Glutathione is a naturally occurring chemical used by the human body to protect against chemical and environmental threats. As a consequence of aging, lifestyle, diet, and disease, a gap can develop between the needs and availability of Glutathione. Glutathione decreases in association with risk factors for disease and undergoes a variation with lowest values beginning in the morning and extending through midday. Decreased Glutathione has been associated with specific diseases, including cardiovascular disease and diabetes, and has been implicated in many others. Abundant biochemical data support a direct causal link between low Glutathione, impaired defenses, and cellular susceptibility in model systems. Emerging personalized health strategies utilize Glutathione as a quantitative indicator of health with the expectation that diet selection, Glutathione supplementation, and lifestyle approaches can be used to manage Glutathione status, thereby providing a health dividend by protecting against disease development.
More than 100 years of research and 81,000 scientific papers have established Glutathione (Glutathione) as one of the most important protective molecules in the human body. This article provides a brief overview of Glutathione and its functions in health and disease. Low Glutathione has been implicated in neuronal, hepatic, renal, pulmonary, cardiac, musculoskeletal, pancreatic, gastrointestinal, visual, auditory, and infectious diseases. Accumulating data have established that poor diet and age-related disease can create a functional disparity between the body’s natural Glutathione defenses and the levels needed for optimal health.
What is Glutathione?
Glutathione is a component of defenses for both acute and chronic health challenges. Acute deficiency can be caused by exposure to toxic chemicals and endogenous oxidative reactions. Under acute Glutathione deficiency, cells cannot maintain normal cell functions, lose ability to divide normally, and can undergo a cell death. Under chronic conditions, variations in Glutathione levels occur due to nutrition, environmental exposures, and activation of the immune system. These variations affect risk of chronic and age-related diseases by limiting protective functions. The protective functions include elimination of cancer-causing chemicals, enhancement of antioxidant defenses, and maintenance of homeostatic conditions. Glutathione protects against hundreds of cancer-causing chemicals. Glutathione is at the apex of a group of protective chemicals, including vitamins C and E, which guard against oxidative damage to tissues. Glutathione is critical for elimination of oxidants.
Glutathione is a simple molecule, composed of 3 common amino acids: glutamate, cysteine, and glycine, which are also found in protein throughout the body. The amino acids are connected in a unique way so that Glutathione can be made and broken down independently of the body’s protein.
Where is Glutathione found in the body?
Glutathione is found in all tissues and body fluids. In general, the concentrations of Glutathione within cells are much higher than outside of cells. Nonetheless, the amounts of Glutathione in the fluids surrounding cells are important because they provide a chemical-defense barrier to protect the cell surfaces.
The total amount of Glutathione in the body is about 15 grams. The organs principally responsible for detoxification (ie, the liver and kidneys), have the highest amounts, but the 15 grams are distributed among all major organ systems, including brain, heart, skeletal muscle, intestines, lungs, skin, and the immune system. The liver (6% of the body) has about 4 grams of Glutathione (25% of the body’s total), which is part of an important homeostatic mechanism. Liver Glutathione varies as a function of diet, time of day, and body needs. The cysteine content of liver Glutathione is similar to the RDA for sulfur amino acids (methionine plus cysteine), which is 1.4 g for a reference 70 kg individual. Thus, the Glutathione in the liver is equivalent to a 1-day reserve for the cysteine needed for the body’s protein synthesis.
Homeostatic mechanisms prevent the hepatic Glutathione content from falling too low. During fasting and starvation, Glutathione and its precursors are derived from muscle and other tissues. Simple calculations show that the entire human body has no more than a 4-day reserve of Glutathione so that loss of Glutathione can become critical in catabolic illness or whenever there is a prolonged period of protein/energy insufficiency. Importantly, Glutathione declines with age and has a variation with lowest values in the morning and early afternoon. The diurnal variation is linked to cysteine, and cysteine variation increases in individuals over 60 years. Thus, older individuals have increased vulnerability in cell injury due to both a decline in total amount of Glutathione and a decline in its homeostatic control.
How is Glutathione Maintained in Tissues and Body Fluids?
Glutathione is maintained by a continuous cycle of turnover at a rate equivalent to the entire body pool of Glutathione being made and degraded daily. Glutathione is synthesized from the precursor amino acids (ie, glutamine, glycine, cysteine) in all tissues. Cells in certain organs (ie, intestines, lung, kidney) can utilize exogenous Glutathione by a secondary active transport mechanism.
Glutathione is depleted by elimination of reactive chemicals dependent upon abundant Glutathione transferases. These enzymes increase in response to toxic challenge, and trials have been conducted to determine whether continuous elevation of these enzymes can protect against cancer. In protection against cancer, Glutathione reacts with cancer-causing chemicals at rates that are faster than the chemical can react with DNA, thereby preventing mutations. To date, however, practical approaches to reduce cancer by increasing Glutathione transferase have not been established. In addition to cellular activities, Glutathione transferase is associated with mucus and provides a detoxifying barrier in the small intestines. The finding that oral and pharyngeal cancer is decreased in association with intake of foods high in Glutathione could reflect the function of this mechanism in protection against cancer-causing chemicals or a better function of the immune system. Studies with human cells in culture further show that added Glutathione protects cells even in the absence of Glutathione uptake, apparently due to protection of proteins on the surface of cells.
How Big is the Functional Need for Glutathione?
In addition to the age-related decline mentioned above, Glutathione levels are inversely associated with environmental exposures and disease risk. Glutathione is decreased in the epithelial lining fluid of human lung in individuals who abuse alcohol. This example is illustrative of the hidden risks of low Glutathione in that these individuals have no apparent lung disease and yet are at considerably increased risk of acute lung injury and death from adult respiratory death syndrome. Direct evidence that the decrease and oxidation of Glutathione occurs due to toxic chemical exposures is available from studies in individuals following chemotherapy. The extensive evidence that Glutathione status is decreased in association with disease and recognized risk factors for disease implies that maintenance of this protective system could reduce risk of disease development.
Because of the known functions and increased disease risk with a decline of Glutathione, systematic efforts are needed to quantify the difference between the available Glutathione and the amount needed. One approach is to consider how much Glutathione is present in a natural diet. Glutathione content has been measured in more than 100 common foods and provides the basis to estimate dietary intake. The best diets contain about 150 milligrams of Glutathione per day; the worst diets contain as little as 3 milligrams per day. Glutathione is present in essentially all raw and freshly prepared foods; the best sources are fresh fruits and vegetables, nuts, and whole-cut meats, including poultry and fish. Glutathione can also be increased by supplements, such as the increase in hepatic Glutathione following ingestion of silymarin, found in milk thistle. Glutathione is lost during most food processing procedures, with the exception of fresh-frozen foods. Processed, cured, and canned meat products have essentially no Glutathione. Similarly, canned or dried fruits and canned vegetables are not good sources. Cereal and grain products are largely deficient, and almost all dairy products, beverages, sweeteners, and condiments lack Glutathione. Thus, a simple conclusion is that modern processed foods are deficient in Glutathione compared to natural, freshly prepared foods. In quantitative terms, up to 150 mg of daily intake of Glutathione can be lost due to food processing.
Many foods also contain reactive chemicals that remove Glutathione through the Glutathione transferase reaction associated with the lining of the small intestines. Measurement of a broad range of foods show that milk, prunes, tea, blueberries, and bottled apple juice have high contents of Glutathione-reactive chemicals. The daily intake of Glutathione-reactive equivalents can range from almost zero to values exceeding the maximum naturally available 150 milligrams Glutathione. Thus, the sum of the amount of Glutathione needed to eliminate reactive chemicals and the amount of Glutathione lost by food processing can be greater than 300 mg of Glutathione per day.
There may be conditions in which the functional need for Glutathione is relatively high, but this upper limit is currently unknown.
Glutathione Support Strategies: How Can We Improve Glutathione Status?
Glutathione is synthesized from amino acid precursors, glutamate, cysteine and glycine. A considerable number of trials have used N-acetylcysteine (NAC) as a cysteine precursor, expecting it to provide a means to increase Glutathione synthesis. The logic for using NAC is complicated but generally assumes that cysteine is limiting for Glutathione synthesis. However, the American diet typically has an excess of sulfur amino acids. According to NHANES III, 99% of adult American males and females consume greater than the RDA, 50% consume more than twice the RDA and 1% of people consume more than 4 times the RDA for sulfur amino acids. Consequently, while NAC is likely to benefit individuals with insufficient sulfur amino acid intake, additional approaches are needed to address a functional need for Glutathione in most Americans. Supplementation with glutamate, cysteine, and glycine provides one alternative, and others include related sources of these amino acids (eg, whey), supplements to enhance synthesis (eg, silymarin), as well as the naturally occurring compound itself, Glutathione.
A common assumption is that dietary or supplemental Glutathione is not available for use by the human body because the intestines contain an enzyme (ie, γ-glutamyl transpeptidase; GGT) that degrades Glutathione. However, a substantial amount of scientific evidence shows that supplemental Glutathione is bioavailable. As indicated above, added Glutathione supports detoxification in body fluids such as the lining fluid of the lung and intestines, enhances macrophage function, and decreases influenza virus production. Thus, even for cells that do not absorb Glutathione, protection can be provided by supplemental Glutathione.
Orally administered Glutathione increases Glutathione in mouse, rat, and human plasma, and the extent of increase is increased by a stress response. Animal and human studies further show direct benefit of oral Glutathione in protection against age-related decline in immune function and enhancement of lymphocyte function
Consequently, the scientific evidence supports the conclusion that the body can utilize exogenously supplied Glutathione. This characteristic is identical to some vitamins (eg, niacin), amino acids (eg, histidine), and amino sugars (eg, glucosamine), which are utilized from the diet even though they are synthesized within the body. While Glutathione is not considered a required nutrient, the same principles apply (ie, a deficiency can develop when the amount of Glutathione synthesized is insufficient for detoxification needs).
Summary and Conclusions
Glutathione is one of the most extensively studied chemicals of the human body and its decline with aging and disease risk is well established. Glutathione is needed both for maintenance of normal metabolism and for defense against a range of disease and toxicity mechanisms. Glutathione is maintained by continuous processes of GSSG reduction and Glutathione transport, degradation, and synthesis. Glutathione concentrations are considerably higher in tissues than in most body fluids, but the fluid concentrations are important because they protect cell surfaces and support protective barrier defenses. Extensive research in model systems establishes that Glutathione is transported by cells and that added Glutathione protects against a range of chemical and infectious threats. Although most Americans consume an adequate supply of dietary precursors for Glutathione synthesis, there is a gap between the amount synthesized and the amount needed (ie, a decline in Glutathione is associated with disease risk). Based upon the loss of Glutathione from food during processing and the measured contents of reactive chemicals in food, this gap can be estimated to be 300 mg/day. However, higher values may be needed to compensate for adverse environmental conditions and disease, but the possible amounts can only be speculated.
Because the American healthcare system is approaching crisis with the ballooning costs of late-stage disease treatment, cost-effective means are needed to preserve health. Available (but not FDA-approved) methods allow prospective assessment of Glutathione in individuals prior to disease onset, and health maintenance programs are beginning to adopt Glutathione analysis as part of quantitative health assessment (but not disease treatment). Simple strategies, including supply of Glutathione, Glutathione precursors, complementary antioxidants, and zinc, are available to improve Glutathione status in individuals with low or oxidized Glutathione. Such strategies could have considerable personal health and economic impact.
This article was summarized from a paper in the 2016 Natural Medicine Journal .
Compiled for Dr.David Jensen by Larry Heinrichs