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Research Guide by Kyowa Hakko Usa NATURAL MEDICINE JOURNAL RESEARCH GUIDE https://setriaglutathione.com/SPONSORED BY KYOWA HAKKO USA Oral Availability of GLUTATHIONE Does the research dispel previously held beliefs? Author: Sarah Cook, ND © 2017 IMPACT Health Media, Inc. All rights reserved. This publication may not be reproduced or distributed in any form without written permission from IMPACT Health Media, Inc. What is Glutathione? GSSH is then recycled back to GSH with help from Glutathione is a potent antioxidant compound and the enzyme glutathione reductase and electrons detoxifying agent that is produced in the cytoplasm donated from the reduced form of nicotinamide of every cell of the human body. Because of its central adenine dinucleotide phosphate (NADPH). role in detoxification, approximately 25% of all the body’s glutathione resides in the liver alone. Glu- Antioxidant Action action of Glutathione of glutathione tathione is also concentrated in the kidneys and in ROOH 2GSH NADP+ (H O ) mucosal secretions of the intestinal lining and lungs. 2 2 It is present inside cells and in extracellular fluids. Glutathione peroxidase Glutathione reductase Hexose-monophosphate shunt ROH (H O) GSSG NADPH Glutathione is a tripeptide molecule, composed of 2 the amino acids glutamate, cysteine, and glycine. It exists in at least 4 different forms within the human The ratio of GSSH to GSH in the body serves as an body, including a reduced form, an oxidized form, important measurement of oxidative stress, or redox a disulfide cysteine-containing form, and a protein- status. Higher levels of GSSH indicate greater oxi- bound form. The pool of glutathione in the human dative stress, whereas higher levels of GSH indicate body is constantly in flux, transforming between protection against toxins and oxidative damage. forms as well as being split into its components and Because GSH provides the primary physiologic ben- synthesized again. efits of glutathione, any mention of glutathione for the rest of this document refers to the reduced form Structural Formula of Reduced Glutathione (GSH), unless otherwise specified. Who Needs Glutathione? More than 100,000 studies have been published related to the physiologic effects of glutathione. In broad terms, these studies have found glutathione to protect against oxidative stress, detoxify chemicals and toxins, boost immune function, and support The reduced form of glutathione (GSH) is the bio- healthy aging. logically active form that has earned glutathione its reputation as the body’s most important anti- Glutathione has both inherent antioxidant activity oxidant. GSH contains a thiol group (—SH), making as well as the ability to regenerate other antioxi- it an effective electron donor to neutralize lipid dants, including vitamins C and E. Glutathione is peroxides, hydrogen peroxide, and other reactive more than simply an electron donor, however. It also oxygen species. serves as a substrate to conjugate drugs, alcohol, pesticides, and carcinogens. Enzymatic conjugation, “Free radicals are a necessary waste product of catalyzed by the enzyme glutathione-S-transferase, cellular energy production, but our cells must occurs in Phase 2 detoxification in the liver and in rid themselves of this waste or succumb to the gastrointestinal mucosal secretions. Glutathione ravaging effects of oxidative damage. Gluta- conjugation provides a mechanism to neutralize thione acts in every cellular compartment—the reactive toxins before they are able to damage body cytosol, the nucleus, and the mitochondria, to tissues. Glutathione also plays an important role quell the free radicals. Adequate glutathione is in immune function, by stimulating natural killer not just desirable, it is essential to the survival (NK) cell function and promoting healthy function of each cell, making it essential to life itself.” of T-cells and other white blood cells. –Tina Kaczor, ND, FABNO (www.RoundTableCancerCare.com) There is mounting evidence that impaired glutathi- one synthesis, dysfunctional glutathione metabolism, or glutathione depletion may be implicated in the The process of neutralizing free radicals, catalyzed etiology and progression of a wide range of chronic by glutathione peroxidase, transforms reduced GSH diseases. For example, polymorphisms in glutathione into its oxidized glutathione disulfide (GSSH) form. peroxidase appear to increase the risk for coronary NATURAL MEDICINE JOURNAL 2 Oral Availability of Glutathione ©2017 RESEARCH GUIDE heart disease and stroke; levels of GSH are substan- “There is a small, but growing body of evidence tially lower in the substantia nigra of patients with that high levels of antioxidants such as vitamin Parkinson’s disease; diminishing levels of GSH are E and NAC, and by inference, perhaps gluta- associated with age-related cataracts, glaucoma, and thione, may support the viability of metastatic macular degeneration; and glutathione depletion cancer cells. There are also animal studies which may be implicated in the pathogenesis of cancer. have found increased chemo resistance during antioxidant administration. However, to date, Conditions that are thought to benefit from therapies human trials have failed to find a reduction in that boost glutathione levels include cardiovascular treatment response when glutathione or other disease, pulmonary disease, liver disease, neuro- antioxidants are used concurrently with oxida- degenerative disease, immune disorders, chronic tive chemotherapeutics. As the body of literature infections, and metabolic disorders. on glutathione in the context of active malig- nancy is small and contradictory, some caution “One of the most surprising benefits I have is warranted. Generally, I do not supplement discovered with the use of glutathione in my glutathione during chemotherapy with curative practice is the positive impact it has had with intent or in individuals with active metastatic women suffering from symptoms of hormone disease. I do supplement glutathione when my imbalances, including PMS, hot flashes, mood goal is to restore cellular antioxidant capacity in disorders like depression and anxiety, inflam- patients who are at risk of cancer, who have a mation, sleep disturbances, low libido, and personal history of cancer, or who are receiving weight gain. I will use it alone or in some cases palliative conventional treatment and suffering paired with bioidentical hormone therapies to from quality of life issues for which glutathione provide optimal results for our patients.” may be helpful.” –Gina Nick, NMD –Lise Alschuler, ND, FABNO (www.DrGina.com) (www.DrLise.net) Even for individuals who are generally healthy, the body’s need for glutathione increases at certain What are Glutathione Precursors times and under certain conditions. The demand and Cofactors? for glutathione increases, for example, in response Glutathione is endogenously produced and therefore to stress, weight gain, poor lifestyle choices, and not considered an essential nutrient from the diet. It normal aging. Glutathione can also become depleted is critical, however, that the body receives a constant by increased exposure to medications, toxins, supply of either glutathione itself or its precursors in heavy metals, solvents, pesticides, or alcohol. If order to maintain adequate levels. glutathione or its precursors are not supplied from the diet on a routine basis, the body will begin to Glutathione is naturally occurring in fresh meats, sequester amino acid precursors from the muscle. dairy, fruits, and vegetables, and studies suggest Animal studies suggest that even short periods of that higher intakes of dietary glutathione corre- fasting, such as overnight, are enough to deplete late with a lower risk of some cancers. Glutathione glutathione levels, resulting in levels being lowest is destroyed by most methods of food processing, in the morning. however, and epidemiological studies report that modern diets typically provide negligible amounts. The essential nature of glutathione may suggest that boosting endogenous levels would benefit all Clinical efforts to boost glutathione levels in the patients and conditions, but this is not necessarily body have historically focused not on directly the case. In cases of advanced cancer or chemother- supplying glutathione but rather on increasing apy, for example, boosting glutathione levels may endogenous production by providing precursor mol- be contraindicated. Whereas glutathione protects ecules and cofactors. To understand the reasoning against oxidative damage that may lead to cancer, behind precursor and cofactor supplementation, we high levels of glutathione can paradoxically have the need to review the biochemical pathways involved opposite effect during cancer treatment. in glutathione production. NATURAL MEDICINE JOURNAL RESEARCH GUIDE ©2017 Oral Availability of Glutathione 3 The endogenous synthesis of glutathione takes place In addition to NAC supplementation, a variety of in 2 steps: first is the formation of a dipeptide from additional strategies are commonly implemented l-glutamate and l-cysteine and second is the addition to boost endogenous glutathione production. These of l-glycine to form the tripeptide, glutathione. The strategies are based on an understanding that glu- first step is catalyzed by glutamate cysteine ligase tathione production does not occur in isolation. (GCL) and requires either magnesium or manganese Both steps of glutathione synthesis, for example, as enzymatic cofactors. The second step is catalyzed are ATP-dependent,
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