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L-Glutathione: An Up-And-Coming Antioxidant

Published in Nutricuticals World - October 2000 Vol. 3, No. 8
by Wendy K. Barkin, JD; Theodore Hersh, MD, MACG
Thione International, Inc. - Atlanta, GA

Introduction

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 introduces this remarkable molecule and reviews its many positive effects on disease prevention and therapy.
 
 Free radicals are created during a cell’s normal metabolism, but countless more are produced from many other sources such as inflammatory reactions, infectious conditions, environmental pollutants, tobacco (including secondary smoke and chewing tobacco), exposure to ultraviolet sunlight, radiation therapy and even from “fatty meals”.  Free radicals affect cell membranes and other metabolic processes and thus, are contributors to premature aging and to many prevalent and chronic diseases, including cardiovascular disease, chronic obstructive pulmonary disease, immune disorders and neurodegenerative diseases.  Free radicals also alter DNA, thereby contributing to the genesis of many cancer malignancies.

 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 defensive mechanisms often fail to provide sufficient protection to the body due to either an  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 acts as the body’s key antioxidant, detoxificant and protectant.  It is the gatekeeper in the respiratory tract and lining of the gut and has multiple functions in disease prevention and in detoxification of chemicals and drugs. For example, through topical administration of GSH, the influenza virus can be prevented from entering and infecting cells in the oro-pharynx and may reduce the severity and the duration of the influenza virus.  Conversely, depletion of GSH in the body 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, suggesting too that GSH may be a key anti-aging factor.  However, GSH does not work alone.  To provide maximum beneficial effects against free radicals, GSH must work synergistically with other cellular enzymes and antioxidants such as glutathione peroxidase, selenium and vitamins C and E.  

For synergistic purposes, selenium, an antioxidant and anti-carcinogen, works as a cofactor for the enzyme glutathione peroxidase.  Since this enzyme cannot work properly without a cofactor, selenium plays a critical role in the synergistic process as it enables GSH and glutathione peroxidase to work together, synergistically, to obliterate oxidative stress.  However, during this process, GSH becomes oxidized and thus, must act in combination with other enzyme systems in order to be reduced back to its useful form so that it may renew its role as a free radical scavenger. The enzyme “glutathione reductase” assumes the pivotal task of converting the oxidized glutathione back to its antioxidant state.  Since an enzyme participates in a specific reaction but is never consumed, glutathione reductase is always available to restore oxidized glutathione in the body. 

 Vitamins C and E play a similar role.  While both vitamins act as protective antioxidants in the body, they too become oxidized in the process of neutralizing free radicals and must be restored to their antioxidant state. Specifically, vitamin C (ascorbic acid) becomes an ascorbate (a pro-oxidant) during the process and requires GSH to reduce it back to its antioxidant moiety, ascorbic acid.  Vitamin E (tocopherol) becomes tocopheryl (another pro-oxidant) and requires GSH and vitamin C working together to regenerate it back to its useful, antioxidant status.  Various studies, including photo-protection of the skin, have shown the value of using synergistically functioning antioxidants compared to the use of single antioxidants. Indeed, such studies have shown an increase in markers of free radical damage, including damage to DNA, when vitamin C accumulates as the free radical ascorbate.  GSH is pivotal in regenerating its cellular antioxidant partners!

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 many cells but especially in the liver 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!

GSH and Aging

There is widespread evidence from human and animal studies that a GSH deficiency in older subjects affects the aging process by shortening life span.  The converse is also 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 carnivorous individuals, have also been shown to have higher levels of glutathione in the body.  Low GSH levels place healthy, elderly subjects at a higher risk of disease because of their 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.  Antioxidant repletion has been shown to help prevent the vascular complications of diabetes and also improve control of blood sugar.  Antioxidants, by minimizing the oxidation of the plasma low density lipoproteins that carry the “bad” cholesterol, contribute to the prevention of atherosclerosis and development of cardiovascular diseases, including heart disease and strokes.

Clinical Entities with Low Levels of GSH

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. Viral diseases such as hepatitis C and HIV/AIDS are good examples of conditions where GSH may play a role by affecting viral levels.

Researchers at Stanford University have shown that restoring GSH levels will diminish HIV replication.  Clinically, sero-postive HIV individuals whose bodies were repleted with GSH were shown to have a longer survival than those HIV+ subjects whose GSH levels remained low.  In chronic hepatitis C, administration of GSH is 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 due to depletion of GSH. In light of GSH’s proven abilities in boosting the immune system, more clinical studies are needed to elucidate further on the beneficial effect of GSH in these diseases.
 
 Table 2 lists conditions known to be associated with a depletion of GSH.  Transient but significant decreases in GSH occur following strenuous exercise or after acetaminophen (Tylenol®) overdose.  In patients with chronic liver diseases and in those with HIV-AIDS whose GSH levels are very low, acetaminophen “overdose” may occur even at recommended daily dosages.  

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 by free radicals from ultra-violet radiation to the retinal pigment cells.  GSH levels in these individuals 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 consume not only fruits and vegetables for their dietary antioxidant content but to also supplement their diet with nutritional supplements.  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, a phenomenon which may be the basis for their extended life span. In one remarkable study, the lifespan of a mosquito was doubled when it was given GSH!

Summary

In summary, GSH plays a key role as the body’s prime antioxidant, protectant, detoxificant and anti-aging factor.  Not only does it participate as an antioxidant working synergistically with selenium and glutathione peroxidase in every cell, but it also serves to regenerate the “spent” dietary antioxidants, vitamins C and E.  GSH and other cellular antioxidants not only decrease in blood and tissue as we age, but are also low in many chronic diseases such as diabetes, hepatitis C, HIV/AIDS and common geriatric diseases.  Oxidative stress is a common culprit in many of these diseases, but repletion of GSH and its antioxidant partners can lessen oxidative stress.  While a diet high in fruits and vegetables will certainly help replete the body of these critical components, for those who do not consume sufficient dietary antioxidants or for those who are afflicted with a “free radical related disease,” nutritional supplements based on the GSH synergistic cycle may offer additional protection.

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