Glutathione and MTHFR

Glutathione and MTHFR

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

June 15, 2025

Table of Contents

    The Relationship Between Glutathione, Methylation, and MTHFR

    Glutathione and MTHFR are intimately linked by their relationship to the methylation cycle. To understand the role that glutathione plays in the body and how MTHFR impacts it, it’s important to understand methylation.

     

    Methylation is the process in which a methyl group is added to another substance—such as DNA or a protein—so that the substance receiving the methyl group can function. The addition of methyl groups to DNA molecules helps change the activity of a DNA segment without changing its sequence. DNA methylation is involved in gene transcription—the process of turning an RNA copy of a gene sequence “off” or “on.”


    Methylation occurs every second in every cell in the body and is required for almost every physiological process. Methylation reactions are vital for the production and the recycling of many important proteins, hormones, and neurotransmitters required for everyday bodily functions. Methylation is responsible for the growth and development of all cells and controls everything from DNA replication to digestive function.


    The efficiency of the methylation cycle is highly dependent on specific nutrients, namely folate, B6, and B12. Deficiencies in these nutrients can occur due to disease, poor diet, and/or a genetic mutation on the MTHFR gene. As a result, the methylation cycle will be compromised or impaired, along with many other functions that depend on it, including glutathione production.


    This article will explain the importance of glutathione and its relationship with methylation and MTHFR. We will also discuss how an MTHFR mutation can affect glutathione levels—and vice versa—and the health conditions this can lead to.

    What is Glutathione?

    Glutathione (GSH) is described as the body’s “master antioxidant.”  It is a potent free radical and reactive oxygen species scavenger.


    High concentrations1 of glutathione are found in nearly every cell in the body, in much the same levels as glucose, potassium, and cholesterol. The highest glutathione concentrations are in the liver, spleen, kidneys, eye lenses, erythrocytes, and leukocytes. Glutathione is the most important antioxidant in the liver, and it plays a critical role in detoxification.

    Glutathione’s main roles include:

    • Neutralizing harmful free radicals
    • Acting as a cofactor for several antioxidant enzymes
    • Regenerating vitamins C and E
    • Neutralizing free radicals produced by Phase I liver metabolism of chemical toxins, including formaldehyde, acetaminophen, benzpyrene, and many other compounds
    • Participating in Phase I and Phase II detoxification reactions
    • Adhering to toxins and heavy metals (including mercury) before carrying them out of the body
    • Regulating cellular proliferation and apoptosis
    • Participating in mitochondrial function and the maintenance of mitochondrial DNA

    Essentially, glutathione is crucial for shielding cells from endogenous and exogenous reactive oxygen and nitrogen species, as well as dealing directly with the causes of oxidative stress such as mercury and pollutants.

    How Can an MTHFR Gene Mutation Affect Glutathione Levels?

    To understand how the MTHFR gene mutation affects glutathione, we first need to understand one-carbon metabolism. This is a series of biochemical reactions that delivers one-carbon units to numerous pathways.


    The folate cycle and methionine cycle are two major components of this network required for regulating amino acid homeostasis, including the three amino acids that make up glutathione: cysteine, glycine, and glutamic acid.


    Homocysteine produced during the methylation process can be converted to cysteine, which is then combined with two other amino acids (glutamate and glycine) to form glutathione.


    The MTHFR enzyme is important to homocysteine metabolism as it is necessary to transfer a methyl group to the methionine.


    Sufficient levels of methionine are required for homocysteine to enter the transsulfuration2 pathway and to transfer sulfur from homocysteine to cysteine.


    Methionine is activated to form S-adenosylmethionine (SAM), the universal methyl donor. S-adenosyl homocysteine (SAH), a by-product of methylation reactions, is then hydrolyzed to homocysteine. Homocysteine is either used to regenerate methionine or is directed to the transsulfuration pathway. Glutathione is a product of the transsulfuration pathway.


    MTHFR also catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the predominant circulating form of folate. However, mutations in the MTHFR gene typically result in a lack of folate required for methylation reactions.


    MTHFR mutations are commonly associated with high homocysteine levels3 and low methionine production, which in turn may lead to the accumulation of S-adenosylhomocysteine (SAH) and low levels of SAMe. Vitamin B12 and SAMe/SAH are essential in regulating methionine activity, and methionine is also a metabolic precursor for cysteine4. Most tissues are dependent on the transport and cellular uptake of cysteine5 for glutathione synthesis.


    If the methylation process does not occur efficiently due to a lack of folate, the transsulfuration pathway will also be compromised, which in turn impairs the creation of glutathione.

    What Issues Could Low Glutathione Cause?

    Low glutathione may have a significant effect on human health. Deficiency or poor glutathione levels increase the body’s susceptibility to oxidative stress, particularly in the tissues and cell types of the tissues in which it is found in the highest concentrations.


    Studies suggest that low glutathione can increase the risk of developing chronic illnesses6 such as cancer, neurodegenerative diseases, and diseases of the cardiovascular, inflammatory, immune, metabolic systems, cystic fibrosis.


    In relation to the immune system, glutathione deficiency may impair macrophage and T-cell function7 in relation to the immune system.


    In addition, imbalances in glutathione levels may also speed up the aging process8. Just as low intracellular glutathione levels (as observed in many cancer cells) can decrease antioxidant capacity9, elevated levels of glutathione are shown to increase antioxidant capacity10 and improve resistance to oxidative stress.


    For this reason, maintenance of adequate glutathione levels may enhance immunocompetence, protect the body from numerous chronic diseases, and improve the ability to recover from illness or physical stress.

    How Does Glutathione Impact Methylation?

    A lack of glutathione may have a significant impact on DNA methylation11. Although human cells are capable of resynthesizing glutathione when it is depleted, this glutathione turnover occurs at the expense of methionine. An increase of methionine catabolism via the cystathionine pathway decreases methionine recycling. This, in turn, limits the availability of SAMe for methylation12.


    One study showed that depleted glutathione could then lead to depleted methionine. This further impairs the methylation process and, as a result, significantly affects DNA methylation13.


    Glutathione also plays an important role in protecting vitamin B1214 from being damaged by toxins. The interaction between glutathione and vitamin B12 may also protect against diseases15 related to low vitamin B12. B12 is an essential precursor in the methylation cycle and the folate cycle. Deficient glutathione may affect the ability of B12 to participate in metabolic functions, which in turn affects both the methylation cycle and the folate cycle. 

    How Can Supplementation Help?

    Supplementation with oral glutathione may not be beneficial as digestive peptidases degrade it, and several studies show no change in glutathione levels16 following supplementation. However, a study in which volunteers were supplemented with N-acetylcysteine (NAC) and oral GSH17 suggested that a sublingual form of glutathione may be beneficial.


    Cystine, methionine, and N-acetyl-cysteine18 are effective precursors of cysteine for glutathione synthesis. A small study showed that supplementation with cysteine and glycine fully restores glutathione synthesis19 and may lower levels of oxidative stress.


    N-acetylcysteine (NAC) has been shown to treat glutathione deficiency20 in some studies. However, this is less likely if the body cannot synthesize glutathione from nutrients21, an ability that decreases with age.


    The B vitamins also play a major role in glutathione synthesis and the metabolism of homocysteine22. Homocysteine may then be converted into cysteine and remethylated into methionine to be used for glutathione. The deficiency of B-vitamins may impair the homocysteine-methionine cycle23, which in turn can lead to reduced glutathione levels. Riboflavin is also a component of the glutathione redox cycle24, and lower riboflavin levels may lead to reduced glutathione.


    Folate supplementation may increase methionine and SAM levels25 and, as a result, improve methylation. It has also been suggested that the combination of folate, vitamin B12, and vitamin B6 may improve methylation, increase transsulfuration, and possibly reduce stress.


    The Methyl-Life® product range includes a Methylated Multivitamin made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate and the most active form of folate in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body. This form of methylfolate can boost glutathione levels and bypasses folate insufficiency due to MTHFR deficiency, entering the folate cycle directly without the need for further enzymatic modification.

    Product Recommendations

    Methylated Multivitamin 3-Product Pack - MTHFR Folate, Sublingual B12 + Cofactors - Methyl-Life® Supplements

    Methylated Multivitamin 3-Product Pack - MTHFR Folate, Sublingual B12 + Cofactors
    (2)

    $96.00

    • Bioactive MTHFR Folate, Methylfolate, for Max Absorption
    • Sublingual B12 to Aid B12 Sufficiency via Active Hydroxy Form
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Day Supply to Optimize Methylation Pathways

    Frequently Asked Questions about glutathione and MTHFR

    Does glutathione lower homocysteine?

    Research has suggested that intravenous glutathione or N-acetylcysteine (the precursor to glutathione) can significantly reduce homocysteine levels, with one animal study showing that glutathione reduced homocysteine by 51%. It appears that higher glutathione levels lead to lower homocysteine levels.26

    What are the symptoms of glutathione deficiency?

    Symptoms of glutathione deficiency may not be immediately obvious, as associated health conditions take some time to develop.
    Glutathione deficiency results in higher susceptibility to oxidative stress, which may lead to poor immune function and faster aging. Low glutathione also increases the risk of developing hemolytic anemia (in which red blood cells are destroyed faster than they can be replaced), metabolic acidosis (an electrolyte disorder) and CNS dysfunction. Long-term glutathione deficiency is linked to diseases such as cancer, Parkinson’s disease, and Alzheimer’s disease.27
    One animal study suggested that severe glutathione deficiency during early development may reduce BDNF (a brain growth factor) in key brain areas, and potentially be linked to schizophrenia-like behavior.28

    Who should avoid glutathione?

    Women who are pregnant, breastfeeding, or planning to conceive are advised to avoid glutathione, as research regarding pregnancy and glutathione is lacking. Glutathione is known for promoting detoxification in the body.
    Talk to your health professional before taking glutathione, especially if you have health conditions or you are taking other medications.

    What depletes glutathione in the body?

    Several drugs and dietary factors can deplete glutathione, including:
    ↦ Acetaminophen, NSAIDs, DL-buthionine-S, R-sulfoximine, menadione (vitamin K3), and sodium deoxycholate.
    ↦ High alcohol intake.29
    ↦ A high-fructose diet can also trigger symptoms of metabolic syndrome and increase oxidative stress and inflammation, reducing glutathione.30
    ↦ Chronic stress, depression and anxiety can lead to oxidative stress, which in turn depletes glutathione.31
    ↦ Exposure to environmental pollutants/toxins.32

    Does methylation produce glutathione?

    Methylation doesn’t directly produce glutathione, but it does play a part in the process that synthesizes glutathione.
    Methylation drives the methionine cycle, which regulates homocysteine levels. Homocysteine can either be remethylated back to methionine or diverted into the transsulfuration pathway to produce cysteine (the precursor to glutathione). If methylation is impaired, less homocysteine enters transsulfuration which reduces cysteine production. As a result, glutathione synthesis is reduced.

    References

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    12. The Journal of Nutrition | A Journal of the American Society for Nutrition

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      https://pubmed.ncbi.nlm.nih.gov/15606130/

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      https://pubs.acs.org/doi/10.1021/tx0497898

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770193/

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536296/

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155927/

    20. Kondala R Atkuri, John J Mantovani, Leonard A Herzenberg, Leonore A Herzenberg; "N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency"; Current Opinion in Pharmacology, Vol. 7, Iss. 4; 2007 Aug

      https://www.sciencedirect.com/science/article/abs/pii/S1471489207000896

    21. Bernard Schmitt, Morgane Vicenzi, Catherine Garrel, Frédéric M Denis; "Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study."; Redox Biology;2015 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536296/

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      https://www.sciencedirect.com/science/article/pii/B9780123750839001446

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    25. Jacob Joseph, Joseph Loscalzo; "Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology"; Nutrients; 2013 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775251/

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    27. Nazzareno Ballatori, Suzanne M Krance, Sylvia Notenboom, Shujie Shi, Kim Tieu, Christine L Hammond; "Glutathione dysregulation and the etiology and progression of human diseases"; Biological chemistry; 2009

      https://pmc.ncbi.nlm.nih.gov/articles/PMC2756154/

    28. Marta Anna Lech, Monika Leśkiewicz, Kinga Kamińska, Zofia Rogóż, Elżbieta Lorenc-Koci; "Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague–Dawley Rats"; International journal of molecular sciences; 2021 Jun

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    29. Pietro Ghezzi, Kevin V Lemley, James P Andrus, Stephen C De Rosa, Arne Holmgren, Dean Jones, Farook Jahoor, Richard Kopke, Ian Cotgreave, Teodoro Bottiglieri, Neil Kaplowitz, Hajime Nakamura, Frank Staal, Stephen W Ela, Kondala R Atkuri, Rabindra Tirouvanziam, Kartoosh Heydari, Bita Sahaf, Andrew Zolopa, Richard Eugene Frye, John J Mantovani, Leonard A Herzenberg, Leonore A Herzenberg; "Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease"; The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine; 2018 Jul

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    30. Luciana Moine, María Rivoira, Gabriela Díaz de Barboza, Adriana Pérez, Nori Tolosa de Talamoni; "Glutathione depleting drugs, antioxidants and intestinal calcium absorption"; World journal of gastroenterology; 2018 Nov

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    31. Ioannis Zalachoras, Fiona Hollis, Eva Ramos-Fernández, Laura Trovo, Sarah Sonnay, Eveline Geiser, Nicolas Preitner, Pascal Steiner, Carmen Sandi, Laia Morató; "Therapeutic potential of glutathione-enhancers in stress-related psychopathologies"; Neuroscience & Biobehavioral Reviews; 2020 Jul

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    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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    Functions of Glutathione In the Body Functions of Glutathione In the Body
    Neutralizing harmful free radicals Adhering to toxins and heavy metals before taking them out of the body
    Acting as a cofactor for several antioxidant enzymes Regulating cellular proliferation and apoptosis
    Regenerating vitamins C and E Participating in mitochondrial function
    Participating in detoxification reactions Maintaining mitochondrial DNA

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