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Glutathione (GSH) |
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Date: 09/01/2002 |
The following monograph includes a general summary overview of Glutathione (GSH) followed by a very detailed, technical overview.
Glutathione is considered to be the most powerful, most versatile, and most important of the body's self-generated antioxidants. Among glutathione's many important properties are:
1) Is found in almost all living cells. The liver, spleen, kidneys, pancreas, and the lens and cornea, have the highest concentrations in the body.
2) It is a powerful antioxidant and thus neutralizes free radicals and prevents their formation
3) Important role in immune function via white blood cell production and is one of the most potent anti-viral agents known
4) It is one of the strongest anti-cancer agents manufactured by the body,
5) Glutathione is able to reduce oxidized Vitamin C and Vitamin E back to their unoxidized state,
6) It is used by the liver to detoxify many toxins including formaldehyde, acetaminophen, benzpyrene and many other compounds and plays a key role in Phase I and Phase II detoxification reactions
7) It is an antioxidant necessary for the protection of proteins; is involved in nucleic acid synthesis and plays a role in DNA repair,
8) It maintains the cellular redox potential
9) Glutathione levels decrease with age. It is involved in cellular differentiation and slows the aging process
10) Protects the integrity of red blood cells
11) Glutathione is involved in maintaining normal brain function.
· Glutathione is synthesized in the body from 3 amino acids: Cysteine, glutamine and glycine. Cysteine is one of the sulfur containing amino acids used for the synthesis of glutathione, which is very critical in detoxification. N Acetyl Cysteine (NAC) is the rate limiting amino acid for the production of glutathione within the cells of the body, has mucolytic properties, and is a powerful antioxidant and detoxifier. Some research indicates that NAC is more readily absorbed into certain cells of the body than glutathione and is therefore an excellent synergist with glutathione. The thiol group is the active part of the molecule which serves as a reducing agent to prevent oxidation of tissues.
· Reduced Glutathione: glutathione acts as one of the major detoxifiers in the body, but it must be in the reduced form to work properly. Sometimes glutathione will be listed on the label of a product, however it wont be specifically listed as being reduced. The unreduced form is much cheaper and isn’t metabolically active. Riboflavin, niacinamide, selenium, lipoic acid and glutathione reductase are all essential cofactors for generating reduced glutathione. Once the cysteine moieties become oxidized, they combine to form cystine. Cystine taken by itself is poorly absorbed.
· Glutathione peroxidase is another compound which is involved in detoxification against peroxides and other xenobiotics. It is synthesized from selenium and cysteine.
· Detoxification
o Heavy metal toxicity including mercury, lead, arsenic and cadmium:
o Common toxins that glutathione may help protect against are car exhaust, cigarette smoke, aspirin and alcohol (Marz, p. 78, 1997)
o Pesticide and industrial chemical exposure
o Steroids
o Bacterial toxins (Clostridia difficile)
o Pharmaceuticals (very long list that need to be detoxified by the liver) (Marz, p. 79, 1997)
· Immune enhancement: 1-3 g q.d. This is especially effective against clostridium in the GI. It helps prevent translocation.
· Psoriasis
· Diabetes mellitus: Especially in ketosis as DM patients will generally excrete increased amounts of sulfur containing amino acids.
· Liver disease including cirrhosis and fatty liver disease caused by alcohol: Studies show mild effects at large doses
· Ulcers intestinal or stomach: In patients with stomach ulcers low levels of GSH have been found.
· Aspirin or phenacetin overdose (useful for rheumatoid arthritis patients or chronic pain sufferers on 8 or more aspirin/day)
· Hematological conditions: myelofibrosis, acute leukemia, chronic myelocytic leukemia, lymphoma, polycythemia vera
· Alcoholism
· Before ionizing radiation therapy
· Cataracts
· Parkinson's disease, Alzheimers, ALS, MS and other neurologic conditions including Autism/Pervasive Developmental Delay
· Chronic kidney failure
Note: Some therapeutics for glutathione can use cysteine, which is considerably less expensive. There are some inborn errors in metabolism that may require glutathione directly. Oral supplementation of glutathione does not necessarily raise tissue levels of glutathione in all cases however and some medical conditions require direct intravenous administration of reduced glutathione.
Other supplements such as vitamin C, selenium and N-acetyl cysteine may have a more significant effect at actually raising glutathione levels in the liver and other tissues. Certain labs can assess glutathione status directly or indirectly.
• RDA: non essential
• Average intake in the U.S.: 5-100mg/day
• Via cysteine, which is very difficult to measure
• yogurt, granola, duck, oatmeal flakes, toasted wheat germ, cottage cheese
• none known
Glutathione, Reduced (GSH): Technical Monograph
Alternative Medicine Review -
Volume 6, Number 6, Decemeber 2001
Introduction
Reduced
glutathione, most commonly called glutathione or GSH, is a relatively small
molecule ubiquitous in living systems.1-3 Occurring naturally in all
human cells, GSH is a water-phase orthomolecule. Its intracellular depletion
ultimately results in cell death and its clinical relevance has been researched
for decades.4
GSH is the smallest
intracellular thiol (SH) molecule. Its high electron-donating capacity (high
negative redox potential) combined with high intracellular concentration
(millimolar levels) generate great reducing power.2 This
characteristic underlies its potent antioxidant action and enzyme cofactor
properties, and supports a complex thiol-exchange system, which hierarchically
regulates cell activity.
GSH levels in human tissues normally range from 0.1 to 10 millimolar (mM), most concentrated in the liver (up to 10 mM) and in the spleen, kidney, lens, erythrocytes, and leukocytes.5 Plasma concentration is in the micromolar range (approx. 4.5 µM).6 Oxidative stressors that can deplete GSH include ultraviolet and other radiation;7 viral infections;2,8 environmental toxins, household chemicals, and heavy metals;2 surgery, inflammation, burns, septic shock;9,10 and dietary deficiencies of GSH precursors and enzyme cofactors.11
Biochemistry and Metabolism
Reduced glutathione
(GSH) is a linear tripeptide of L-glutamine, L-cysteine, and glycine.
Technically N-L-gamma-glutamyl-cysteinyl glycine or L-glutathione, the molecule
has a sulfhydryl (SH) group on the cysteinyl portion, which accounts for its
strong electron-donating character. As electrons are lost the molecule becomes
oxidized, and two such molecules become linked (dimerized) by a disulfide
bridge to form glutathione disulfide or oxidized glutathione (GSSG). This
linkage is reversible upon re-reduction. GSH is under tight homeostatic control
both intracellularly and extracellularly.2 A dynamic balance is
maintained between GSH synthesis, its recycling from GSSG/oxidized glutathione,
and its utilization.
GSH synthesis
involves two closely linked, enzymatically controlled reactions that utilize
ATP.12-14 First cysteine and glutamate are combined, by
gamma-glutamyl cysteinyl synthetase. Second, GSH synthetase combines
gamma-glutamylcysteine with glycine to generate GSH. As GSH levels rise, they
self-limit further GSH synthesis; otherwise, cysteine availability is usually
rate-limiting. Fasting,11 protein-energy malnutrition, or other
dietary amino acid deficiencies15 limit GSH synthesis.
GSH recycling is
catalyzed by glutathione disulfide reductase, which uses reducing equivalents
from NADPH to reconvert GSSG to 2GSH. The reducing power of ascorbate helps
conserve systemic GSH.16 GSH is used as a cofactor by (1) multiple
peroxidase enzymes, to detoxify peroxides generated from oxygen radical attack
on biological molecules; (2) transhydrogenases, to reduce oxidized centers on
DNA, proteins, and other biomolecules; and (3) glutathione S-transferases (GST)
to conjugate GSH with endogenous substances (e.g., estrogens) and to exogenous
electrophiles (e.g., arene oxides, unsaturated carbonyls, organic halides), and
diverse xenobiotics. GST underactivity may increase risk for disease17
but paradoxically, some GSH conjugates can also be toxic.18,19
Direct attack by
free radical and other oxidative agents can also deplete GSH. The homeostatic
glutathione redox cycle attempts to keep GSH repleted as it is being consumed.21
Amounts available from foods are limited (less than 150 mg/day),5
and oxidative depletion can outpace synthesis.
The liver is the
largest GSH reservoir. The parenchymal cells synthesize GSH for P450
conjugation and numerous other metabolic requirements, then export GSH as a
systemic source of SH/reducing power.12 GSH is carried in the bile
to the intestinal luminal compartment. Epithelial tissues of the kidney
tubules, intestinal lining, and lung, have substantial P450 activity and modest
capacity to export GSH.13
GSH equivalents circulate in the blood predominantly as cystine, the oxidized and more stable form of cysteine. Cells import cystine from the blood, reconvert it to cysteine (likely using ascorbate as cofactor),16 and from it synthesize GSH. Conversely, inside the cell GSH helps re-reduce oxidized forms of other antioxidants such as ascorbate and alpha-tocopherol.16
Mechanisms of Action
GSH is an extremely
important cell protectant. It directly quenches reactive hydroxyl free
radicals, other oxygen-centered free radicals, and radical centers on DNA and
other biomolecules.2 GSH is a primary protectant of skin, lens,
cornea, and retina against radiation damage, and the biochemical foundation of
P450 detoxication in the liver, kidneys, lungs, intestinal epithelia, and other
organs.
GSH is the
essential cofactor for many enzymes which require thiol-reducing equivalents,
and helps keep redox-sensitive active sites on enzymes in the necessary reduced
state.20 Higher-order thiol cell systems the metallothioneins,
thioredoxins, and other redox regulator proteins are ultimately regulated by
GSH levels and the GSH/GSSG redox ratio. GSH/GSSG balance is crucial to
homeostasis, stabilizing the cellular biomolecular spectrum, and facilitating
cellular performance and survival.2,20
GSH and its metabolites also interface with energetics and neurotransmitter syntheses, through several prominent metabolic pathways.21 GSH availability down-regulates the pro-inflammatory potential of leukotrienes and other eicosanoids. Recently discovered S-nitroso metabolites, generated in vivo from GSH and NO (nitric oxide) further diversify GSH's impact on metabolism.
Clinical Indications: Proven Deficiency States
Glutathione status
is a highly sensitive indicator of cell functionality and viability. As
intracellular GSH becomes reduced, the cell's functionality is progressively
reduced until it dies. In humans, GSH depletion is linked to a number of
disease states.2,3,22
Inherited
Deficiencies:
Individuals with inherited deficiencies of the GSH-synthesizing enzymes exhibit
limited or generalized GSH deficiency,3,14,22 with hemolytic anemia,
spinocerebellar degeneration, peripheral neuropathy, myopathy, and
aminoaciduria, and often develop severe neurological complications in the
fourth decade of life. These conditions are not necessarily lethal because of
their incomplete penetrance; in some tissues GSH can attain 50 percent of
normal. In addition, some GSH is obtained from the diet. Low erythrocyte GSH
also manifests in hereditary nonspherocytic lymphocytic leukemia, and
glucose-6-phosphate dehydrogenase (G6PD) deficiency.
HIV
Infection/Immunity: Immune cell functionality and proliferation rely on adequate
intracellular GSH,2,8 and healthy humans with low lymphocyte GSH can
have low CD4 counts. HIV infection and sequelae feature systemic GSH depletion.12
Oxidative stress is elevated at all stages of HIV disease; HIV infection lowers
GSH in the plasma, erythrocytes, T-cells and other lymphocytes, and monocytes.23
Children with HIV also demonstrate low plasma GSH.8,222 The cachexia
and wasting of AIDS may be amenable to GSH repletion.12 HIV
depletion of lung epithelial lining fluid (ELF) glutathione may predispose to
opportunistic infections, and the ELF may be repleted using aerosolized GSH.12
Liver Cirrhosis,
Inflammation:
Plasma and erythrocyte GSH can be low in patients with cirrhosis6,24 or result
from acute or chronic alcohol intake.22 In nonalcoholic liver
disease, liver GSH can be abnormally low and GSSG high.25
Acetaminophen and other pharmaceutical or environmental xenobiotics can deplete
liver GSH. Viral hepatitis can deplete GSH, and in hepatitis C patients monocyte
GSH has been found to be depleted.26
Pulmonary
Disease:
GSH deficiency has been linked to various pulmonary diseases,3,12,22
including chronic obstructive pulmonary disease (COPD), acute respiratory
distress syndrome (ARDS), neonatal lung damage, and asthma. The lung is
particularly vulnerable to oxidative attack from inhalation of pure oxygen,
airborne toxins, and oxygen radical release by lung phagocytes. GSH in lung ELF
may be the first line of defense.
The GSH content of
ELF was found abnormally low in idiopathic pulmonary fibrosis, ARDS, and
HIV-positive patients.23 ARDS patients with sepsis had low GSH and
high GSSG in their ELF.12 GSH repletion can accelerate ARDS patient release
from intensive care.27 GSH in the ELF can be lifesaving for premature
infants. Pulmonary GSH levels have been found to be low in premature infants,12
and in perinatal hypoxia cases umbilical blood GSH has also been found to be
low.3 Newborns with low GSH in the ELF may be at higher risk of
chronic lung disease.12
Crohn's Disease,
Gastrointestinal Inflammation: Gastric mucosa of aged subjects can have low GSH,24
as can patients with gastritis and/or duodenal ulcer linked to Helicobacter
pylori infection.22 In Crohn's disease cases the affected ileal
zones were found to have low GSH and high GSSG, and GSH enzymes were altered.28
Circulation: Acute myocardial infarction
patients29 and men with familial coronary artery disease30
exhibit lowered GSH. Glutathione given i.v. prior to cardiopulmonary bypass
surgery favorably influenced postoperative renal function while improving
systemic arterial function.31
Infusion of GSH
into patients with atherosclerosis enhanced microvascular vasodilation in
response to acetylcholine, especially in subjects with baseline abnormal vessel
wall reactivity.30 Similar benefits were reported for the epicardial
coronary artery system.32 S-nitrosoglutathione also has platelet
anti-aggregation activity in humans, as reviewed in Prasad et al.30
The mechanism of vasodilation is suspected to be via glutathione's enhancement
of nitric oxide.
Metal
Storage/Wilson's Disease: In several copper-overloaded (Wilson's Disease) patients, hepatic GSH
was markedly lowered.2 This preliminary finding correlates with an
impressive body of animal data.
Pancreatic
Inflammation:
Plasma GSH was significantly lowered in chronic pancreatitis linked to alcohol
intake,33 and patients with acute pancreatitis responded well to
glutathione repletion.2
Diabetes: Subjects with impaired
glucose tolerance, including early hyperglycemics, had reduced blood GSH.34
In diabetics, the erythrocytes and platelets can be low in GSH.22,35
Mild to moderate exercise can help normalize GSH status in diabetics,22
although strenuous exercise can deplete GSH.36,37
Neurodegeneration/Central
Nervous System: A variety of neurodegenerative diseases manifest abnormally low GSH.2,3,22
In Alzheimer's a decrease in lymphoblast GSH has been reported. In Parkinson's
disease the substantia nigra becomes greatly depleted of GSH.
The threshold of
GSH depletion, below which the cell will usually die, is 70-80 percent.2,22
The mitochondria, with their high oxygen radical flux, are particularly
vulnerable.38 Mitochondrial failure has been specifically implicated
in retinal degeneration7 and in Parkinson's disease.39
Aging: The aging process is
associated with deterioration of GSH homeostasis. Plasma GSH trends lower while
GSSG becomes more elevated7 Limited data suggests higher GSH levels
correlate with better health, regardless of age, and that subjects with chronic
disease have poorer GSH status than those free of disease.12 Exercise training
can strengthen GSH homeostasis.37 With progressively more disease
states manifesting GSH deficiency, repletion is a viable preventive,
therapeutic, and anti-aging strategy.
Glutathione Repletion Strategies
Oral/I.V. Glutathione: Tradition holds that GSH is not systemically bioavailable when given by
mouth.40 However, copious data confirm it is efficiently absorbed
across the intestinal epithelium, by a specific uptake system.41,42
Catabolism of newly-absorbed GSH after it reaches the portal blood intact but
prior to its accessing the liver accounts for the paradoxical findings.43
Such breakdown of circulating GSH does not rule out its oral use for GI
conditions such as Crohn's Disease.28
Results from two
controlled trials seem to suggest oral GSH had no significant benefit, but do
not rule out benefit from high-dose GSH to depleted subjects.4,40 In
one trial, the plasma concentration was high-normal at baseline. In the second,
the dose administered (to cirrhosis patients), at 300 mg/day for 28 days, may
have been insufficient to replete liver GSH in the context of severe impairment
of biosynthesis.4
Perlmutter reported
case histories indicating success with GSH repletion in various
neurodegenerative diseases.44 He reported marked benefit from its
intravenous administration in Parkinson's, and successful oral application of
orthomolecular GSH precursors to cases of Alzheimer's, stroke, multiple
sclerosis, amyotrophic lateral sclerosis, and post-polio syndrome.
N-acetylcysteine: Cysteine availability most often limits GSH biosynthesis in vivo. One
orally bioavailable cysteine source is N-acetylcysteine (NAC). NAC is a potent
antioxidant with antimutagenic and anticarcinogenic properties, and an
established antidote for acetaminophen overdose known to deplete liver GSH.
Oral dosing with NAC supplants oral L-cysteine, which is highly unstable and
potentially toxic.45
Following its
intestinal absorption, NAC is converted to circulating cysteine and can
effectively replenish GSH in depleted patients.46 In HIV/AIDS,
plasma GSH and cysteine levels are often low. Two clinical trials, one of them
double-blind, reported NAC had clinical benefit.3 Administered
intravenously or as an infusion over 15-30 minutes, it can replete glutathione
in the ELF and improve lung function in patients with septic shock.10
In one trial on pulmonary disease, oral NAC at 1800 mg/day failed to increase
GSH.47
Alpha-Lipoic Acid (ALA): The antioxidant alpha-lipoic acid (ALA) is another effective GSH
repleter. Orally, it raises GSH levels in HIV patients,48 and is
extremely safe and well tolerated.49 ALA is a broad-spectrum, fat- and
water-phase antioxidant with potent electron-donating capacity, and has added
biochemical versatility as a Krebs cycle cofactor and transition metal
chelator. It is superior to NAC in being recyclable in vivo from its oxidized
form.
Methionine, Ascorbic Acid, Taurine: Oral L-methionine is a cysteine precursor but can
cause nausea and vomiting, whereas its activated counterpart S-adenosylmethione
(SAMe) is well tolerated. When given i.v. in high doses to cirrhotic patients,
SAMe repleted erythrocyte GSH.13 Ascorbate conserves intracellular
glutathione and probably is a redox GSH cofactor.16 Taurine is a
sulfur amino acid which, given orally, can raise the platelet aggregation
threshold and increase platelet GSH in healthy males.2
Other Methods of Glutathione: Repletion One synthetic cysteine delivery agent is
L-2-oxothiazolidine-4-carboxylate (OTC, Procysteine), which can be
enzymatically converted to cysteine within liver cells. Oral OTC is converted
to GSH in humans.12 Given intravenously to HIV patients, it
increased blood GSH levels after six weeks of treatment.50 In
patients with coronary artery disease, oral OTC markedly improved arterial
flow-mediated dilation.51
Glutathione esters have been heavily researched as potential oral delivery compounds but their long-term safety is in question. Their reported toxicity is perhaps attributable to metal impurities.3
Toxicity/Contraindications
GSH and other
thiols tend to be sensitive to redox-active minerals, and care should be taken
to omit these from therapeutic preparations. GSH use in cancer must be
approached with caution, since some tumors may utilize it intracellularly to
resist chemotherapy drugs.19
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