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.

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

High concentrations 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:

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.

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 transsulfuration 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 levels 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 cysteine. Most tissues are dependent on the transport and cellular uptake of cysteine 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.

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 illnesses 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 function in relation to the immune system.

In addition, imbalances in glutathione levels may also speed up the aging process. Just as low intracellular glutathione levels (as observed in many cancer cells) can decrease antioxidant capacity, elevated levels of glutathione are shown to increase antioxidant capacity 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. 

A lack of glutathione may have a significant impact on DNA methylation. 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 methylation.

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 methylation. 

Glutathione also plays an important role in protecting vitamin B12 from being damaged by toxins. The interaction between glutathione and vitamin B12 may also protect against diseases 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. 

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

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

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

The B vitamins also play a major role in glutathione synthesis and the metabolism of homocysteine. 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 cycle, which in turn can lead to reduced glutathione levels. Riboflavin is also a component of the glutathione redox cycle, and lower riboflavin levels may lead to reduced glutathione.

Folate supplementation may increase methionine and SAM levels 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.