ComparativeGuide.com

Systemic Protector

Science is wonderfully equipped to answer the question "How?" but it gets terribly confused when you ask the question "Why?"
— Albert Einstein (1879-1955)
Nobel Laureate in Physics

Glutathione (GSH) is a simple tripeptide, a small protein that consists of three amino acids: glutamic acid, cysteine and glycine. Because of the chemical nature of sulfur-containing cysteine, glutathione effortlessly donates electrons, accounting for its powerful antioxidant properties (the ease by which an antioxidant donates electrons to quench free radicals is its defining prowess). Intracellular glutathione status is a sensitive indicator of cellular health and of the cell’s ability to resist toxic challenge. Severe glutathione depletion quickly leads to cell death; experimental glutathione depletion has been found to induce cellular apoptosis (suicide).^[i],[ii]

An important water-phase antioxidant, glutathione is an essential component in the Glutathione Peroxidase System, one of three pre-eminent free radical scavenging mechanisms in the cell. Glutathione peroxidase enzymes serve to detoxify peroxides, including hydrogen peroxide (H₂O₂), generated within cellular membranes and lipid-dense areas of the cell, in particular the mitochondrial membrane.

Guarding the Mitochondria

Glutathione depletion at the cellular level invokes extensive damage to the mitochondria, the energy centres of the cell. Depletion of mitochondrial glutathione, in fact, may be the ultimate factor determining a cell’s vulnerability to oxidative attack.^[iii] Nowhere is glutathione’s presence more vital than in these cellular “furnaces,” where a cascade of oxidation-reduction reactions complete the final steps in respiration—a process known as oxidative phosphorylation.

Throughout this process, electrons invariably escape and react with ambient oxygen to generate toxic free radicals.^[iv] It is estimated that two to five percent of the electrons that enter the mitochondrial “furnaces” are converted to oxygen free radicals,^[v] generating considerable oxidative stress for the cell.^[vi],[vii] These free radicals, like sparks from a fire, pose an immediate threat to other cellular components, such as the DNA, enzymes, structural proteins and lipids.

The cumulative damage wrought by oxygen and other free radical species is now recognized as a principal contributor to the degenerative disease process and the progressive loss of organ function, commonly recognized as aging.^[viii] Consequently, the cell is constantly challenged to seek out and destroy these free radical “sparks” before they can inflict lasting damage. Minimizing such oxidative assaults may prove to be the ultimate challenge of being alive. For this reason, the formidable reducing power of glutathione is of profound importance to the cell.

Regenerator and Synergist

Several other applications call on glutathione’s talents, including protection against exogenous (external) oxidative insults and as an agent in the various detoxification pathways of the body.

Glutathione helps regenerate other antioxidants, themselves depleted from their task of fending off free radical challenges. Glutathione-induced regeneration, in fact, may be the mechanism used by the cell to conserve the lipid-phase antioxidants, vitamin A, vitamin E and the carotenoids.^[ix] Recent investigations confirm that dietary vitamin C can protect against tissue damage resulting from glutathione depletion; likewise, supplementation with glutathione or its precursors can quickly replenish vitamin C deficiencies.^[x],[xi]

Thus, glutathione and ascorbic acid — two of the pre-eminent cellular antioxidants — are tightly linked: glutathione can conserve vitamin C and vitamin C can conserve glutathione. Together, these two antioxidant powerhouses protect the entire spectrum of biomolecules within the cell and facilitate the cell’s optimal performance.^[xii]

Detoxicant Supreme

We live in an increasingly dangerous world, as documented daily in the media. Yet, a far more immediate threat than the headlines of crime and the portents of war are the thousands of toxic substances that we breathe, consume in our foods and absorb through our skin everyday. From a single puff of cigarette smoke, with its trillions of free radicals, to the ubiquitous halocarbons found in plastics, pesticides, herbicides and dry cleaning solvents, we are chronically exposed. From the toxic effects of heavy metals, industrial solvents and pharmaceutical products^[xiii] — even the amalgams in our teeth — we are increasingly vulnerable. From birth to death, our bodies must prevail against an unrelenting assault from these exogenous toxic agents.

Fortunately, nature, in her wisdom, has evolved mechanisms through which the cells of our bodies can rid themselves of this toxic debris. Unfortunately, modern humankind, in its ignorance, has created such a flood of xenobiotics (materials foreign to the cell) that these protective systems are very frequently overwhelmed.

The liver is the organ most involved with the detoxification of xenobiotics, and it is the main repository for glutathione. In the specialized hepatocyte cells of the liver glutathione is conjugated (joined) to many of the toxic chemicals, including heavy metals, solvents and fat-soluble pesticides. Conjugation of a toxin with glutathione renders the toxin water-soluble and prepares it for excretion from the body via the kidneys and the bile. The power of glutathione in the conjugation and elimination of toxins is prodigious, accounting for up to 60% of all liver metabolites in the bile. While our cells use six different detoxification pathways, conjugation with glutathione appears to be the primary route employed.

The glutathione status of a cell … will perhaps turn out to be
the most accurate single indicator of the health of the cell.
That is, as glutathione levels go, so will go the fortunes of the cell.
                                                       — Parris Kidd, PhD

Glutathione Depletion — Exogenous Stresses

Because of its twin roles as a lipid-phase antioxidant and as a primary agent for detoxification, the demands on the cellular glutathione pool can be overwhelming, frequently leading to depletion.

Many pharmaceutical products are known to diminish glutathione from the liver, kidneys, heart and other tissues.^[xiv] For example, overuse of acetaminophen, a common over-the-counter painkiller, can deplete liver glutathione, rendering the organ vulnerable to acute damage from other exogenous toxins, such as alcohol.^[xv] (The combination of acetaminophen and alcohol can have serious consequences beyond a simple hangover.)

Many other exogenous factors have been shown to deplete glutathione stores, including a dietary deficiency of methionine (a glutathione precursor),^[xvi] ionizing radiation,[xvii] acute tissue injury,^{[xviii],[xix]} iron overload from hemochromatosis ^[xx] and excessive alcohol intake.^[xxi] Even strenuous aerobic exercise can rapidly deplete glutathione and other antioxidant stores from muscle tissue. For habitual exercisers and elite athletes, supplementation with glutathione precursors appears to be a prudent preventive measure. ^[xxii]

Probably more than for any single nutrient, lifestyle choices and their effects on glutathione status can prove fateful. A combination of negative lifestyle factors, including smoking, alcohol and drug abuse, prolonged emotional and physical stress, and unhealthy dietary choices, can summon a sustained oxidative assault to the body, depleting glutathione reserves to the point of distress. Beyond this, the body’s defences are quickly overwhelmed and free radical damage compounds, with grim consequences for the cell.

Here is how it appears to unfold: as tissue levels of glutathione and other antioxidants diminish, cells (usually those enduring the highest level of oxidative attack) begin to die. Zones of damaged tissue appear and begin to spread as free radical damage spreads outward, eventually encompassing other tissues and organs. This propagating wave of destruction is the manifestation of degenerative disease.

Glutathione Deficiency and Disease

According to several studies, glutathione depletion is a major contributory factor in diseases of the liver.^{[xxiii],[xxiv]} Shigesawa and co-workers^[xxv] documented marked decreases in plasma and liver glutathione levels in individuals with viral hepatitis, alcoholic and non-alcoholic liver disease. Studies of a number of pulmonary diseases, including obstructive pulmonary disease and pulmonary fibrosis, also note glutathione deficiencies.^[xxvi]

Other studies document a reduced capacity to detoxify free radicals in individuals with multiple sclerosis; the key factor appears to be a reduced level of the glutathione peroxidase enzyme system.^{[xxvii],[xxviii],[xxix]} Many of these studies note that supplementation with selenium significantly enhances glutathione peroxidase activity. One study, conducted on AIDS patients, found that supplementation with selenium provided a dramatic elevation of glutathione peroxidase activity in HIV-positive subjects.^[xxx] The likely mechanism is via selenium-induced activation of the glutathione peroxidase enzyme. Correlations also exist between depleted levels of glutathione, low glutathione peroxidase activity and the onset of atherosclerosis.

Glutathione depletion also dramatically inhibits immune functions^{[xxxi],[xxxii]} and increases vulnerability to infection. As well, chronic viral infections deplete glutathione stores. Patients diagnosed with hepatitis C and early HIV infection have been found to be deficient in blood glutathione.^{[xxxiii],[xxxiv]}

Depletion of glutathione stores is also implicated in the development of several neurological disorders. Because the brain is highly oxygenated and rich in polyunsaturated lipids, it is a fertile area for nutrient deficiency-induced free radical assault. Correlations between the level of lipid peroxidation in Parkinson’s disease^[xxxv] and glutathione status point toward glutathione depletion as a causative factor.^[xxxvi] Alzheimer’s patients show similar patterns of abnormally low glutathione.

Supplementation

While dietary glutathione is efficiently absorbed in the gut, the same may not be the case for nutritional supplementation. Oral dosing appears to raise glutathione levels, albeit with great variability between subjects. In one study, oral supplementation raised glutathione levels from two to five-fold.^[xxxvii] In another study, absorption of a single dose of 3,000 mg was negligible.^[xxxviii] Such variations raise concern about the efficacy of supplementing with glutathione itself. As a tripeptide (protein fragment), glutathione would tend to be hydrolyzed (broken down) during the digestive process. This leads some researchers to conclude that oral supplementation with glutathione does not appear to be cost effective in light of other methods available.^[xxxix]

Vitamin C Replenishes Glutathione

In contrast, daily supplementation with vitamin C appears sufficient to enhance and maintain good tissue glutathione levels, provided the necessary metabolic precursors for glutathione synthesis are also available. One double-blind study found that red blood cell glutathione levels increased nearly 50 percent when subjects were given 500 mg per day of ascorbic acid (vitamin C).^[xl] In patients with hereditary glutathione insufficiency, Jain and co-workers found vitamin C to be more effective and less costly in raising glutathione levels than N-acetyl cysteine, another well-known and effective glutathione booster.^[xli] Vitamin C appears to boost glutathione levels by helping the body manufacture it.

When given orally, S-adenosyl methionine (SAM-e) is also effective in raising red blood cell and liver glutathione.^[xlii] Unfortunately, while sold in the United States, SAM-e is not yet commercially available in Canada.

Cysteine, the metabolic precursor that most severely limits the synthesis of glutathione, is another nutrient that has proven very effective in boosting glutathione levels.^[xliii] Unfortunately, at high doses cysteine has been found to auto-oxidize, raising questions about its safety as an oral supplement.^[xliv] N-acetyl cysteine (NAC), however, is another story.

N-Acetyl Cysteine

N-Acetyl Cysteine (NAC) is a cysteine precursor that appears to avoid the problems of auto-oxidation attributed to cysteine. In the cell, NAC converts easily to cysteine, which, in turn, converts to glutathione. NAC is well absorbed in the intestinal tract and has been found to significantly boost glutathione levels in deficient subjects. As well, NAC demonstrates strong antioxidant, anti-mutagenic and anti-carcinogenic properties. Doses of up to 600 mg per day have proven to be an effective and safe means of optimizing tissue glutathione levels.^[xlv] Interestingly, while both NAC and vitamin C are effective in boosting tissue glutathione insufficiency, one study demonstrated that vitamin C was both more effective and less expensive than NAC.^[xlvi]

The use of NAC products has become increasingly popular as a means of optimizing tissue glutathione; however, caution against too much of a good thing is advised.^[xlvii] There is evidence that, at high doses (exceeding 1-2 g/day), NAC can also act as a pro-oxidant and begin contributing to the level of oxidative stress.^[xlviii]

Other Nutritional Factors

Several other nutrients play a vital role in glutathione metabolism through their participation in the glutathione peroxidase pathway. Selenium, essential for the activation of glutathione peroxidase, acts as a cofactor for the enzyme; its supplementation markedly boosts enzyme activity.

Selenium dosing significantly enhances the activity of glutathione peroxidase in HIV-positive individuals who exhibit abnormally low enzyme activity.^[xlix] As well, a study of patients with multiple sclerosis found that supplementation with high doses of selenium, vitamin C and vitamin E raised glutathione peroxidase activity five-fold, conferring a marked enhancement of cellular antioxidant status.^[l]

Other nutrients required for the optimal functioning of the glutathione peroxidase system are riboflavin (vitamin B₂) and niacin (vitamin B₃). Both nutrients are important for their role in the energy transfer reactions that are a part of this vital antioxidant enzyme system.

The combination of detoxification and protection from free radicals
results in glutathione being one of the most important anticarcinogens
and antioxidants in our cells—which means that a deficiency is devastating.
—Michael T Murray ND and Joseph Pizzorno
Encyclopedia of Natural Medicine, 1998

Implications

The scientific evidence supporting the importance of glutathione as an antioxidant and detoxicant is cogent. Few experts in the field seriously continue to doubt that free radical propagation, antioxidant depletion and the accumulation of endogenous toxins are involved in the degenerative disease process. Glutathione is the one nutrient that is active on all these fronts. For this reason, optimal tissue levels of glutathione are an absolute prerequisite for cellular health and longevity.