Glutathione is a tripeptide found in most cells, in surprisingly high levels such as in the same concentration as potassium, cholesterol, and glucose in some cells. High metabolic activity is required to produce glutathione, such high level may underline its importance.

Glutathione is exclusively produced in cytosol and pumped into mitochondria. Glutathione can exist in 2 states: Reduced GSH and oxidized GSSG, oxidized is actually reduced glutathiones bound at sulfur atoms, the ratio of GSH to GSSG determines cell redox status of cells. Resting healthy cells typically will have a ratio of >100 dropping to 1 to 10 in cells exposed to oxidant stress. Glutathione is also a thiol buffer maintaining sulfhydryl group of many proteins in reduced forms.

GHS is available in 3 ways: de novo synthesis via catalyzation process by enzymes glutamate cysteine ligase and glutathione synthetase requiring ATP; regeneration of oxidized GSSG to reduced GSH by glutathione reductase requiring NADPH; and recycling of cysteine from conjugated glutathione via GGTP requiring NADPH. All 3 ways require energy, rate of synthesis, regeneration, and recycling is determined by 3 factors: de novo glutathione synthesis is controlled by cellular levels of amino acid cysteine, availability of which is the rate limiting step; GCL activity is partially regulated by GSH feedback inhibition; and if GSH depletion is due to oxidative stress, inflammation, or exposure to xenobiotics de novo synthesis of GSH is upregulated by increasing availability of cysteine via recycling of GSSG.

Glutathione plays critical roles in detoxification and inflammation which can’t be overstated such as crucial roles in shielding cellular macromolecules from endogenous and exogenous reactive oxygen and nitrogen species, while directly quenching some free radicals, and directly dealing with causes of oxidative stress including mercury and POPs, while being vital to mitochondrial function and maintenance of mitochondrial DNA. It is a cofactor for several antioxidant enzymes, and regeneration of vitamins C and E; and regulator of cellular proliferation and apoptosis; being involved in detoxification of xenobiotic and endogenous compounds by facilitating excretion from Hg cells, facilitating excretion from the body, and directly neutralizing POPs and many oxidative chemicals. Plasma membrane transportation of toxins is facilitated by at least 4 different mechanisms the most important being formation of glutathione S-conjugates.

Low levels of glutathione and/or transferase activity are associated with chronic exposure to chemical toxins, alcohol, AIDS/HIV, cadmium exposure, Parkinson’s disease, macular degeneration, and other neurodegenerative disorders.

Glutathione scavenges diverse oxidants such as nitric oxide, superoxide anion, carbon radicals, and hydroxyl radicals while catalytically detoxifying lipid peroxides, hydroperoxides, and peroxynitrites; and protects cells from oxidants by recycling vitamins C and E.

Accumulation if GSSG due to oxidative stress is toxic to cells, inducing apoptosis by activation of SAPK/MAPK pathways. Depletion of glutathione triggers apoptosis, it is unclear whether mitochondrial or cytosol pools of GSH are determining factors. Mitochondrial and cellular levels of glutathione are directly highly associated with health and longevity.

Depletion of GSH is strongly implicated in many chronic degenerative diseases such as HIV, autoimmune disease, hypertension, cholesterol oxidation, myocardial infarction, glaucoma, hearing impairment, cataracts, macular degeneration, liver disease, cystic fibrosis, COPD, acute respiratory distress syndrome, asthma, many neurodegenerative disorders, and the aging process itself. Higher levels are associated with higher levels of physical health, and fewer illnesses. GSH status has been found to be parallel to telomerase activity which is an indicator of lifespan. Depletion can also show up as progressive loss of mitochondrial function due to accumulation of damage to mtDNA, ability to protect mtDNA is directly proportional to longevity.

Gamma glutamyl transferase is upregulated in proportion to need for glutathione, providing rate limiting cysteine through catabolic salvage pathways such as for detoxification of POPs. Increases correlate with many disease such as cancers, diabetes, metabolic syndrome, atherosclerosis, hypertension, and fatty liver. Elevations within “normal” ranges may have a 20 fold increase risk of diabetes, and association with doubling the risk of all cause mortality.

Many researchers are investigating ways to increase levels at intracellular and intramitochondrial levels and have found several effective strategies including decreasing the need for it by decreasing toxic loads by limiting alcohol consumption, exposure to conventionally grown foods, providing other antioxidants to help decrease oxidative stress, and directly administering glutathione which can be done orally, topically, intranasally, intravenously, in nebulized form, or providing nutrients to promote glutathione production.

Administered intravenously, inhaled, and ingested intranasally increases systemic levels, IV glutathione has a short half life but has shown short term efficacy in several diseases. Oral administration of glutathione has been controversial with more studies showing it does not increase RBC glutathione and a few showing efficacy. Unmodified oral glutathione is unlikely to consistently increases cellular levels; transdermal and oral liposomal glutathione early research shows promise.

Cysteine availability is the rate limiting step in de novo production, oral cysteine does not make it through the digestive tract, supplemental cysteine in the form of whey or NAC is effective at elevating levels. 1000 mg/d of NAC has been shown to increase levels, SAMe can be used for those who have reactions to NAC. Do not use methionine as it increases homocysteine. NAC supplements of 600 mg/d for 4 weeks was shown to decrease GGT by 25% suggesting increasing de novo synthesis lowers the need for GGT recycling.  

Non-supplemental solutions of 500mL of alcohol free beer per day can raise RBC glutathione by 29%; 83 g/d of almonds can increase glutathione levels by 16% and decreases DNA damage by 29%; and practitioners of meditation have been found to have 20% higher levels of glutathione. Foods that contain glutathione tend to be sulfur rich foods containing cysteine, glycine, methionine, and glutamate amino acids such as dietary proteins including fish, beef, poultry, whey, avocados, nuts, mushrooms,and cruciferous vegetable such as kale, mustard greens, broccoli, brussels sprouts, watercress, cauliflower, turmeric, cardamom, cinnamon, tomato, oranges, strawberries, and grapefruit, as well as increase methylation nutrients such as vitamins B6, B12, folate, and selenium. Sleep is also important to the body’s ability to produce adequate amounts of glutathione, and exercise boosts its production.

Direct administration and promotion of glutathione production has been used effectively in a wide range of diseases from peripheral obstructive arterial disease and emphysema to chronic otitis media and nonalcoholic fatty liver disease, the list is fairly long and diverse. Adequate availability of glutathione is critical for maintaining health, protection from toxins, and promoting longevity making it important to optimize levels by decreasing toxin exposure which includes alcohol, and promote production with regular consumption of NAC.

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