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Volume 38, No. 2

Intracellular Antioxidants

The most important antioxidant is glutathione

The words free radical and antioxidant are in the news almost daily. "Reports of how antioxidants protect us against cancer, heart disease, and nearly eighty other diseases appear regularly in the media. Vitamin C is the major antioxidant in the blood; vitamin E is the vital antioxidant in cell membranes and lipoproteins. However, in the cell interior – where the real toxin war is being waged – the most important antioxidant is glutathione." Alan H. Pressman, D.C., Ph.D., C.C.N.

There is now much interest in the idea that a wide range of human conditions such as aging, cancer, atherosclerosis, arthritis, viral infections (including AIDS), stroke, myocardial infarction, pulmonary conditions, bowel disease, neurodegenerative disease, and others may be produced (or made worse) by reactive oxygen species (e.g., oxygen free radicals, hydrogen peroxide).

There is related interest in the treatment or prevention of such conditions by administration of antioxidants including ascorbate, alpha-tocopherol, and beta-carotene. Some of the studies that underlie this 'free radical hypothesis of disease' and the proposed preventatives or therapies are based on epidemiological approaches that involve data collected on nutritional intake. In some instances administration of vitamin supplements is suggested; experience has shown that these are essentially nontoxic. At this time, the hypothesis, though highly attractive, is unproven. Studies in our laboratory on the functions of glutathione appear relevant to this hypothesis. Thus, there is clear evidence for an essential glutathione-ascorbate antioxidant pathway in animals. The dramatic effects of glutathione deficiency emphasize the importance of maintaining the intracellular reducing milieu and the cellular reducing power. Normal cells produce substantial quantities of reactive oxygen species, which are normally destroyed by the glutathione system. A deficiency of this system leads to significant morbidity." [1]

Glutathione, known as GSH, is a unique non-essential tri-peptide that can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid and glycine. It is a naturally occurring protein that protects every cell, tissue, and organ from toxic free radicals and disease. Research shows that oral glutathione supplements do not increase intracellular glutathione levels because it is not well absorbed across the GI tract. [2] However, glutathione precursors rich in cysteine including N-acetylcysteine (NAC) and un-enatured whey protein have been shown to increase glutathione levels within the cell. Additionally, alpha lipoic acid and silymarin (milk thistle) have also shown an ability to restore intracellular glutathione. [3, 4] The most thoroughly researched of all the methods used to increase cellular levels of glutathione involves variants of cysteine. [5]

A nutritious diet high in glutathione includes almost all fresh fruits and vegetables, and walnuts (not other nuts). Avocados, asparagus, raw spinach, cauliflower, okra, broccoli, tomatoes, squash, and potatoes are vegetables that are particularly high in glutathione. Citrus fruits, all melons, strawberries, and fresh peaches are the fruits highest in glutathione. Fresh apples, pears, and bananas are also good sources of glutathione.

While dairy products, grain products and prepared foods are usually low in glutathione; the best dietary sources of cysteine include eggs, meat, poultry, fish, whole grains, dairy products, and beans. [6] The cysteine content of most foods is low compared to the other essential amino acids. However, a number of plant foods seem to stimulate your body to produce glutathione, even though the foods themselves are relatively low in amino acids. Researchers are still exploring the compounds that stimulate glutathione production. So far, they've learned that cyanohydroxybutene (CHB), a substance found in cruciferous vegetables such as broccoli, cabbage, brussels sprouts, and cauliflower, seems to stimulate glutathione production in your body. So do two other compounds found in cruciferous vegetables: sulforaphane and iberin. Glutathione-stimulating substances are also found in spinach, cantaloupe, and watermelon. The best source of all, however, may be parsley. Parsley is an excellent source of antioxidant vitamins. Used as a healing herb for centuries, parsley today is thought of mostly as a garnish. In fact, however, you might be better off skipping the main course and eating the parsley sprig instead. Caution: In large amounts parsley can act as a diuretic, sun sensitivity in very fair skinned people, and can cause uterine contractions. Pregnant women should avoid parsley in large amounts. [6] Scientifically, the best way to increase glutathione levels is to take a supplement rich in cystine (a disulfide-bonded form of cysteine). Un-enatured whey protein provides one of the richest sources of cystine known to science because cystine contains two weakly bonded molecules of cysteine. [7]

Glutathione is not a stand alone fix all antioxidant. Cofactors are required for glutathione to optimize its effectiveness. Lipoic acid, an antioxidant by itself, is a cofactor for glutathione synthesis that also helps recycle other antioxidants in the body (vitamin C and vitamin E) along with helping to preserve nerve cell growth and liver cell function. [3, 6] The mineral selenium and vitamin B2 (riboflavin) are two other cofactors necessary for maximum glutathione function. Selenium is a necessary component of glutathione peroxidase, an essential catalyst enzyme for glutathione. Selenium also works synergistically with vitamin E – each improves the effectiveness of the other, and both improve the effectiveness of glutathione. Riboflavin is needed to help your body combine amino acids, including glutathione, into proteins [6]

Glutathione participates in many cellular reactions and displays remarkable metabolic and regulatory versatility. There is a direct correlation with the speed of aging and the reduction of glutathione concentrations in intracellular fluids. As individuals grow older, glutathione levels drop, and the ability to detoxify free radicals decreases. Glutathione deficiency contributes to oxidative stress, and, therefore, may play a key role in aging, and the pathogenesis of many diseases. This presents an emerging challenge to nutritional research. Protein (or amino acid) deficiency remains a significant nutritional problem in the world, owing to inadequate nutritional supply, nausea and vomiting, premature birth, HIV, AIDS, cancer, cancer chemotherapy, alcoholism, burns, and chronic digestive diseases. Thus new knowledge regarding the efficient utilization of dietary protein or the precursors for GSH synthesis and its nutritional status is critical for the development of effective therapeutic strategies to prevent and treat a wide array of human diseases, including cardiovascular complications, cancer, and severe acute respiratory syndrome. [6]

"Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases." [8]

By Gloria Braunberger-Christensen, MS, CCN

1. Packer, Lester & Cadenas, Enrique Biothiols in Health and Disease
2. Witschi A, Reddy S, Stofer B, Lauterburg BH (1992) "The systemic availability of oral glutathione".Eur J Clin Parmacol.43 (6): 667-9.
3. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM (2009). "Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential". Biochem Biiophys Acta (Aug 4)
4. Nencini C, Giorgi G, Micheli L (2007) "Protective effect of silymarin on oxidative stress in rat brain". Phytomedicine. 14(2-3): 129-35
5. Acetylcysteine and glutathione. PubMed
6. Pressman, Alan H., D.C., Ph.D., C.C.N. Glutathione The Ultimate Antioxidant.
7. Uretsky, Samuel. Pharm D., The Gale Group, Inc. Gale, Detroit Gale Encyclopedia of Alternative Medicine. 2005
8. Guoyao Wu, Yun-Zhong Fang, Sheng Yang, Joanne R. Lupton and Nancy D. Turner "Recent Advances in Nutritional Sciences – Glutathione Metabolism and Its Implications for Health" Faculty of Nutrition, Texas A&M University, College Station TX 77843; Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China 100850; Department of Animal Nutrition, China Agricultural University, Beijing, China 100094

For informational purposes only - not intended as medical advice, diagnosis or treatment, nor an endorsement by the American Nutrition Association®. Use permitted for non-profit and non-commercial uses or by healthcare professionals in their practice, with attribution to Other use only with written ANA℠ permission. Views expressed are those of the author and not necessarily those of the ANA℠. Works by a listed author subject to copyrights as marked. © 2010 ANA℠