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L-Glutathione: The Body's Key Antioxidant
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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