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L-Glutathione: The Body's Key Antioxidant and Defender

Published in Georgia Pharmacy Journal - June, 1999
by: Theodore Hersh, MD, MACG
Professor of Medicine, Emeritus, Emory University

To retaliate against toxic chemicals called free radicals, the body has a well-developed antioxidant system. The prime antioxidant is L-glutathione, known as GSH by the scientific community. This summary will introduce you to this remarkable molecule and its many positive effects on prevention and therapy.

Free radicals are created during a cell’s normal metabolism, but countless more are produced from many other sources including inflammatory reactions and infectious conditions, environmental pollutants in the air we breathe, the tobacco we smoke and smoke inhaled from other smokers, as well as from chewing tobacco and after “fatty meals”. Free radicals are also created from exposure to ultraviolet sunlight, artificial radiation and radiation therapy. These free radicals alter DNA, causing mutations that lead to cancer, affect cell membranes and other metabolic processes. Free radicals may cause cell injury and thus are contributors to premature aging and to many prevalent and chronic diseases, including cardiovascular disease, emphysema, various cancers, immune disorders, arthritis, neurodogenerative diseases, HIV-AIDS and chronic hepatitis C, to name but a few.

Antioxidants scavenge and neutralize oxygen and other free radical species to a less toxic or non-toxic compound. While the human body has built-in antioxidant mechanisms to suppress uncontrolled free radicals, which may lead to cellular damage and cell death, these mechanisms may fail due to a combination of overwhelming production of free radicals or a depletion of critical compounds used by the body’s antioxidant defenses. An overabundance of free radicals or the decrease of antioxidant protectants in the body can lead to a condition known as “oxidative stress”.

Glutathione, a tripeptide composed of glutamate, cysteine and glycine, is the most important and ubiquitous low molecular weight thiol compound. Working intra and extra-cellularly in its reduced form, glutathione is the body’s key antioxidant and protectant. It is the gatekeeper in the respiratory tract and lining of the gut. GSH has multiple functions in disease prevention and in detoxification of chemicals and drugs while its depletion is associated with increased risks of toxicity and disease. GSH levels inside the cells must be maintained in order to have healthy cells and a strong defense system. Cells die without adequate levels of glutathione. However, to provide its beneficial effects, GSH must work synergistically with the other cellular enzymes and antioxidants, including selenium and vitamins C and E, to neutralize the free radicals and thereby prevent or diminish “oxidative stress”. Selenium plays a role as a cofactor for the enzyme glutathione peroxidase, while glutathione reductase assists in converting the oxidized glutathione back to its antioxidant status.

Glutathione is present in most plant and animal tissues from which the bulk of the human diet is derived. It is available from the diet because the cells of the gastrointestinal tract are able to transport GSH intact, although GSH may also be synthesized by most cells from its constituent amino acids. Dietary GSH is supplied primarily from fruits, vegetables, liver, meats, fowl and fish. Chicken is very high in GSH content and this may truly account for “chicken soup’s” legendary medicinal attributes!

Since L-glutathione is itself oxidized in its reactions with free radicals, it must act in combination with other enzyme systems in order to be reduced so that it may renew its role as a free radical scavenger. Similarly, the antioxidant vitamin C (ascorbic acid) becomes an ascorbate (a pro-oxidant) and requires GSH to reduce it to its antioxidant moiety, ascorbic acid. Various studies, including photo-protection of the skin, have shown the value of using synergistically functioning antioxidants compared to the use of only a single antioxidant. GSH is pivotal in regenerating its cellular antioxidant partners.

GSH & AGING

There is widespread evidence from human and animal studies that GSH deficiency in older subjects affects the aging process by shortening life span. The converse is true: GSH repletion increases longevity! Various clinical studies have documented that healthy, elderly subjects have lower GSH levels than their younger counterparts. Vegetarians whose life span is reportedly longer than their carnivorous neighbors have also been shown to have higher blood GSH levels. Low GSH levels place healthy, elderly subjects at a higher risk of disease because of the decreased ability to deal with conditions that increase toxic free radicals. Oxidative stress also occurs when the body has a decreased capacity to maintain its usual defensive and detoxifying activities, where GSH is the prime defender. Studies in various other diseases associated with a decreased life span, like diabetes, reveal a cellular depletion of GSH and concurrent higher levels of free radicals. Investigators at Duke also point to the value of antioxidant repletion in preventing the vascular complications of diabetes. Ms. Brewer’s excellent article on antioxidants in the March issue of this Journal already stressed the importance of nutrition and antioxidant supplementation in prevention of disease. Well described was the minimizing of the oxidation of the low density lipoproteins that carry the bad cholesterol to help in the prevention of atherosclerosis and development of coronary heart disease.

Low GSH Clinical Entities

There are a number of clinical conditions associated with low GSH levels in blood and in affected tissues. Studies reveal that repletion with GSH may be beneficial in at least decreasing or ameliorating the progress of the disease. As examples of a couple of viral diseases, HIV-AIDS and chronic hepatitis C, GSH may play its role by affecting the viral levels. Researchers at Stanford University have shown that restoring GSH levels will diminish HIV replication. Clinically these sero-postive HIV individuals were shown to have a longer survival than those HIV+ subjects whose GSH levels remained low. In chronic hepatitis C, administration of GSH is also associated with a decrease in the viral load and an improvement of the patient’s liver tests, the serum transaminases. Indeed, the so-called interferon resistance to therapy in hepatitis C may be at least in part due to depletion of GSH. More clinical studies are needed to elucidate further on the beneficial effect of GSH in these diseases, as GSH helps boost the immune system.

The adjacent table lists conditions shown to be associated with GSH depletion. Each could be the subject of its own review, yet mention should be made of decreases in GSH such as following strenuous exercise or after acetaminophen (Tylenol®) overdose. Indeed, in patients with chronic liver diseases and with HIV-AIDS whose GSH levels are low, acetaminophen “overdose” may occur even at so called recommended daily dosages. Thus, there patients need to be so alerted and encouraged to curtail use of this drug.

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases may result from free radical damage to those specific areas of the brain responsible for causing these geriatric conditions. Many of these patients have low GSH levels. Recent studies are suggesting that antioxidants may stop their clinical progression. Likewise, macular degeneration, the leading cause of blindness in adults, may be caused from free radicals of ultra-violet radiation to the retinal pigment cells. GSH levels have also been demonstrated to be low. It is vital for those with macular degeneration to be protected by sunglasses from high UV exposure and to be consuming not only fruits and vegetables for their GSH and other antioxidant contents but also to assure its supplementation. Clinical studies will be required to prove these tenets but at least today we can and should initiate preventive measures. Centenarians appear to maintain their levels of GSH and that indeed may contribute to their long and healthy life! We will be learning more about the clinical value of antioxidants and particularly the ever present glutathione.

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