What is Glutathione?

Learn about the basics of Glutathione, it's vital role in the body, importance to remove toxins, prevent disease and improve quality of life.

What is Glutathione?
Glutathione Molecular Composition
Significance of Cysteine
Forms of Glutathione GSH & GSSG
Regulation of glutathione in our Cells
Glutathione Peroxidase
The Function of Glutathione
Glutathione is the Master Antioxidant
Glutathione Regulates the Growth & Division of Cells
Glutathione & the Liver
Glutathione, the real anti-aging
Glutathione & Cognitive Function
Autism
Other Neurological Diseases

Glutathione, the master antioxidant of our body, acts as a protective shield against free radicals and various factors that can damage our cellular components. These factors include poor nutrition, stress, exposure to aggressive medical treatments, chemicals, fertilizers, heavy metals, as well as substance abuse like alcohol and smoking.

Glutathione (GSH) is a tripeptide non-protein thiol that acts as an antitoxin & antioxidant which combats oxidative stress. Specifically, glutathione protects cells from being damaged by free radicals that are produced as a by-product of chemical oxidation. Glutathione is found in plants, animals, fungi, and some bacteria. In mammals, glutathione is found in every cell of the body, with particularly high concentrations in the liver (given that the liver is the main detoxifying organ), the spleen (main immune defense system), and especially the skin (the largest organ of the body).

Glutathione concentrations are thousands of times higher than vitamins C, E, and A in the body.

Glutathione also plays a major part in redox signaling, xenobiotic detoxification, the regulation of cell proliferation, apoptosis, immune function, and fibrogenesis.

After childhood, past a certain point, the body starts producing less glutathione than it once did. This decrease in GSH levels may contribute to chronic diseases such as diabetes mellitus, pulmonary fibrosis, liver fibrosis, cholestatic (reduction in bile flow), liver injury, endotoxemia (microbial products circulating in the blood to cause toxicity), and drug-resistant tumor cells. In other words, glutathione helps to prevent all of these pathological diseases and conditions.

Glutathione Molecular Composition

Inside the cell, Glutathione (GSH) is biosynthesized in the cytosol, which is the aqueous part of the cytoplasm that suspends organelles and particles inside a cell.

Glutathione is a tripeptide composed of three amino acids bound together with covalent bonds. Specifically, glutathione is composed of:

Glutamic Acid

Cysteine

Glycine

Significance of Cysteine

Of the three molecular components, cysteine is perhaps the most important. Cysteine is the rate-limiting molecule, meaning that the production of glutathione relies on how much cysteine it is available. Glycine and glutamic acid are not rate-limiting for glutathione production, because they are both plentiful compared to cysteine.

Cysteine is also a conditionally essential amino acid, meaning that, although the body can produce some of the cysteines it needs, the body also requires cysteine through diet if enough cannot be produced. The body’s production of cysteine cannot keep up when glutathione production is increased in the case of illness, disease, and toxin exposure. Note: If oxidative stress and toxins are increased, the body uses more glutathione to combat these.

Cysteine contains a sulfhydryl group that is able to donate an electron, which neutralizes free radicals.

For example, egg whites contain the amino acid cysteine. When an egg is cracked and left sitting out for a while, cysteine’s sulfhydryl group reacts with the free radicals that are in the air/environment by donating an electron (oxidation), thereby rebalancing the radical molecule. In the aftermath, you can quite literally “smell” the reaction as rotten eggs.

Forms of Glutathione GSH & GSSG

Glutathione has two forms that it can exist in: the reduced glutathione (GSH) and oxidized glutathione (GSSG).

Reduced glutathione is the active form of glutathione that acts as an antioxidant by absorbing or bonding to the free radical electrons that are let loose/produced when an oxidation reaction occurs.

When GSH bonds with a free radical, GSH transforms into the oxidized form of glutathione (GSSG). Note: Oxidized glutathione is also known as glutathione disulfide. Oxidized glutathione does not act as an antioxidant, so it isn’t necessarily useful to the cell in this form.

However, GSSG is transformed back into the useful form of reduced glutathione by an enzyme called glutathione reductase.

Observing the ratio of GSH to GSSG inside our cells can be used to measure cellular toxicity. Normally, healthy cells have about 90% of glutathione in its reduced form. Without sufficient levels of active glutathione, our cells and our DNA are likely to be damaged by free radicals.

Regulation of glutathione in our Cells

Our cells detect when there is a decrease in the level of GSH inside and outside of our cells and respond by producing more enzymes that increase the synthesis of glutathione and glutathione peroxidase. Note: Glutathione peroxidase is an enzyme that neutralizes hydrogen peroxide and organic peroxide types of free radicals. On the other hand, when there is an increase of GSH in the cell, enzymes are created that transport excess glutathione into the blood plasma to be distributed elsewhere.

Glutathione Peroxidase

Glutathione Peroxidase (Gpx1), although useful to the cell by neutralizing hydrogen peroxide free radicals, is not apparently required for cell survival, as seen through Gpx1 knockout mice (mice that don’t have the gene to produce glutathione peroxidase) that don’t show any signs of physical illness when compared to regular wild mice.

One explanation why glutathione peroxidase is not required is that cells have other enzymatic antioxidants, such as catalase and glutathione that can compensate for glutathione peroxidase by being able to detoxify H2O2.

The knockout of the Gpx1 gene also doesn’t cause the mice to be more susceptible to dietary, selenium, and vitamin E deficiencies.

Overall, glutathione peroxidase is not required for cell survival. However, glutathione peroxidase may improve a cell’s resistance to oxidative stressors such as the biodegradable herbicide paraquat and hydrogen peroxide.[3]

The Ratio of GSH to GSSG Changes with Age

Glutathione in our body changes in its amount depending on our age. Usually, young people have 90 percent of glutathione GSH. When we get older, more of our glutathione shifts to being GSSG, the oxidized form of glutathione that does not actively quench free radicals from our body.

When there is too much GSSG in our body, enzymes are made that build more GSH, the reduced form of glutathione. Most of the time, more GSH is built in the liver, the organ responsible for detoxification. Also, note that the liver is the organ with the highest concentration of glutathione per cell.

Note: Old people who live longer generally had higher levels of GSH than normal for their age group. This may indicate that glutathione may be important for life-extension purposes.

The Function of Glutathione

Glutathione isn’t only an antioxidant. Glutathione also serves many other functions in the body, in addition to neutralizing free radicals. Its role as an antioxidant also allows the body to perform certain functions that are otherwise hindered by Reactive Oxygen Species (ROS). These include:

- • Master Antioxidant
- • Regulation of Cell Growth
- • Detoxifying or Neutralizing Toxins
- • Immune System Activation
- • Regeneration of Antioxidants
- • Transporting Proteins Inside and Between Cells

Glutathione is the Master Antioxidant

Glutathione has the capacity to prevent cellular damage caused by Reactive Oxygen Species (ROS). ROS includes things like free radicals, peroxides, lipid peroxides, and heavy metals.

If a glutathione molecule is oxidized by donating an electron, it becomes glutathione disulfide- also known as L-glutathione.

Once a glutathione molecule is oxidized, it can be reduced back (gain back an electron) through the use of the glutathione reductase enzyme and NADPH as an electron donor.

Also, the ratio of reduced glutathione to oxidized glutathione inside a cell can be measured to determine the existing level of cellular oxidative stress. The more oxidative stress, the more glutathione is oxidized to protect the cell from the ROS.

Glutathione Regulates the Growth & Division of Cells

So how does glutathione help in the growth and division of cells? The process that a cell undergoes in order to develop and divide is very complex, and can easily be disturbed by a ROS reacting with it. When a cell is damaged, the cell dies (apoptosis) in order to prevent itself from becoming cancerous. What glutathione does is simply reduce the reactive oxides (i.e., hydrogen peroxide H2O2) inside the cell so that it doesn’t interfere with the process of cell division.

Glutathione & the Liver

Glutathione is essential for our body’s ability to handle toxins. Glutathione effectively detoxifies heavy metals, pesticides, food preservatives and environmental pollutants and other toxic substances after the liver initially “detoxifies” them by changing them into free radicals. This shows that our liver absolutely requires glutathione for the detoxification of toxins.

The liver also has cells called “parenchymal cells,” which sends GSH to the blood plasma. In the blood plasma, GSH neutralizes free radicals, toxins, and heavy metals.

Glutathione, the real anti-aging

The history of thiols and thiones in biology can be traced back to as early as 1888 when Joseph de Rey-Pailhade first discovered the sulfur-containing compound, philothion (13), which was later rediscovered as glutathione (GSH) by Frederick Gowland Hopkins (30).

https://www.liebertpub.com/doi/pdfplus/10.1089/ars.2017.7300#:~:text=The%20history%20of%20thiols%20and,Frederick%20Gowland%20Hopkins%20(30).

Glutathione & Cognitive Function

Autism

Glutathione is extremely important for the healthy development and function of the brain. To understand this, let’s take a look at autistic children.

Autistic children have cells with impaired mitochondria that produce less-than-normal amounts of ATP (adenosine triphosphate, the energy-carrying molecule found in the cells of all living things). If this is also true for the brain cells, it would explain the observed reduction in brain function and neuronal development. It is believed that mitochondria can become impaired from being exposed to high levels of free radicals.

Indeed, a study[4] shows that autistic children’s brain cell mitochondria is exposed to a higher-than-normal load of free radicals. Specifically, it was observed that children with autism have higher-than-normal mitochondrial rates of hydrogen peroxide (free radical) production.

This indicates that there is a lack of sufficient antioxidants, especially the primary one, GSH glutathione. If there are sufficient amounts of GSH glutathione, one can assume that the level of oxidative stress would be lower.

In fact, autistic children show improvements in their symptoms when supplemented with N-acetylcysteine (NAC), which provides the precursor molecule cysteine for the body to use. Remember, cysteine is the rate-limiting amino acid required for the production of GSH glutathione. Therefore, supplementing NAC would in effect boost a person’s level of GSH glutathione in the body.

In one study[5], researchers gave an autistic child 800 mg per day of NAC to boost active glutathione levels, in order to combat the raised oxidative stress and neuroinflammation that is thought to cause autism in children. Through a period of two months, the researchers observed improvements in autistic symptoms, social interaction, and aggressive behavior.

Other Neurological Diseases

Does boosting glutathione through NAC only appear to benefit autistic patients? NAC was found by researchers[6] to help patients with direct injuries such as traumatic brain injury, cerebral ischemia, and in the treatment of cerebrovascular vasospasm after subarachnoid hemorrhage. It’s believed that NAC has a wide range of actions for neurological problems. Raising glutathione levels through NAC supplementation may decrease the number of proteins that are misfolded in the brain.

When the number of proteins misfolded in the brain increases in number over time, they end up causing amyloid diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. It is usually the older generation who end up getting age-related neurological problems like the ones mentioned.

Glutathione comes into the picture because active GSH glutathione protects against oxidative stress. Oxidative stress is one of the triggers or causes for the misfolding of proteins.

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What is Glutathione?

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