The secret is out on Glutathione. First discovered in 1888, it took almost one-hundred years for medical science to describe its effects on the immune system.
Apparently that was the big breakthrough since by 1997 there were 66,000 literature citations on this master antioxidant, and just ten years later, there were 77,000.
So here we are, now entering the second decade of the 21st century and GSH is still not very well known among practicing physicians. Why is that?
It's the same old story over and over. The building blocks of glutathione can be taken as a supplement and that is the death knell in the medical community. If it's not an FDA approved drug that the doctor can prescribe, then forget it.
Also, doctors don't have time to read all the articles being published in medical journals and they don't teach natural health and supplementation in medical school. Again why is that? Just ask who largely funds medical schools today and the path leads directly to the pharmaceutical industry. They don't like supplements.
To begin, glutathione is a powerful antioxidant created in our cells that has been shown to fight cellular inflammation, detoxify cells, improve liver function and support the immune system.
Glutathione (GSH) is a tri-peptide and not an essential nutrient since it is synthesized from three amino acids. For brevity, the shorthand term "GSH" will be used throughout this page.
L-glutamic acid is synthesized from glutamine (among others) and its salts (electrical neutral compounds) are called glutamates of which our old friend and headache maker, MSG (monosodium glutamate) is one.
Glycine is synthesized in the body from the amino acid serine.
GSH is synthesized in the cell by way of two adenosine triphosphate (ATP) dependent steps.
For this reason, mitochondria are often referred to as the cells power plant.
ATP is a cofactor; that is, a chemical compound that is required for the protein's biological activity. These proteins are commonly enzymes and cofactors (or coenzymes) and can be considered "helper molecules and/or ions" that assist in biochemical transformations.
Having reviewed ATP, we can now describe steps one and two in the synthesis of GSH.
In step one, two of the three amino acids, L-glutamate and L-cysteine, in conjunction with an enzyme, gamma-glutamylcysteine synthetase (glutamate cysteine ligase, GCL), form the protein gamma-glutamylcysteine.
This first step is rate limiting; in other words, it controls how fast GSH can be synthesized.
In step two, the third amino acid, glycine, is added to gamma-glutamylcysteine (the product of step one), using another enzyme glutathione synthetase. The product of step two is GSH.
As you might have gathered, any chemical substance that ends in "ase" is most likely an enzyme. Amylase and lipase are two enzymes in saliva that break down protein and fats respectively.
A logical question might be, "Why does GSH have to be synthesized in the cell?" and the answer is that the GSH molecule is too big to be taken into the cell directly; thus the building blocks (the three amino acids) enter the cell where the ATP already resides and then the two-step construction process can proceed.
Attempts have been made to create GSH supplements but have not been very successful due to the large molecular size plus the fact that when the preformed GSH hits the digestive tract, the proteins get digested and it is destroyed.
So even if it were of a size suitable for absorption, the digestive environment would preclude it from ever having a chance to be absorbed.
Our choices then become one of ensuring that we get enough of the three glutathione building blocks in our food or supplement with the three components (or both).
There are also several other natural substances that enhance the conversion of proteins to GSH and are necessary for the recycling of GSH, both of which will be discussed shortly.
It's most important role by far is that of antioxidant, in fact it is the master antioxidant. There are four antioxidants produced by the body as opposed to antioxidants we ingest such as vitamins C, E and D3 for example.
Those produced by the body are called endogenous antioxidants and consist of glutathione, superoxide dismutase, catalase and coenzyme Q 10 (CoQ10). From the names, it is obvious that the last three are enzymes (enzymes end in "ase") while GSH is the tri-peptide amino acid compound.
While GSH is produced by the body, the bad news is that its production starts to decline steadily after age 20 or so. As GSH production declines, unresolved free radicals increase.
The result is more and more diseases of aging and general deterioration of the body. The consequences of decreased levels of GSH are numerous and include:
The whole list shown above can be boiled down into just a few statements.
Without GSH every cell in our bodies would die prematurely from its own waste products; the entire immune system would cease to function; the liver would cease to detoxify the body of all the toxins we ingest daily; and with a total absence of GSH, oxygen based life would be no more.
Along with GSH, we would include the master hormone, HGH or human growth hormone, as another "must have" nutrient for optimal health. This is what Suzanne Somers is best known for promoting and Dr. James Forsythe's book, shown to the left as an interactive link, covers it very well.
Since GSH synthesis depends on the presence of certain amino acids, it figures that most foods rich in protein would be good sources of the basic building blocks, and they are.
L-cysteine is found in most high-protein foods, including pork, sausage meat, chicken, turkey, duck, luncheon meat, eggs, milk, whey protein, ricotta, cottage cheese and yogurt. Vegetable sources include red peppers, garlic, onions, broccoli, Brussels sprouts, oats, granola and wheat germ.
Whey protein contains 8 times more of the amino-acid cysteine than casein, a protein that accounts for about 80% of the protein in cow’s milk and cheese. However, it is important that if one is supplementing whey protein for GSH production, it must be bio-active, meaning not denatured and not pasteurized.
L-glutamic acid comes from all meats, poultry, fish, eggs and dairy products. An edible kelp known as kombu, or konbu, in Japan is extremely rich in glutamic acid. In addition, some protein-rich plant foods are also good sources, Ninety-five percent of the dietary glutamate is metabolized by intestinal cells.
Glycine also comes from high-protein foods, such as fish, meat, beans, milk, and cheese.
If the protein building blocks are so plentiful in such common foods, why should we ever have low GSH levels, especially as we age? The answer most likely is in the cooking and preparation.
These proteins are delicate and can be injured or destroyed by heat or by rapid agitation such as blending. So we think we are getting a lot of the three amino acids from eggs? Not if they are fried, poached, scrambled, hard boiled or whipped into a froth and baked into grandma’s pies and cakes.
For GSH purposes at least, raw is the way to go when it comes to eggs and other amino acid containing foods. So who eats raw eggs, raw meat or raw fish (besides the Japanese)? Not many people in North America.
Well, that leaves us with GSH supporting supplements. Read on.
There are several products on the market that attempt to function as GSH
supplements but care must be taken in selecting the proper product.
The problem is that most of them involve the direct intake of GSH but, for reasons previously given, it doesn't work.
The one that works takes the more proven approach of providing nutrients that cells can absorb and use to produce GSH.
The undisputed leader in GSH support products is uniquely designed and focused on supporting the cellular production of glutathione. It is arguably the best, most effective product of its type on the market today; in fact, due to the company’s tight patents, it may be the only product of its type on the market.
The GSH recycling and absorption blend consisting of 580 mg of cordyceps, curcumin/black pepper, resveratrol, alpha lipoic acid, grape seed extract, quercetin, milk thistle extract, broccoli extract, acemannan Aloe Vera extract and BioPerine is a super supporting cast for the GSH toolkit.
As we alluded to earlier, supplementing GSH directly has been difficult. Research suggests that it is not well absorbed in the gastrointestinal tract due to its molecular size and acidic environment of the digestive tract.
In a study of oral administration of a very large dose (3 grams) of GSH, it was found that it is not possible to increase circulating GSH to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.
The following is a U-tube video by Dr. Mark Hyman, M.D. and co-author of the "UltraPrevention" books that have been highly recommended throughout this "Healthy by Nature" website. Click on the book cover shown below his video to review or buy the book.
It would be productive and highly informative to take time now to watch this nine minute video and then read on for additional discussion of Dr. Hyman's comments on GSH supplementation. To my knowledge, Dr. Hyman is not selling any products and his tutorial should be totally unbiased by commercial considerations.
As Dr. Hyman alluded to in the video, there is a genetic connection to low GSH levels. A gene designated GSTM1 (glutathione S-transferase Mu 1) is a human glutathione S-transferase (GST) enzyme thought to play a role in the biotransformation of pollutants, drugs, toxins, all generally known as xenobiotics.
GSTM1 is one of the family of glutathione S-transferases, which allow GSH to interact with harmful organic hydroperoxides to neutralize and excrete them from the body.
There is strong evidence linking chronic fatigue syndrome and GSTM1 dysfunction. It is possible that the effectiveness of GSH supplementation in those with chronic fatigue syndrome may be in part dependent upon their genetic status with reference to the GSTM1 gene. It is also possible to possess a mutant genetic makeup (GSTM1-0/0) that does not allow for the production of GSH.
It has been estimated that 40-60% of the population may have two copies (one from each parent) of the same mutant form of the GSTM1 gene, lacking that gene's normal function. The health outlook for chronic fatigue patients with GSTM1-0/0 is worse than for those who do not possess that genetic make-up.
If someone is in that population without an active GSTM1 gene, they may need to compensate by eating more broccoli or by eating “super broccoli” that has higher levels of the active plant chemical sulforaphane. Consuming larger portions of broccoli or super broccoli makes it possible to retain greater amounts of sulforaphane not to mention other vitamins and minerals.
Considering that most of us have no idea what type of GSTM1 gene we carry nor do we know how much broccoli is enough, eating broccoli and other cruciferous vegetables as part of a healthy lifestyle is highly recommended.
If someone can't handle all that broccoli, then consider broccoli sprouts in salads or on sandwiches. They are higher in sufloraphane anyway.
Genetics aside, as Dr. Hyman stated, as we age our levels of glutathione steadily decline.
This correlates with his observations that the lowest GSH levels are seen in the oldest, sickest, hospitalized patients and the highest levels in the younger, healthier individuals. The charts shown above and to the right illustrate this quite well.
The good news is that supplementation with a GSH accelerator product GSH levels are restored across all groups, both the healthy and catastrophically ill.
The chart above illustrates the remarkable increase in GSH after even short periods of supplementation.
Methylation refers to the attachment or substitution of a methyl hydrocarbon group on various molecules through the interaction of appropriate enzymes.
It's called methylation because the hydrocarbon in question is methane and in human biochemistry, a hydrogen atom gets replaced with the methyl group.
Dr. Van Konynenburg, PhD., an independent researcher in glutathione and the methylation cycle for many years, believes that the fundamental biochemical issue in a large subset of chronic fatigue syndrome (CFS) patients is that the methylation cycle is blocked. The main goal of this treatment approach is to remove this block and restore the methylation cycle.
He also believes that GSH depletion is directly responsible for many of the features of CFS, but that it is usually not possible to normalize the GSH levels on a permanent basis by direct supplementation of glutathione building blocks.
Rather, the methylation cycle block must be corrected first to break the cycle that is holding down the glutathione levels. In addition to this, about one-third of CFS patients, because of particular genetic mutations described in the previous paragraph, cannot tolerate supplementation with GSH or other substances intended to help them directly build GSH.
In biological systems, methylation is enabled by enzymes and is extremely important in several areas. Methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA metabolism. Methylation of heavy metals can also occur outside of biological systems.
Thus, if the process is blocked and unable to occur, we will have problems in a lot more areas than chronic fatigue.
The 70,000 to 80,000 papers submitted on glutathione are backed up by numerous clinical studies. There is no doubt about the importance and function of GSH on one’s health. So we can safely talk about the benefits of glutathione all day without worry.
This linked page deals with GSH and, what is interesting about it, is that it contains probably 200 or so links to Glutathione related PubMed articles detailing many of the aforementioned clinical trials. The links are in the drop down menu of the "Glutathione" tab.
Besides the actual amino acid building blocks of GSH, there are a number of nutrients that must be present for optimal absorption of the building blocks by the cell.
Mandatory supplements for general health are a high quality omega-3 fish oil to help control the production inflammation agents such as leukotrienes and prostaglandins. A high quality, natural multi-vitamin, mineral and phytochemical formulation is also mandatory.
Then we come to the GSH absorption enhancers.
Alpha Lipoic Acid
Alpha Lipoic Acid (ALA) is mentioned first because cellular energy in the form of Adenosine Triphosphate is needed to drive the process that builds glutathione in the cell.
ALA is a fatty acid found naturally in every cell and it converts glucose into energy. It is also a strong antioxidant in its own right but also works to recycle other antioxidants such as vitamin C and depleted glutathione (GSSH) back to a useable form. Stated plainly, Alpha Lipoic Acid increases the formation of glutathione.
Methionine synthase is required for the synthesis of the amino acid,
methionine, from homocysteine. Methionine in turn is required for the
synthesis of S-adenosylmethionine, a methyl group donor used in many
biological methylation reactions, including the methylation of a number
of sites within DNA and RNA.
So it appears that B12 is critical to the proper functioning of the methylation cycle
Folate is also essential for the metabolism of homocysteine, and helps maintain normal levels of this amino acid. From prior discussions, we know that high levels of homocysteine is a strong marker for heart disease.
Selenium is an essential mineral and micronutrient which is required for biologic activity in proteins to occur; in other words, it is a cofactor.
It is needed for the reduction of the oxidation number of an atom in antioxidant enzymes such as glutathione peroxidases. Glutathion peroxidases are a family of enzymes that work mainly to protect an organism from oxidative damage.
So the bottom line is that the incorporation of selenium into proteins acts to prevent cellular damage from free radicals and we would think that it would be found in glutathione support supplements. If you check the labels on GSH support supplements, chances are selenium will be missing.
This is probably because selenium deficiency in North America is extremely rare since a normal diet in the U.S. is already rich in selenium. Supplementing selenium on top of normal food intake of Sn would likely take most people to upper limit or over the recommended daily allowance.
If the word silybum or silymarin appears on a supplement label, you can be sure it is the Milk Thistle herb. For some 2000 years herbalists have been using the seeds to treat chronic liver disease and protect the liver from toxins.
Extracts of milk thistle are now used to treat cirrhosis of the liver, chronic hepatitis and toxin induced liver damage. The latter includes acetominophen damage which has been getting a lot of press recently
Silymarin, or milk thistle, has antioxidant and anti-inflammatory properties, and it may help the liver repair itself by growing new cells. Thus it is no wonder that such an herb would be included in the formulation of a glutathion support supplement.
Quercetin is one of the phytochemical flavonoids and if you see a red skin on apples or onions, you will know that quercetin is present. It is a powerful antioxidant and has been shown to have anti-histamine and anti-inflammatory benefits.
The American Cancer Society says that while quercetin "has been promoted as being effective against a wide variety of diseases, including cancer," and "some early lab results appear promising, as of yet there is no reliable clinical evidence that quercetin can prevent or treat cancer in humans."
That statement doesn't mean that quercetin can't or won't help fight cancer cells, it just means that reliable testing acceptable to the FDA hasn't been conducted.
Cordyceps is a fungus long used in Chinese medicine where it was valued in restoring energy and promoting longevity. It affects numerous human body systems including the circulatory, respiratory, and immune systems, as well as the liver and kidneys.
According to Sloan-Kettering, "Cordyceps stimulates the number of T helper cells, prolongs the survival of lymphocytes, enhances TNF-alpha and interleukin 1 production, and increases the activity of natural killer cells in cultured rat Kupffer cells".
"Another study shows that cordyceps may be effective against tumor celIs by down-regulating MHC class II antigen expression. In addition, anecdotal data suggest reduction of cyclosporin and aminoglycoside-induced renal toxicity, although the mechanism of action is not known".
While Cordyceps is good for us humans, it's a true horror movie for the insect world. The short video below is embedded here just for the fun of it. Be glad you're not an ant in the jungle.
Credit: Cordyceps: Attack of the Killer Fungi - Planet Earth BBC Wildlife, narrated by David Attenborough; Nov. 3, 2008, standard YouTube License.
Throughout this article, one might wonder how GSH levels are measured in the body and why it isn't done as a routine thing whenever we visit a doctor's office. Is it complicated, expensive, time consuming and reliable? Yes, to all of those items.
Why isn't a simple test kit available that can be used to get a quick reading on our GSH levels? There is; in fact several of them, but they are also expensive and unless one really knows what they are doing, it is best that a trained medical practitioner in this area conduct and interpret the test.
Quite a few patents have been issued for glutathione testing methods.
A Culture Testing Approach
A more recent one is U.S. Patent #7279301, issued October 9, 2007 to J. Fred Crawford, titled "Methods of determining Deficiencies in Intracellular Levels of Cysteine and Glutathione". It uses cultures of various mediums to assess the growth of lymphocytes in response to the addition of or withholding of specific nutrients.
From "Patent Storm", we read the description as, "The present invention relates to the measurement of levels of intracellular function of cysteine and GSH so as to provide one measurement of an individual's capability of preventing degenerative disease and dealing with oxidative stress.
An Optical Density Approach
Way back in 1975, US patent No. 3864085 was assigned to Princeton Biomedix in Princeton, NJ. for "A method for the Quantitative Colorimetric Determination of Reduced Glutathione in Blood".
The method involves mixing a sample of blood with a reagent containing stabilized tungstic acid, ethanol, and 5,5'-dithiobis (2-nitrobenzoic acid). The mixture is centrifuged and the optical density of the supernatant is measured.
The supernatant is mixed with a buffer to get a final pH of from about 7 to about 10, and the optical density is again measured. The glutathione concentration is determined from the optical density measurements. For interested parties, the URL for this patent is:
A Flow Cytometry and Fluorescing Laser Approach
A small randomized controlled trial of oral N-acetylcysteine(NAC), organized primarily by Drs. Leonard and Leonore Herzenberg, both PhD’s, at Stanford University, and designed by them and Greg Dubs, Ph.D., who conducted the trial -- was run in San Francisco in 1993 and 1994.
They examined the survival rates of HIV patients against their levels of glutathione.
GSH levels were measured within individual cells, using flow cytometry, the same technology used to measure CD4 and CD8 cell counts.
The "CD" stands for "cluster of differentiation or cell differentiation glycoproteins" CD4 is a name given to T-helper cells, white blood cells that fight infection, and CD8 refers to suppressor T-cells.
Blood cells from the patient were treated so that the glutathione within the cells was changed chemically, to a florescent substance which glowed when hit by certain laser light. The strength of the glow, indicating the concentration of glutathione in that cell, was measured as the cells were passed single file through a small tube, and the result for each cell was separately recorded by a computer.
To help check that the technology was working correctly, the glutathione level in CD4 cells was correlated with that in the blood (measured by more standard chemical tests), and with that in CD8 cells, monocytes, natural killer cells, and B-cells.
The glutathione levels turned out to be comparable no matter where they were measured. The Herzenberg’s developed the use of flow cytometry for medical purposes and their laboratory is among the best in the world in using this technology. The URL to read more about this method "http://www.aids.org/atn/a-266-01.html".
A quick search of the internet found several companies offering glutathione test kits. The two mentioned below were selected just for the purpose of showing that they are available and to give an idea of their cost.
1. A total Glutathione Detection Kit is offered by Assay Designs for $330.00. It is labeled as a "Creatinine Colorimetric Detection Kit" and uses a urine sample to normalize it with creatinine.
The URL is:
2. A test kit from BioAssay Systems in Hayward, CA. called the "QuantiChrom Glutathione Assay Kit" is based on a quantitative colorimetric assay of reduced glutathione. It takes 30 minutes and costs $279 for the kit. The URL to see this kit is:
How about a cosmetic application for the Mother of all Antioxidants.
Who would ever believe an antioxidant could be used to lighten dark skin? Nevertheless, GSH has recently been used by the cosmetics industry to inhibit melanin. Melanin is the substance that gives skin its color and is formed as part of the process of metabolizing the amino acid tyrosine.
It's not so hard to believe knowing that GSH is the product of enzyme reactions on several amino acids driven by cellular adenosine triphosphate. Melanin production is dependent on reactions involving the amino acid enzyme tyrosinase and the dopamine precursor L-Dopa.
GSH has been shown in studies to inhibit melanin synthesis in the reaction of tyrosinase and L-DOPA.
When melanin synthesis was inhibited, it was restored by increasing the concentration of L-DOPA, but not by increasing tyrosinase indicating that GSH inhibited the binding between tyrosinase and L-DOPA. Although the synthesized melanin was concentrated within an hour, the aggregation or concentration was inhibited by the addition of glutathione.
These results indicate that glutathione inhibits the creation and joining of melanin molecules by interrupting the function of L-DOPA. The end result of the inhibition is a reduction of melanin in the skin and thus a lighter skin color.
So because of the relationship between GSH, L-dopa and tyrosinease, we have a whole host of cosmetic products designed to make dark skin lighter. In several countries, glutathione products (or counterfeit GSH) are sold as whitening soaps, creams or lotions.<
GSH and Acetaminophen
Acetaminophen, the active ingredient in Tylenol, has been in the news lately for its implication in liver failure.
The FDA will likely put new restrictions on acetaminophen per an advisory committee recommendation, saying "the move would protect people from the potential toxicity that can cause liver failure and even death".
The implications for glutathione and treatment of acetaminophen toxicity are impressive.
Baby mice have a story to tell. While every cell in the human body is capable of synthesizing GSH, liver synthesis of glutathione has been shown to be essential.
If fetal mice are genetically modified to block the synthesis of GSH only in their liver, they will die within 1 month of birth. So the ability of the liver to correctly construct glutathione would seem to be a life or death proposition.
Thus it follows that if acetaminophen toxifies a liver to the point of failure and knowing that GSH is the best antioxidant and detoxifying agent known and if GSH levels in the body and liver in particular are low, the patient’s fate is sealed.
The very scientific description of the acetaminophen and glutathione reactions as given in Wikipedia is,
"GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria.
However, it is also capable of participating in non-enzymatic conjugation with some chemicals, as in the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by acetaminophen that becomes toxic when GSH is depleted by an overdose of acetaminophen".
"Glutathione conjugates to NAPQI and helps to detoxify it, in this capacity protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process.
The preferred treatment for an overdose of this painkiller is the administration of N-acetyl-L-cysteine, which is processed by cells to L-cysteine and used in the de novo synthesis of GSH."
What all this means in plain English is that if we take large doses of Tylenol (or any acetaminophen compound) we should keep our GSH levels as high as possible because it protects and detoxifies the liver. Now wasn't that easy?
In leaving "Glutathione", the message should be clear that everyone needs to maintain their intracellular levels of GSH as high as possible and the only way to do that these days is through supplementation.
It is never too late to start; well it might be too late when they start to shovel the dirt onto the casket.
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