upregulate glutathione-S-transferase activity in the liver cyotosol raction. SamE also upregulates it.


Things That Are Associated With Low Glutathione

Environmental Toxins: smoking, mercury

Smoking increases the rate of utilization of glutathione, both in the detoxification of nicotine and in the neutralization of free radicals produced by the toxins in the smoke.

Mercury has a high affinity for thiol (sulfhydryl (-SH)) groups. Glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. High levels of mercury will use up glutathione.

Health Conditions - acutely may be increased in some diseases, but over time, decreased
  • Protein malnutrition
  • Herpes
  • Cancer
  • Type 2 diabetes
  • Hepatitis
  • Parkinson's disease
  • Acetaminophen (tylenol) toxicity
  • Heavy metals
  • Dexamethasone
  • Erythropoeietin
  • Tumor gorwth factor B
  • Hyperglycemia


The rate limiting enzyme for making gluatathione, γ-glutamylcysteine synthetase is down-regulated by Transforming Growth Factor - beta (TGF-beta) and by prolonged oxidant exposure in in vitro studies. People who have mold related illness have high TGF-beta 1

Acetaminophen is conjugated wtih glucuronate(80%) and sulfate (10%). The remaining acetaminophen is oxidized by CYP450 to the toxic metabolite, N-acetyl-p-benzoquinone imine. This undergoes glutathione conjugation. However, in an overdose, the glucuronidation and sulfation pathways become saturated and acetaminophen is metabolized into more N-acetyl-p-benzoquinone imine than the glutathione (GSH) can keep up with. The GSH is depelted. This leads to cellular toxicity and liver necrosis.


The Immune System and Glutathione

  • The central role of glutathione in a variety of cell functions related to immune defense has been demonstrated in studies.
  • A decrease in glutathione in antigen-presenting cells correlates with increased Th2 response.
  • Decreased glutathione found in macrophage cells from children with chronic asthma has been shown to be related to decreased bacterial phagocytosis.
  • Children with chronic asthma, had decreased glutathione related to post-translational modification of Nrf2.
  • Decreased glutathione and decreased macrophage defense against intracellular infection with Mycobacterium tuberculosis occurs in the macrophages of individuals with HIV. The decrease in glutathione in the macrophage of HIV+ individuals was shown to be due to a decrease in the gene expression of the enzymes of glutathione production .
  • Restoration of glutathione levels in the mycotoxin exposed mouse dendritic cells using NAC or glutathione ethyl ester restored IL-12 secretion and prevented the mycotoxin-induced increase of airway inflammation and airway hyperreactivity.
  • Restoration of glutathione using NAC in the macrophages of children with asthma restored phagocytosis in the ex vivo model.



An increase in urinary excretion of 5-oxoproline, an intermediate of the γ-glutamyl cycle, is a useful indicator of reduced availability of cysteine and/or glycine for GSH synthesis in vivo.

Decreased 5-oxoproline in the urine is seen with even mild glutathione synthetase deficiency. This might be a useful marker.


Mold And Mycotoxins

Mycotoxins can decrease the formation of glutathione by decreasing gene expression of the enzymes needed to form glutathione. In humans this chronic depletion of glutathione has been shown to lead to chronic health conditions, including chronic asthma and nuerological issues. A decrease in glutathione due to mycotoxin-related depletion may contribute to the range of conditions associated with mycotoxin accumulation. Since the mycotoxins destroy the action of the enzymes necessary for glutathione production, glutathione may need to be supplemented rather than supplementing the rate limiting amino acid as n-acetyl-cysteine. Glutathione has been beneficially used in animal research of aflatoxin-related hepatocellular carcinoma. Clinicians and individuals with mold related illness, or also called CIRS due to water-damaged buildings, suggest that studies using liposomal glutathione in the management of mycotoxin-related conditions is warranted. Acetyl-glutathione is used with good results also. I use an acetylated form of glutathione as it has better absorption when acetylated. By acetylating it, the glutathione is not oxidized and broken down into it's componant amino acids as other gluathiones usually are. The acetylation of the glutathione Nebulized glutathione is also used but should only be used under the care of a trained practitioner. Bronchoconstriction has occured among patients some patients.

Glutathione depletion in antigen presenting cells inhibits Th1-associated cytokine production and/or favors Th-2-associated responses. Multiple chemical sensitivities in individuals are thought to be associated with decreased Th-1, increased Th-2 response. Mycotoxins (as well as other toxins) can deplete the body of glutathione and could add to the problems with an improper antigen presenting cells activity that has already be theorized to be an issue for people with mold sensitivity.

Research is proving that oxidative stress is a significant factor in the pathophysiology of mycotoxin-related illness. Oxidative stress appears to be directly related to suppression of glutamate-cysteine ligase catalytic subunit (GCLC), gene function, post-translational modification of Nrf2 or the presence of excess tranforming growth factor-beta (TGF-β). This suggests that the lack of glutathione may be due to the inability of mycotoxin-affected cells to adequately form glutathione.

The demonstration that the oxidative stress associated with mycotoxins can be related to direct suppression of enzymes for glutathione synthesis, post-translational modification of Nrf2 or the presence of excess TGF-β suggests that the lack of glutathione may be due to the inability of mycotoxin-affected cells to adequately form glutathione. Decreased function of the enzymes of glutathione production results in a microenvironment depleted of glutathione on a chronic basis. In humans, deficiency of glutathione can lead to chronic conditions. Mycotoxin-related depletion of glutathione may contribute to the range of conditions associated with mycotoxin accumulation. The lack of function of the enzymes of glutathione production in these conditions suggests that more efficient resolution of the effects of glutathione depletion may require the administration of the complete glutathione molecule. These observations echo an early report regarding the benefit of glutathione in the management of aflatoxin-related hepatocellular carcinoma in an animal model, which proposed that administration of the intact glutathione molecule was needed for benefit of the use of glutathione.

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