Pharmacologic Category Antioxidant & Cell Protectorant;1 Reducing Agent
General Information: Glutathione (GSH) is a peptide composed of the amino acids glutamine, cysteine, and glycine. Glutathione is water-soluble, a potent reducing agent, high-abundance and low-molecular-weight intracellular thiol, and antioxidant.
Glutathione catalyzes glutathione S-transferases (GST) and glutathione peroxidases (GPx). Thus, playing a role in detoxification by eliminating toxic electrophilic molecules and reactive peroxides. Glutathione plays a crucial role in a detoxification system that is fundamental in plants, mammals, and fungi.2
Aside from its detoxification role it is important for a variety of essential cellular reactions. Its presence in the glyoxalase system, is fundamental to DNA and RNA nucleotide reduction. Glutathione is also a constituent in the regulation of protein and gene expression, exchange reactions including thiol to disulfide ratios involve glutathione.3
Glutathione can exist intracellularly in either an oxidized (glutathione disulfide) or reduced (glutathione) molecular state. The ratio of reduced glutathione to glutathione disulfide has been shown to be critical in cell survival, this system is very tightly regulated.
Deficiency of glutathione puts the cell at risk for oxidative damage. An imbalance of glutathione is present in many pathologies including cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging.
Glutathione therapy: Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility1
- Intramuscular injection every other day of either 600 mg glutathione
- Glutathione therapy demonstrated a statistically significant positive effect on sperm motility, in particular on the percentage of forward motility, the kinetic parameters of the computerized analysis and on sperm morphology
Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease4
Administration: Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks
- Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.
Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial5
- glutathione prolongs pain-free walking distance, improvement of macrocirculatory parameters, improvement microcirculatory parameters
Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism6
- mice supplemented with (2.0%, 5 μL/g body weight)
- supplementation improved lipid metabolism and acidification in skeletal muscles during exercise less muscle fatigue
Mechanism of Action: Glutathione is an essential molecule required for detoxification. Glutathione acts by assisting the body’s machinery in the removal of harmful destructive oxygen containing molecules.
During the body’s normal functioning an excess of oxygen containing molecules are produced, these molecules are typically very reactive with other molecules they come in contact with. In modern biochemistry these are referred to as reactive O2 species.
Reactive O2 species molecules include peroxide (H2O2) and superoxide anions (O2 with unpaired electron) these molecules are very toxic to the cell. The toxicity can be explained by the tendency of these molecules to bind or destroy important biomolecules.
The body has a natural system to remove these reactive O2 species. These systems metabolize and scavenge for reactive oxygen species, in a controlled and precise fashion.
The system that removes these toxic reactive oxygen species includes a host of enzymes including four enzymes
- Glutathione peroxidase (GPX)- GPX detoxifies peroxides with glutathione acting as an electron donor in the reduction reaction, producing glutathione disulfide as an end product.
- is a 80 kDa protein that is composed of four identical subunits. It is expressed throughout the entire body, individual isoforms are present in specific tissues. When the body is in a state of excess oxidative stress the expression of this enzyme is induced. Abnormal expression has been associated with a wide variety of pathologies, including hepatitis,7 HIV,8 and a wide variety of cancers, including skin,9 kidney,10 bowel,11 and breast.12
- Glutathione reductase (GR)- catalyzes reduction of glutathione disulfide is by requires NADPH producing two glutathione molecules as an end product. GR is a member of the flavoprotein disulfide oxidoreductase family and exists as a dimer.3 Expression of GR is upregulated during periods of increased oxidative stress, to prepare for reactive oxygen species removal. The level at which regulation takes place is at the transcriptional level as well as at the post-translational level. Down regulation of GR production and activity are thought to be associated with cancer and aging.4
- Catalase- is involved in detoxification of reactive oxygen species.
- Superoxide dismutase (SOD)- is involved in the removal of superoxide species.
Parkinson’s disease: Glutathione is present in millimolar concentrations throughout brain tissue.13 Oxidative stress and tissue damage can occur at a greater rate in the brain when compared to other tissues.14 Glutathione homeostasis disruption may lead to oxidative stress in the brain, leading to disease states including Parkinson’s disease. Parkinson’s disease affects 1% of individuals over the age of 65, symptoms include impaired motor function, cognitive function and neurodegeneration.15 The disease stems from the chronic-age-related degradation of dopaminergic neurons.16 Parkinson’s disease is characterized dopamine deficiency. During metabolism of dopamine reactive oxygen species are generated including H2O2.
Removal of reactive oxygen species by glutathione involving pathways might reduce incidence of Parkinson’s disease. This assumption is based on the fact that reactive oxygen species are in high concentration, while glutathione is present in low concentration in Parkinson disease affected neurons.1718 In theory, one study demonstrated that selective damage to the neurons and glutathione depletion may lead to progression of the disease.19 It is thought that restoring glutathione levels may halt the progression of Parkinson’s disease. Clinical studies involving glutathione and Parkinson’s disease patients show improvements in patients following administration of glutathione.20 It is unknown whether systemic reductive agents, that can transcend the blood brain barrier, given for a prolonged period would be an effective preventive treatment for Parkinson’s disease.
Liver disease: Increased intracellular concentration of glutathione in liver are present with increased detoxification processes.
Dysfunction in glutathione synthesis and molecular breakdown can impair the functions of the liver and sometimes more seriously be lethal. Precursor sulfur containing amino acids are important to maintain intracellular glutathione in the liver. These amino acids must be present in the diet. Lower than normal glutathione levels are present in many disease states including alcoholism. Mitochondrial glutathione stores are insufficient due to the oxidative stress of alcohol Reactive oxygen species can cause damage that, when left unchecked by repair mechanisms, may ultimately lead to cell death and cirrhosis of the liver.
Abnormalities that cause reduced levels of glutathione in the mitochondria also inactivate certain mitochondrial transport proteins.21 Thus, when cytosolic glutathione accumulation occurs in associative inability to transport glutathione to the inner mitochondria is also present. This is due to chronic exposure to ethanol. Glutathione depletion can increase sensitivity of liver cells to the oxidative effects of cytokines including tumor necrosis factor.22
Aging: There has been much conjecture and speculation discerning the plausible correlation between the generation of reactive oxygen species and the longevity of an organism.
The natural mechanism for detoxification and protection from damage due to reactive oxygen species has been provided through natural selection. These systems protect cells from oxidative stress.
However, the natural system is imperfect and efficient at protecting the body for long periods of time.
The system provided enables organisms to reproduce before incurring oxidative damage. After reproduction excessive damage occurs and leads to the death of the organism. This is due to the fact that natural selection only affects organisms that reproduce, screening only for detoxification systems that enable reproduction.
Due to the aforementioned facts deterioration of the body’s natural systems to protect from reactive oxygen species is apparent throughout lifespan of an organism. Throughout the lifespan damage accumulates and becomes so excessive that the cellular machinery is unable to function. However, because there has been sufficient time for the organism to reproduce a selective advantage is not present.
Any or all of the following natural detoxification molecules can contribute to protection against reactive oxygen species: water soluble radical scavengers including GSH, ascorbate or urate; lipid soluble scavengers, α-tocopherol, γ-tocopherol, flavonoids, carotenoids, ubiquinol; enzymatic scavengers such as SOD, catalase and GPx and some GSTs; small molecule thiol-rich anti-oxidants such as thioredoxin and metallothionein; the enzymes that maintain small molecule anti-oxidants in a reduced state, thioredoxin reductase, GR, dehydroascorbate reductase, the glyoxalase system; the complement of enzymes that maintain a reduced cellular environment including glucose-6-phosphate dehydrogenase, in part responsible for maintaining levels of NADPH. The functional redundancy and cooperative interactions between this collection of defense pathways illustrates just how critical protection against reactive oxygen species is to survival.
It is therefore important for intelligent organisms to assist detoxification pathways present in the body.
Who should not take this medicine? Taking glutathione or its precursors in reasonable amounts appears to be quite safe, although it should be avoided in people with milk protein allergies and in those who have received an organ transplant. Pregnancy and breast-feeding: Not enough is known about the use of glutathione during pregnancy and breast-feeding. Stay on the safe side and avoid use.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
What are some possible side effects of this medicine? Taking glutathione long-term has been linked to lower zinc levels.
How should I store this medicine? Keep this medicine in a refrigerator between 35°F to 46°F (2°C - 8°C). Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
General statements: Do not share or take any one else's medicine. Talk with your healthcare provider before starting any new medicine, including over-the-counter, natural products, or vitamins. This patient information summarizes the most important information about your medication; if you would like more information, talk with your doctor.
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