Glutathione is one of the most important organic compounds in the human body. Many people know that glutathione is a powerful antioxidant, but most are still unaware of its function, supplementation, and the health consequences of deficiency. In this article I will share an overview the pathophysiology of glutathione, how this process is disturbed, the health consequences of decreased levels, and the supplementation needed.
Glutathione is commonly known as the ‘Master Antioxidant’, that helps cleanse the body of toxins. What does an antioxidant do and why is glutathione the ‘Master’? Throughout the body many enzymatic and catalytic processes require oxygen, this occurs because oxygen can transfer electrons and form bonds easily. The byproduct in many of these processes is water, which we easily reuse or eliminate. Other times the oxygen picks up an extra negative charge making it unstable (also known as a free radical). In an effort to become more stable the molecule passes the negative charge to any other passing molecule/ compound that will accept it. If an antioxidant like glutathione is there, the charge will be picked up and no damage will occur. But if antioxidants/ glutathione is in short supply the charge will continually be passed down the line. Picture a chemical game of hot potato, each pass of the charge creates more instability and damage to the cellular structure. Free radicals such as superoxide and hydrogen peroxide damage the cell walls, damage our DNA causing epigenetic/ genetic changes, damage mitochondrial DNA, and signal premature apoptosis (cellular death).
Glutathione is considered the ‘Master Antioxidant’ because it is the most abundant (equivalent to potassium/ glucose inside the cell), is vital in clearing free radicals from the cell and mitochondria (cell structures that produce all of the bodies energy through oxidative reactions), and it helps recycle other antioxidants. the It is comprised of three peptides (cysteine, glycine and glutamic acid), and functions in two forms, GSH and GSSG. GSH is produced in the cytosol of the cell and pumped into the mitochondria where it draws negatively charged ions from compounds, which then converts GSH into GSSG (consists of 2 GSH bound by the negative charge). This process improves the stability of the mitochondria but leaves the glutathione in a negative state. Glutathione is then converted back to the stable form of GSH by an enzyme and Riboflavin (Vitamin B7). Glutathione levels are an important marker for health of the body as well is the ratio of GSH to GSSG. The critical role of glutathione illustrates the need to maintain adequate if not optimal levels of this antioxidant.
So how do we end up with low glutathione? The primary cause of decreased levels is due to environmental pollutants that we ingest through the air, water, and food we ingest. Pollutants such as formaldehyde that are found in common building components such as flooring, carpet, particle board (used in furniture) are inhaled, pesticides are eaten, and mercury is found in tap water. These pollutants damage vital genes needed to produce cysteine and glutathione. Cysteine is one of the building blocks needed to create glutathione, many pollutants prevent the conversion of cysteine from homocysteine (resulting in increases of homocysteine, known as a marker of inflammation). If cysteine is made, pollutants or mold exposure can damage the gene that converts cysteine to glutathione. This results in chronically low levels of glutathione, which increases the levels of free radicals.
It is easy to see then how low levels of this ‘Master Antioxidant’ results in health problems. Low levels of glutathione have been associated to numerous health conditions including, Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, COPD, asthma, HIV, autoimmune disease, hypertension, myocardial infarction, liver disease and more. This does not mean that increasing glutathione will cure these conditions, but due notice that these are all chronic conditions. Chronically low glutathione means increased levels of free radicals in the body over a long period of time. Free radicals have been shown to cause systemic inflammation as well as damaging cell walls. The conditions listed above almost unilaterally are related to an inflammatory process or damage to the cell structures. Along with the extensive list of health conditions related to low levels of glutathione. Increased levels through supplementation has been shown to decrease oxidative stress. Studies have shown supplementation may improve some health conditions including improvement in Parkinson’s, depression, respiratory illnesses.
Supplementation of glutathione is complicated by the fact that oral supplements have poor bioavailability. N-acetylcysteine is a building block of glutathione and has been shown effective in raising serum levels, this is no longer on the market as a nutritional supplement. It was removed by the FDA and deemed a medication when it was shown to improve covid symptoms[BD1] . Oral liposomal supplementation has some studies supporting its’ use. This leaves few choices in effective supplementation regimens. IV glutathione has been effective in raising blood levels, it is the fastest way to raise levels. This should be augmented with the use of selenium and riboflavin to boost the efficacy of the IV glutathione supplementation.
Prep with molybdemun, potassium, cofactors, pqq to decrease oxygen reactive species, riboflavin, selenium, phosphocholine
Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in surprisingly high levels—5 millimolar—concentrations in most cells. As can be seen in Figure 1, this is the same concentration in cells as glucose, potassium, and cholesterol
Glutathione exists in cells in 2 states: reduced (GSH) and oxidized (GSSG). As can be seen in Figure 2, oxidized glutathione is actually 2 reduced glutathiones bound together at the sulfur atoms.
The ratio of GSH to GSSG determines cell redox status of cells. Healthy cells at rest have a GSH/GSSG ratio >100 while the ratio drops to 1 to 10 in cells exposed to oxidant stress.
Glutathione is produced exclusively in the cytosol and actively pumped into mitochondria.
It plays a crucial role in shielding cellular macromolecules from endogenous and exogenous reactive oxygen and nitrogen species. While it directly quenches some free radicals, of perhaps greater importance is that it deals directly with the causes of oxidative stress such as mercury and POPs.
- Direct chemical neutralization of singlet oxygen, hydroxyl radicals, and superoxide radicals
- Cofactor for several antioxidant enzymes
- Regeneration of vitamins C and E
- Neutralization of free radicals produced by Phase I liver metabolism of chemical toxins
- One of approximately 7 liver Phase II reactions, which conjugate the activated intermediates produced by Phase I to make them water soluble for excretion by the kidneys
- Transportation of mercury out of cells and the brain
- Regulation of cellular proliferation and apoptosis
- Vital to mitochondrial function and maintenance of mitochondrial DNA (mtDNA)
Facilitates excretion from cells (Hg), facilitates excretion from body (POPs, Hg) and directly neutralizes (POPs, many oxidative chemicals). Glutathione facilitates the plasma membrane transport of toxins
Low levels of glutathione and/or transferase activity are also associated with chronic exposure to chemical toxins and alcohol, cadmium exposure, AIDS/HIV, macular degeneration, Parkinson’s disease, and other neurodegenerative disorders.
Glutathione directly scavenges diverse oxidants: superoxide anion, hydroxyl radical, nitric oxide, and carbon radicals.
Another way glutathione protects cells from oxidants is through recycling of vitamins C and E as shown in
Glutathione depletion triggers apoptosis, although it is unclear whether it is mitochondrial or cytosol pools of GSH that are the determining factor.
Perhaps the best indicator of the importance of glutathione is that its cellular and mitochondrial levels directly are highly associated with health and longevity.
- Neurodegenerative disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, Friedreich’s ataxia)
- Pulmonary disease (COPD, asthma, and acute respiratory distress syndrome)
- Immune diseases (HIV, autoimmune disease)
- Cardiovascular diseases (hypertension, myocardial infarction, cholesterol oxidation)
- Chronic age-related diseases (cataracts, macular degeneration, hearing impairment, and glaucoma)
- Liver disease
- Cystic fibrosis
- Aging process itself
Higher glutathione levels were associated with higher levels of physical health, fewer illnesses, and higher levels of self-rated health.
This depletion of GSH also shows up as progressive loss of mitochondrial function due to accumulation of damage to mtDNA.17 The ability of animal species to protect their mtDNA is directly proportional to longevity.
The first, of course, is to decrease the need for glutathione, which means decreasing toxic load. The most obvious is limiting alcohol consumption (see my editorial in IMCJ 11.6).6,25 Less obvious is decreasing exposure to POPs, the primary source of which are conventionally grown foods
α-lipoic acid, supplementation of which increases mitochondrial glutathione levels
IV glutathione has a short half-life but has shown at least short-term efficacy in several diseases.
oral glutathione is unlikely to consistently elevate cellular levels.
N-acetylcysteine (NAC) is effective at raising levels.
For the rare patient who reacts to NAC, SAMe can be used.
almonds increase glutathione in smokers by 16% and decreases their DNA damage by 29%
Finally, there is meditation—practitioners have 20% higher levels of glutathione.35
Oral and transdermal liposomal glutathione show promise, but research is early.29
Direct administration and promotion of production of glutathione have been used effectively in a wide range of diseases: Parkinson’s, peripheral obstructive arterial disease, cystic fibrosis, emphysema, COPD, preterm infants’ autism, contrast-induced nephropathy, chronic otitis media, lead exposure, nail biting(!), nonalcoholic fatty liver disease, exercise-induced fatigue—the list is long and surprisingly diverse
Clearly, adequate availability of glutathione is critical for maintaining health, protecting the body from toxins, and promoting longevity. Fortunately, there is much we can do to optimize glutathione levels: primarily decrease toxin exposure (including alcohol) and promote production with regular consumption of whey or NAC.