from Allergy Research Group

Glutathione is our body’s most important water-soluble antioxidant and is found in impressively high concentrations inside cells. Since oxidative stress can disrupt normal cell function and even lead to cell death, it’s not surprising that low levels of glutathione are implicated in a surprisingly wide array of disorders””Parkinson’s, Alzheimer’s, autism, asthma and cystic fibrosis, cardiovascular disease, cancer, immune dysfunction, mercury toxicity, diabetes, macular degeneration, chronic fatigue syndrome and the aging process itself. The newest research continues to uncover the significance of glutathione in health, and offers promising routes to boosting glutathione through targeted supplements, such as whey protein and concentrated whey protein that are rich in precursors, or extracts such as curcumin, which protects and preserves glutathione in the body.

Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). The consequences of low glutathione include:

• A reduced ability to detoxify environmental toxicants
• A reduced ability to chelate and clear heavy metals
• Increased gut permeability
• Increased Th2 (pro-inflammatory t-cells)
• Reduced levels of the potent antioxidants, Vitamin C and Vitamin E, both of which depend on glutathione

Here’s a look at the latest, cutting-edge research on glutathione and health.

• Parkinson’s Disease. Oxidative stress can promote neurodegeneration in Parkinson’s disease, and has been correlated to the severity of the condition. The disease is also associated with loss of glutathione, and intravenous glutathione administration has been used clinically with success, according to researchers at the Robert Wood Johnson Medical School. In one Italian study of nine Parkinson’s patients, intravenous glutathione given once a day for a month decreased their symptoms by 42%, a therapeutic effect that lasted up to four months. In a 2008 study, depletion of glutathione was found in the neurons of the substantia nigra””the part of the brain affected in Parkinson’s disease.
• Alzheimer’s Disease. A study on Alzheimer’s patients found that the worse their cognitive ability, the lower their levels of glutathione. Beta amyloid (which leads to the plaques that are a signature of the disease) have been shown to increase oxidative stress and lipid peroxidation. Glutathione has been shown to protect cells in culture against beta amyloid.
• Immune Function. White blood cells produce more antibodies in the presence of glutathione. The immune system’s t-cells, b-cells, macrophages and neutrophils rely on glutathione, and a deficiency is linked to higher levels of the cytokines interleukin-8 and -4, and even t-cell inactivation.
• Lung Diseases. The lung is a primary site for glutathione, and the level of extracellular glutathione in the lung’s epithelial lining fluid (ELF) is 140 times that in blood plasma. Cystic fibrosis is marked by a severe deficiency of glutathione in the ELF. According to a 2008 study, pulmonary fibrosis (IPF) is characterized by a huge alveolar oxidant burden and a deficiency of glutathione, a major antioxidant, in the pulmonary epithelial lining fluid (ELF). When 1.8 grams of N-acetylcysteine (NAC), a building block for glutathione, was given intravenously to eight pulmonary fibrosis patients and six healthy patients, total glutathione in the patients increased markedly, while it remained unchanged in their healthy counterparts. Higher doses of NAC had no additional effect on the patients.
• Asthma. Asthma, too, is marked by low and oxidized glutathione. A 2008 study from the Kurume University School of Medicine in Japan notes that inflammatory cells (particularly eosinophils) in the airways of asthmatics release large amounts of harmful free radicals. According to another 2008 study of the sputum of 44 asthmatics and 31 healthy individuals from the University of Newcastle in Australia, oxidized glutathione and alpha-tocopherol are elevated in asthmatics. And an animal study from Gunma University in Japan found that glutathione status regulates airway hyperresponsiveness and airway inflammation. Type 2 t-cells and cytokines are characteristic of asthma and inflammation. In this study, a membrane-permeating glutathione precursor was used to elevate intracellular glutathione (GSH). In response, the infiltration of allergenic cells (eosinophils) was suppressed. The authors conclude, “These findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio…ameliorate bronchial asthma…by suppressing chemokine production and eosinophil migration itself.”
• Liver Function. Our livers are rich in glutathione, which exports glutathione to other organs, and liver cells synthesize glutathione from its precursors, and recycle it after it is oxidized. In patients with liver damage, from cirrhosis to viral hepatitis, glutathione is often abnormally low and can be a predictor of inflammation and fibrosis.
• Cardiovascular Disease. Glutathione improves symptoms in patients with clogged arteries who find walking painful. In a double blind Verona University study, 40 patients suffering from stage II peripheral artery disease were studied. Twenty were given intravenous glutathione twice a day, and the other twenty were given saline. There were significant increases in pain-free walking, and in blood flow measured with laser Doppler flowmetry after a treadmill test, in the glutathione group. Other research published in the New England Journal of Medicine in 2003 found that low levels of glutathione in red blood cells were linked to an increased risk of heart problems among cardiovascular patients. Patients who have had heart attacks have lowered levels of glutathione, and patients with peripheral artery disease showed improvement in microcirculation after glutathione treatments.
• Autism: Recent research in children with autism reveals a distinct pattern of abnormalities indicating oxidative stress. Their blood levels of key molecules such as methionine, cysteine, adenosine, SAH (S-adenosylhomocysteine), SAMe (S-adenosylmethionine), and homocysteine are all abnormal, according to a 2004 study in he American Journal of Clinical Nutrition. These substances are important in the synthesis of glutathione, which was found to be as much as 80% depleted in autistic children. They have far lower levels of GSH and higher levels of oxidized glutathione (GSSG).
• Chronic fatigue syndrome and aging. A 1999 article in Medical Hypotheses suggested that since glutathione is important both in the functioning of lymphocytes, and in skeletal muscle, low levels might be implicated in chronic fatigue syndrome. The authors note, “As an antioxidant, glutathione (GSH) is essential for allowing the lymphocyte to express its full potential without being hampered by oxiradical accumulation… Because GSH is also essential to aerobic muscular contraction, an undesirable competition for GSH precursors between the immune and muscular systems may develop. It is conceivable that the priority of the immune system for the survival of the host has drawn to this vital area the ever-diminishing GSH precursors, thus depriving the skeletal muscle of adequate GSH precursors to sustain a normal aerobic metabolism resulting in fatigue and eventually myalgia.” In addition, a 2007 article points out that glutathione, with its key role in oxidative stress, is a significant factor in aging and age-related diseases.

How to Boost Glutathione: Specialized Precursors

Vitamin C, N-acetylcysteine, whey protein and concentrated whey protein, as well as curcumin, have all been proven in research to reliably increase and preserve intracellular glutathione.

• Vitamin C: A 2006 study found that Vitamin C increases glutathione levels in those with ascorbate deficiency. The effect of vitamin C supplements was determined before supplementation, after 13 weeks of vitamin C supplements (500 or 1000 mg/d), and after 13 weeks of matching placebo. The supplementation group was selected on the basis of low plasma ascorbate (<33 mmol/L) and consisted of 48 healthy men and women, smokers and nonsmokers, aged 25-64 years. Ascorbate and glutathione were measured in purified lymphocytes. On supplementation with vitamin C, lymphocyte ascorbate increased by 51% and was accompanied by an increase of lymphocyte glutathione by 18%.
• Curcumin. According to a 2008 study in Free Radical Biology & Medicine, curcumin treatment alleviates the effects of glutathione depletion both in vitro and in vivo. Curcumin is a natural polyphenol derived from turmeric, and treatment of mouse neurons with curcumin restores depleted glutathione levels, protecting against oxidation and preserving mitochondrial activity.
• N-acetylcysteine. According to a 2007 article from Stanford University School of Medicine, supplementing with NAC, a cysteine “prodrug” or cysteine-based glutathione precursor), is safe, well-tolerated and successfully treats GSH deficiency in a wide range of infections, genetic defects and metabolic disorders. “Over two-thirds of 46 placebo-controlled clinical trials with orally administered NAC have indicated beneficial effects,” researchers conclude. Intracellular levels of the amino acid cysteine are rate-limiting for glutathione synthesis. Increasing cysteine is one mechanism by which cells can meet the demand for glutathione. Neurons are highly dependant on cystine and cysteine uptake for glutathione synthesis, and are very vulnerable to heavy metal-induced oxidative stress.
• Concentrated whey protein. Whey protein has been shown to be a potent building block that increases levels of intracellular glutathione. Whey proteins have captured the attention of many physicians, and have been found clinically extremely useful in chronic fatigue syndrome and chronic illness. A 2006 study on whey protein and asthma tested eleven children before and after one month of 10 grams of whey protein daily. IgE significantly decreased. However, to obtain significant levels, large amounts of whey protein need to be taken daily. In contrast, whey protein extract/filtrate (WPEF) is a hydrolysed whey protein powder that is highly concentrated and specifically designed to support glutathione production in the liver. A tablespoon can be taken daily. The key active ingredients in WPEF are cysteine-containing peptides that are easy for the body to absorb. In an informal study, eleven volunteers taking WPEF reported improved energy, motivation, sleep and mental alertness.  In an independent animal study, rats were fed a standard diet in which the supply of glutathione precursors was increased by 40%, using WPEF. In the WPEF group almost two times more GSH was synthesized compared to controls. In a second study, researchers examined the effect of WPEF on liver glutathione levels after toxic and oxidative stress. In rats given WPEF after oxidative insult, high baseline glutathione levels were re-established.
• Finally and most significantly, a 21-day placebo controlled, double blind study of WPEF demonstrated remarkable benefits. Individuals consumed 40 grams of alcohol daily (2 glasses of red wine) while on a controlled diet. Alcohol presents a challenge to the liver, and thus was chosen as a model for this particular study on oxidative stress. One group received 3.4 grams of WPEF (one level tablespoon) daily, while the placebo group received 3.4 grams of an amino acid mixture that looked identical to WPEF but did not contain the key, cysteine-containing peptides. Three weeks later, urine markers of lipid peroxidation were found to be significantly reduced in the WPEF group, and blood levels of inflammatory C-reactive protein, were reduced.

Conclusion

We can clearly see the utility and even necessity of restoring adequate glutathione levels in a host of chronic illnesses. Though there are no magic bullets in medicine, glutathione is one of our body’s most important antioxidants and can help protect cells across a stunningly diverse range of illnesses and disorders.

 

References:
• Bounous G and Molson J Competition for Glutathione Precursors Between the Immune System and the Skeletal Muscle: Pathogenesis of Chronic Fatigue Syndrome Med Hypotheses. 1999 Oct;53(4):347-9.
• Schauer RJ, Gerbes AL, Vonier D, Meissner H, Michl P, Leiderer R, Schildberg FW, Messmer K, Bilzer M. Glutathione Protects the Rat Liver Against Reperfusion Injury After Prolonged Warm Ischemia. Annals of Surgery. Feb 2004. 239(2):220-231
• Arosio E, De March S, Zannoni M, Prior M, Lechi A. 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 trial. Mayo-Clin-Proc. 2002 Aug; 77(8): 754-9
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• Hoshino T, Okamoto M, Takei S, Sakazaki Y, Iwanaga t, Aizawa H. Redoc-regulated mechanisms in asthma. Antioxid Redox Signal 2008 Apr;10 (4):769-83.
• Koike Y, Hisada T, Utsugi M, Ishizuka T, Shimizu Y, Ono A, Murata Y, Hamuro J, Mori M, Dobashi K. Glutathioen redox regulates airway hyperresponsiveness and airway inflammation in mice. Am J Respir Cell Mol Biol. 2007 Sept;37(3)322-9
• Lothian JB, Grey V, Lands LC. Effect of whey protein to modulate immune response in children with atopic asthma. Int J Food Sci Nutri. 2006 May-June;57(3-4):204-11
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