This antioxidant, made from the combination of three amino acids cysteine, glutamate, and glycine, forms part of the powerful natural antioxidant glutathione peroxidase which is found in our cells. Glutathione peroxidase plays a variety of roles in cells, including DNA synthesis and repair, metabolism of toxins and carcinogens, enhancement of the immune system, and prevention of fat oxidation. However, glutathione is predominantly known as an antioxidant protecting our cells from damage caused by the free radical hydrogen peroxide. Glutathione also helps the other antioxidants in cells stay in their active form. Brain glutathione levels have been found to be lower in patients with Parkinson’s disease.

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Glutathione in our diet
Glutathione is found in foods, particularly fruits, vegetables and meats. Cyanohydroxybutene, a chemical found in broccoli, cauliflower, brussels sprouts and cabbage, is also thought to increase glutathione levels. Various herbs -- for instance cinnamon and  cardomom -- have compounds that can restore healthy levels of glutathione. Although glutathione is available in pill form over the counter, its utilization by the body is questionable since we don’t know if it can easily enter cells, even after it is absorbed in the bloodstream.

Supplements that help make glutathione
Certain nutrients help raise tissue levels of glutathione including acetylcysteine, methyl donors, alpha lipoic acid, polyphenols such as Pycnogenol, and vitamin B12.
     An excellent review article in the April 1998 issue of Alternative Medicine Reviews summarizes the known effects of acetylcysteine. The author writes, “N-acetylcysteine is an excellent source of sulfhydryl groups, and is converted in the body into metabolites capable of stimulating glutathione synthesis, promoting detoxification, and acting directly as a free radical scavenger. Administration of acetylcysteine has historically been as a mucolytic [mucus dissolving] agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased glutathione or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking.”

Glutathione busters
The frequent use of acetaminophen (Tylenol) depletes glutathione peroxidase levels.

Recommendations
There appears to be a feedback inhibition in glutathione synthesis. This means that if glutathione levels are excessively increased with the help of nutrients, the body may decrease its natural production.
     Glutathione is sold in pills with dosages ranging from 50 to 250 mg. Glutathione is a promising antioxidant. However, due to the inconsistencies in the medical literature on the ability of glutathione to enter tissues and cells when ingested orally, and the possibility of feedback inhibition, I can’t recommend supplementation with this nutrient until more information is published. I do think Acetylcysteine is a good alternative since it can help make more glutathione.

What happens if Glutathione levels are low?
Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the worsening of many diseases including Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, and diabetes.

Glutathione and Aging
The concentration of glutathione declines with age and in some age-related diseases.

Glutathione and HIV
AIDS: Several recent scientific papers have found a correlation between glutathione levels and viral activity for hepatitis B and C. When viral load increases, glutathione decreases. Researchers from Germany report that adding NAC (N-acetyl cysteine) to HBV producing cells lines can reduce hepatitis viral load 50 fold. Glutathione is used by the liver to help break down toxins. Patients who have chronic infection for more than 90 days should ask their physicians to check their Glutathione levels. An amino acid, L-Glutamine, can be used with Alpha Lipoic Acid and NAC to increase Glutathione levels. Chlorophyll also offers benefits to people with hepatitis and other infections.

Glutathione and Radon Exposure
Gene variants that result in decreased amounts of glutathione -S- transferase M1 (GSTM1), may raise the risk of lung cancer related to radon exposure. Such variants also seem to increase the cancer-causing effect of secondhand smoke. Both radon and secondhand smoke are thought to promote carcinogenesis through the formation of reactive oxygen species. GSTM1 is an enzyme that detoxifies these species and their derivatives.

Glutathione Research Update
The effect of polyphenolic extract from pine bark, Pycnogenol on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD).
Redox Rep. 2006;11(4):163-72. Department of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic.
Attention deficit hyperactivity disorder (ADHD) belongs to the neurodevelopmental disorders characterized by impulsivity, distractibility and hyperactivity. In the pathogenesis of ADHD genetic and non-genetic factors play an important role. It is assumed that one of non-genetic factors should be oxidative stress. Pycnogenol, an extract from the pine bark, consists of bioflavonoids, catechins, procyanidins and phenolic acids. Pycnogenol acts as powerful antioxidant, chelating agent; it stimulates the activities of some enzymes, like SOD, eNOS, and exhibits other biological activities. AIM: The aim of this randomized, double-blind, placebo-controlled trial was to investigate the influence of administered Pycnogenol or placebo on the level of reduced glutathione and oxidized glutathione in children suffering from ADHD and on total antioxidant status (TAS). This is the first investigation of the redox glutathione state in relation to ADHD. RESULTS: One month of Pycnogenol administration (1 mg/kg body weight/day) caused a significant decrease in oxidized glutathione and a highly significant increase in glutathione levels as well as improvement of glutathione   / oxidized glutathione ratio in comparison to a group of patients taking a placebo. TAS in children with ADHD was decreased in comparison with reference values. Pycnogenol administration normalizes TAS of ADHD children.

Polyphenols and glutathione synthesis regulation.
Am J Clin Nutr. 2005 Jan;81(1 Suppl):277S-283S.
Polyphenols in food plants are a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention. In vitro cell culture experiments have shown that polyphenols possess antioxidant properties, and it is thought that these activities account for disease-preventing effects of diets high in polyphenols. However, polyphenols may be regarded as xenobiotics by animal cells and are to some extent treated as such, ie, they interact with phase I and phase II enzyme systems. We recently showed that dietary plant polyphenols, namely, the flavonoids, modulate expression of an important enzyme in both cellular antioxidant defenses and detoxification of xenobiotics, ie, gamma-glutamylcysteine synthetase. This enzyme is rate limiting in the synthesis of the most important endogenous antioxidant in cells, glutathione. We showed in vitro that flavonoids increase expression of gamma-glutamylcysteine synthetase and, by using a unique transgenic reporter mouse strain, we showed increased expression in vivo, with a concomitant increase in the intracellular glutathione concentrations in muscles. Because glutathione is important in redox regulation of transcription factors and enzymes for signal transduction, our results suggest that polyphenol-mediated regulation of glutathione alters cellular processes. Evidently, glutathione is important in many diseases, and regulation of intracellular glutathione concentrations may be one mechanism by which diet influences disease development. The aim of this review is to discuss some of the mechanisms involved in the glutathione-mediated, endogenous, cellular antioxidant defense system, how its possible modulation by dietary polyphenols such as flavonoids may influence disease development, and how it can be studied with in vivo imaging.

(R)-alpha-lipoic acid reverses the age-related loss in glutathione redox status in post-mitotic tissues: evidence for increased cysteine requirement for glutathione synthesis.
Arch Biochem Biophys. 2004 Mar 1;423(1):126-35.
Age-related depletion of glutathione levels and perturbations in its redox state may be especially deleterious to metabolically active tissues, such as the heart and brain. We examined the extent and the mechanisms underlying the potential age-related changes in cerebral and myocardial glutathione status in young and old F344 rats and whether administration of (R)-alpha-lipoic acid (LA) can reverse these changes. Our results show that glutathione /GSSG ratios in the aging heart and the brain declined by 58 and 66% relative to young controls, respectively. Despite a consistent loss in glutathione redox status in both tissues, only cerebral glutathione levels declined with age. Treating old rats with LA (40 mg/kg body wt; by i.p.) markedly increased tissue cysteine levels by 54% 12 h following treatment and subsequently restored the cerebral glutathione levels. Moreover, alpha lipoic acid improved the age-related changes in the tissue glutathione /GSSG ratios in both heart and the brain. These results demonstrate that LA is an effective agent to restore both the age-associated decline in thiol redox ratio as well as increase cerebral glutathione levels that otherwise decline with age.

Low blood glutathione levels in acute myocardial infarction.
Indian J Med Sci. 2003 Aug;57(8):335-7.
Although experimental studies have demonstrated that reduced glutathione (glutathione) is involved in cellular protection from deleterious effects of oxygen free radicals in ischaemia and reperfusion, there are controversial data on the correlation between levels of glutathione and the ischaemic process. AIM: The present study was planned to evaluate erythrocyte glutathione levels in patients with acute myocardial infarction (AMI). SETTING & DESIGN: Erythrocyte glutathione levels were determined in 22 patients with AMI and 15 age matched healthy volunteers served as control. MATERIAL & METHODS: Erythrocyte glutathione levels were measured by using Bentler in AMI and control patients. Also lipid profile was analyzed enzymatically in these subject. STATISTICS: The values were expressed as means +/- standard deviation (SD) and data from patients and controls was compared using student's 't'-test. Results and CONCLUSION: glutathione levels were significantly decreased in AMI as compared to control (p<0.001). Also, total cholesterol and triglycerides were higher is AMI subjects.

Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein.
J Cystic Fibrosis. 2003 Dec;2(4):195-8.
The lung disease of cystic fibrosis is associated with a chronic inflammatory reaction and an over abundance of oxidants relative to antioxidants. Glutathione functions as a major frontline defense against the build-up of oxidants in the lung. This increased demand for glutathione in cystic fibrosis may be limiting if nutritional status is compromised. We sought to increase glutathione levels in stable patients with cystic fibrosis by supplementation with a whey-based protein. METHODS: Twenty-one patients who were in stable condition were randomly assigned to take a whey protein isolate (Immunocal, 10 g twice a day) or casein placebo for 3 months. Peripheral lymphocyte Glutathione  was used as a marker of lung Glutathione . Values were compared with nutritional status and lung parameters. RESULTS: At baseline there were no significant differences in age, height, weight, percent ideal body weight or percent body fat. Lymphocyte Glutathione  was similar in the two groups. After supplementation, we observed a 46.6% increase from baseline in the lymphocyte Glutathione  levels in the supplemented group. No other changes were observed. The results show that dietary supplementation with a whey-based product can increase glutathione levels in cystic fibrosis. This nutritional approach may be useful in maintaining optimal levels of Glutathione  and counteract the deleterious effects of oxidative stress in the lung in cystic fibrosis.

Inhaling a compound that is normally produced in the lungs but is lacking in people with cystic fibrosis seems to be helpful for such patients. Cystic fibrosis is a genetic condition, characterized by thick mucus build-up in the lungs as well as other organs such as bile ducts and intestines. People with the disorder suffer from difficulty breathing, frequent bouts of pneumonia, and numerous other afflictions. The secretion of a peptide called glutathione by lung cells is impaired in cystic fibrosis, and there is good evidence to suggest that the lack of glutathione in lung fluid plays a key role in the chronic inflammation and infection that occurs. Previous studies have investigated inhaled glutathione as a treatment for cystic fibrosis. The current study is different from the others in that it compared active treatment with inactive placebo treatment, and involved a higher daily dose of glutathione over a longer period. In the study, 19 patients with cystic fibrosis were randomized to receive inhaled glutathione or placebo for 8 weeks. Glutathione-treated patients experienced an increase in peak expiratory airflow whereas the comparison group experienced a drop.  When asked to rate their condition on a 5-point scale, the participants given glutathione reported significantly more improvement than those given the placebo. Also, inhaled glutathione therapy was well tolerated, and the frequency and nature of side effects was similar in the two groups. SOURCE: Chest, January 20057.

Effect of dietary restriction and acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats.
Exp Gerontol. 2004 Sep;39(9):1323-32.
The age-related changes of glutathione (glutathione) levels and the effect of hypocaloric regimen and N-acetylcysteine supplementation were investigated in intestinal mucosa and liver mitochondria of 28 months rats. Old rats exhibited lower proteins, glutathione and protein sulphydrils (PSH) concentrations, higher glutathione-peroxidase (glutathione-Px) activity and protein carbonyl deposit, partial inhibition of succinate stimulated mitochondrial state III respiration and decreased mitochondrial nitrosothiols (RSNO) concentration. Lower electric potential and current intensity were found in the colonic mucosa. Old rats undergone hypocaloric regimen showed higher intestinal concentrations of glutathione, lower oxidized protein accumulation and glutathione-Px activity and higher mitochondrial RSNO levels. Mitochondrial state III respiration and intestinal transport were improved. N-acetylcysteine supplementation enhanced glutathione and PSH levels in the ileal but not in the colonic mucosa, glutathione and RSNO in liver mitochondria, while glutathione-Px and protein carbonyls were decreased everywhere. Mitochondrial respiration ameliorated. In conclusion, ageing is characterized by a spread decrease of glutathione concentrations, increased protein oxidation and decreased mitochondrial NO content. Hypocaloric diet ameliorated intestinal transport and, as well as N-acetylcysteine, was effective in enhancing glutathione levels but at different extent according to the investigated districts. Both interventions reduced the age-associated increase of glutathione-Px and protein carbonyls and improved mitochondrial respiration.

Anti-oxidant effects of cinnamon (Cinnamomum verum) bark and greater cardamom (Amomum subulatum) seeds in rats fed high fat diet.
Indian J Exp Biol. 1999 Mar;37(3):238-42.
In order to gain insight into the antioxidant effect of cinnamon (Cinnamomum verum; Lauraceae) and cardamom (Amomum subulatum; Zingiberaceae) hepatic and cardiac antioxidant enzymes, glutathione content and lipid conjugated dienes were studied in rats fed high fat diet along with cinnamon or cardamom. The antioxidant enzyme activities were found to be significantly enhanced whereas glutathione content was markedly restored in rats fed a fat diet with spices. In addition, these spices partially counteracted increase in lipid conjugated dienes and hydroperoxides, the primary products of lipid peroxidation. Thus, it appears that these spices exert antioxidant protection through their ability to activate the antioxidant enzymes.

Glutathione Chemistry
Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol within cells. The synthesis of glutathione from glutamate, cysteine, and glycine is catalyzed by two cytosolic enzymes, gamma-glutamylcysteine synthetase and glutathione synthetase. Compelling evidence shows that glutathione synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and glutathione feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of glutathione homeostasis.

In aerobic cells, free radicals are constantly produced mostly as reactive oxygen species. Once produced, free radicals are removed by antioxidant defenses including the enzymes catalase, glutathione peroxidase, and superoxide dismutase. Reactive oxygen species, including nitric oxide and related species, commonly exert a series of useful physiological effects. However, imbalance between prooxidant and antioxidant defenses in favor of prooxidants results in oxidative stress. This results in damage to lipids, proteins, and nucleic acids. Alone or in combination with primary factors, free radicals are involved in the cause of hundreds of diseases.

L-Glutathione Reduced

Glutathione questions
Q. What do you think of a glutathione supplement.
   A. Glutathione, taken as a supplement, may not be able to cross across the cell membrane, so I suspect a glutathione supplement would not be helpful, although I am not 100 percent sure.

Q. Have you heard about glutathione eye drops as a treatment for cataracts? I am a huge believer in taking glutathione in powder form orally which has helped my allergies tremendously. I just had one cataract removed surgically and have the other eye with just the beginnings of a cataract. I was hoping to possibly use glutathione eye drops to prevent it from getting worse.
   A. We are not familiar with glutathione eye drops and don't have experience using this product.

Q.  what oral supplement is good for skin. I heard about glutathione that after a couple of months taking it , it can make your skin whiter and healthy. is this true?
   A. We have not come across any research that says glutathione supplements taken orally improve skin.

Q. I was doing some research on glutathione and came across your article. One of your concerns was the difficulty in getting into the cells where is matters the most. I am not sure if you are aware of Dr. Keller’s work with MaxGXL or not. I have decided to join the team. Here is what Dr. John C. Nelson has to say about this product and it's inventor. “This product in my opinion, this product ( MaxGXL ), represents the single most important breakthrough in health that I will witness in my life time. I believe it will revolutionize, change, and transform the practice of medicine world-wide and make Dr Robert Keller more famous than Jonas Salk who created the polio vaccine.”
   A. I get turned off when I hear such marketing pitches.

Q. Have you heard of MaxGXL created by immunologist and medical researcher Dr. Robert H. Keller, MD, MS, FACP.
He has developed a product that makes your body increase its glutathione levels. It is in a pill form. I am a Max International Independent Associate.
   A. I did a search for MaxGXL in Medline in January 2008 and did not find any references or any studies regarding this product.

Q. Was reading Q and A on your glutathione peroxidase website and went looking for MaxGXL. Thought you might be interested in what I found and to know the cost is $85. for a 28 day supply but if it's bought on the autoship plan one can get it for $66. Think the person that wrote that question was smart enough to know anyone reading it would check into it and he might have another customer! Afraid I would prefer to take individual pills than the convenience of all-in-one and save the money.

Q. Diagnosed with beginning cataracts by two different ophtomologists a few years back. Read your studies on L-Glutathione and took a supplement. Conditions of haloes around my eyes when viewing lights at night -- which I had for months -- disappeared within two weeks. Conditions have not returned. I have no doubt L-Gluthathione did the trick. I took -- and still take about twice a week now -- the GNC 50 mg vegetarian brand. I chew it to absorb it better, and wash it down with water. The taste is not that bad. No other benefits or side effects noted.
   A. Interesting.

Q. What is the best way to increase glutathione levels? taking r- alpha lipoic acid or n-acetylcysteine, and at what
dosage?
   A. There is no easy answer to this since studies regarding ways to increase glutathione through supplement use have not available as of December 2007. To complicate matters, it may be possible to have a short term effect from a supplement, but we don't know whether the glutathione increase would persist over time. A practical option is to alternate the use of r alpha lipoic acid with acetylcysteine every other day and to take 2 days off each week.

Q. My question is about L Glutathione. Since in the article it says it is good for liver detoxification, would a glutathione supplement help? I have fatty liver, but very very mild NASH Non alcoholic fatty liver. My Cholesterol is down, my weight is down....would glutathione help the liver?
   A. I have not come across any evidence that taking a glutathione supplement is able to enter individual cells in the body to be effective.

Q. i recently received a massage from someone who used glutathione mixed with coconut oil. he also used a sonar device. he said that the glutathione would penetrate into the body and work with neuro peptides to aid in reducing inflammation and release of muscle contraction. is this possible?
   A. We find this hard to believe until research studies confirm it.

Q. I have just heard about the MAX GXL product that several people asked about on your website concerning glutathione. Dr. Robert H. Keller (who created this pill made to be taken orally) works with HIV patients. He said on his dvd that this pill is a combination of the three amino acids that make up glutathione. He has a composition patent on this pill. Have you heard any more research on it, I am a skeptic, but it is of interest to me.
   A. As of April 2008, I have not come across independent research regarding Max GXL.