MS MuSings
Monthly Online Magazine
by and for those with MS,
Multiple Sclerosis
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MS MuSings Monthly Online Magazine by and for those with MS, Multiple Sclerosis |
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MS MuSings does not endorse any particular treatment for Multiple Sclerosis. We encourage you to talk to your own doctor before engaging in any treatment options you may find here. RAISING GSH LEVELS If glutathione is manufactured within the body, what can we do to maintain or increase GSH levels? Some pharmaceutical drugs can do it, and so can some natural sources. Eating glutathione cannot. There are many ideas about how to raise GSH levels in the body but only a few actually work – and some of them have side effects. In order to take advantage of the great potential of GSH in health and disease we must dispel the myths and clarify the facts. This requires an understanding of the biochemical makeup of this important protein. GSH is a tripeptide – a protein made up of three amino acids – in this case, glycine, glutamate (glutamic acid), and cysteine. The chemical structure of glutathione does not easily survive the digestive process, so eating it will not raise GSH levels. The body manufactures it within the cell from building blocks (precursors) of GSH in our food. Glycine and glutamate are readily available in North American diets, but cysteine-containing proteins are much harder to come by. Figure 12 shows sources of these three component amino-acids of glutathione. Cysteine – a sulfur-containing, or "thiol" amino acid – is responsible for the biological activity (bioactivity) of the whole molecule. Cysteine as an isolated amino acid has trouble getting from your mouth to your cells. Much of it is broken down or altered in the digestive tract and bloodstream. So we must take cysteine in a form that resists breakdown. If the body doesn’t get these sulfur-containing amino acids into the blood, we can’t make GSH. Other thiol amino acids include cystine (different from cysteine) and methionine. Cystine is known as a "disulfide" amino acid because it contains two cysteine molecules connected by their sulfur atoms – a so-called dilsulfide bridge. Cystine is not generally found as a free amino acid. Methionine may serve as a glutathione building block, but it has the tendency to convert into homocysteine, which raises the risk of heart disease. There are several ways to raise GSH levels. Both pharmaceutical and natural products are listed in figure 13 and described in this chapter. We also describe how GSH as a whole works with other nutrients or co-factors.
GSH PRECURSORS & CELLULAR MANUFACTURE The building blocks (precursors) glutamate, cysteine and glycine from any source must be in a form that can be transported from the mouth, through the digestive system, into the blood and finally through the cell wall. Once there, the cell combines them into GSH. Glutamate is derived from food sources containing uncooked glutamic acid, glutamine and glutamate. It is found in protein supplements such as Immunocal and other whey derivates. Cysteine comes from such protein sources as eggs, raw milk, undenatured whey protein and in small amounts from other foods. The amino acid methionine can break down into cysteine. Various pharmaceutical drugs serve as cysteine delivery systems. Glycine is found in foods rich in the amino acids choline, glycine, serine and threonine. Only when these three precursors are absorbed by the body and have passed through the wall of individual cells can the body manufacture glutathione. DRUGS Many of the research studies described in this book were carried out using pharmaceutical drugs to raise GSH levels in test subjects. These drugs are described first. Afterwards, we discuss natural GSH-promoting substances. NAC (N-ACETYL-CYSTEINE) NAC is a potent glutathion precursor that has been available as a drug (Mucomist, Parvolex, etc.) and also on the shelves of health supplement stores for years. It is a variant of the amino acid L-cysteine, with an ‘acetyl’ molecule attached. This greatly enhances the bioavailability (usefulness) of cysteine to the cell, enabling it to survive the trip from the digestive system into the blood, and finally through the walls of individual cells. For many years this drug has been used to break up mucus in lung diseases such as cystic fibrosis, chronic bronchitis, asthma and emphysema and is still the standard treatment for acetaminophen overdose. Most GSH studies on humans used NAC. Together with other animal and laboratory experiments they measured the effectiveness of NAC against a host of diseases characterized by oxidative stress, free radical formation and glutathione depletion. Such diseases include infection by AIDS/HIV, cancer, heart disease, tobacco damage and heavy metal poisoning. Its use in cancer therapy is exciting because it can substantially raise glutathione levels and has emerged as a promising anticarcinogen, especially for smokers and others at high risk for cancer. It is also known to have direct anti-tumor effects and its ability to detoxify normal cells helps it counteract the side effects of both chemotherapy and radiotherapy. However, its effectiveness depends on circumstances and it must be used wisely. Cancer patients wishing to take NAC must discuss it with their oncologist. NAC has been used in AIDS research since the early 1990’s when it was found that HIV patients become profoundly glutathione deficient. Must data has resulted from studies at the National Institute of Health, Stanford University, and many other highly respected institutions around the world. NAC therapy has two common problems: firstly, it is a pharmaceutical drug and carries a certain toxicity itself; secondly, NAC-induced GSH levels reach a rapid peak and decline within hours. The drug is thus described as having a short half-life. Rapid peaks are often followed by a rapid drop, often to below normal levels. To maintain constantly elevated GSH levels, NAC must be swallowed or injected several times per day, and this is very hard on the body. Many people eating NAC report unwanted symptoms, including rash, wheezing, nausea, vomiting, cramps and diarrhea. Others find the smell and taste unacceptable. Although rare, death has been reported in association with NAC. However, it is still the most commonly used way to raise glutathione levels in clinical settings. Treating drug overdoses or acute pulmonary disease with NAC requires the monitoring of health professionals. Suggested non-prescription oral doses range from 200-2,400 mg/day depending on one’s state of health. SAM (S-ADENOSYL-METHIONINE) SAM is a form of methionine that has already been partially converted to cysteine. It can be useful in the treatment of cirrhosis and cholestasis and is becoming popular as a mood stabilizing medication in Europe. Its possible use in America as an antidepressant is currently under investigation. SAM is expensive to synthesize and may react poorly with other antidepressants. Its side effects at therapeutic doses can include dry mouth, agitation and gastrointestinal problems. OTC AND OTZ OTC (ornithine decarboxylase, procysteine) and OTZ (Oxothiazolidine carboxylate) are synthetic delivery sources – a substrate for the enzyme 5-oxyprolinase which first converts them to S-carboxy-cysteine, and later hydrolyzes them to cysteine, which the liver uses to make GSH. However, the required enzyme 5-oxyprolinase is not present in all tissue and the value of OTC/OTZ is limited. Most studies have used either laboratory animals or human tissue cultures. Small studies have been conducted with AIDS and cancer patients, and further work is in progress. These drugs are not readily available to doctors or the general public. GSH MONOESTERS, GSH DIESTERS These synthetic compounds make quite effective GSH delivery systems but they can be metabolized into alcohol, which potentially depletes GSH. Very few studies have been carried out on humans, but well-recognized GSH researchers such as the late Alton Meister and Mary Anderson have been optimistic about further elaboration of its clinical applications. However, the long-term safety of these products is open to question. NATURAL PRODUCTS ORAL GLUTATHIONE Why not just eat GSH? After all, it is freely available in fresh fruits, vegetables and meats. It is also commercially available in pill form or powder from a variety of chemical companies. Unfortunately, pre-manufactured GSH is not particularly helpful to the body. A small amount of reduced protein-bound GSH may make it into the blood stream, but most is lost to the digestive process and cannot effectively raise intracellular GSH levels. Researchers have demonstrated oral GSH’s poor bioavailability, especially in the liver where it is most needed. E.W. Flagg and his team at Emory university, Atlanta even point to a possible decrease in blood GSH after oral ingestion of GSH-containing foods. To put it in medical terms, oral GSH has negligible effect on immunologic parameters. CYSTEINE (L-CYSTEINE) The availability of cysteine determines how much GSH we can synthesize. Why not just eat this non-essential amino acid? It is available through pharmacological supply outlets and at health food stores and may in fact raise intracellular GSH to a small degree. However, cysteine as a dietary supplement can promote hypercysteinemia and potential toxicity. Because cysteine is easily oxidized in the digestive tract, its absorption into the bloodstream and cells is limited. Cysteine that manages to reach the bloodstream is further oxidized into potentially toxic by-products, some of which contain the hydroxyl radical – a highly reactive oxidant. This defeats its intended purpose as an antioxidant. Clinical proof that dietary cysteine has a negligible effect upon immune response has been demonstrated by the Montreal researchers Drs. Gustavo Bounous and Gerry Batist. They compared specific protein precursors in the bioactive whey-protein Immunocal with a cysteine/casein combination. Animals fed oral cysteine showed no positive response. METHIONINE (L-METHIONINE) Methionine is an essential amino acid present in many foods and has been identified as a GSH precursor. It is also available from pharmacological supply outlets and health food stores. The metabolic transformation of methionine into GSH is a complex process, greatly affected by other factors. For example, methionine levels are very low when liver disease is present and non-existent in newborns. Above certain doses it can be toxic. Of great concern, methionine is also a precursor of homocysteine, recently identified as a high risk factor in the development of atherosclerosis (hardening of the arteries). MELATONIN Melatonin is a naturally-occurring hormone manufactured by the pineal gland, which lies deep within the brain. Melatonin is a derivative of the amino acid tryptophan and the neurotransmitter serotonin. It has long been recognized for its role in the regulation of sleep and waking cycles and has gained popularity as a supplement for the treatment of jet lag, insomnia and other sleep disturbances. Like most hormones, melatonin is rarely involved in just a single function. Recent research has led to a great number of papers describing the functions of melatonin, including potential anti-aging effects, application against Alzheimer’s disease, cluster headaches, cancer prevention, cancer therapy, and as an immunostimulant. Melatonin is known to be a powerful antioxidant and plays a role in stimulating other antioxidants as well. Apart from its ability to function independently as an antioxidant, melatonin has been shown to effectively raise glutathione levels in many tissues including the brain, liver, muscle and blood serum. Some of its positive benefits have been ascribed specifically to this ability. An interesting scientific study measured melatonin levels against glutathione levels during sleep. A research team at the University of Texas showed that subjects given melatonin doubled their brain glutathione levels within 30 minutes. Like GSH anywhere in the body, it eliminates toxic hydroxyl radicals, but this brain GSH is more effective with sleep. It seems that melatonin may protect brain and nerve tissue because of its GSH-enhancing ability. Several European studies have supported these findings. This same team in Texas led by R.J. Reiter has published many papers linking melatonin to GSH production. In a sports physiology experiment, muscle glutathione was measured before and after extended exercise. By using melatonin to pre-treat subjects before the stress of exercise, the usual, significant decreases in GSH levels due to oxidative stress were eliminated. The long term safety of melatonin has not yet been established and response to it varies from person to person. This product should only be used in consultation with an appropriate health professional. GLUTAMINE Glutamine (GAM) is the most abundant free amino acid found in the body. It is common in both blood and muscle tissue, and is the second most common amino acid in the brain after glutamic acid (GA). The three semi-essential amino acids – glutamine, glutamic acid and gamma-amino butyric acid (GABA) – are closely related and are classified as glutamate amino acids. Glutamate is a salt of glutamic acid. Described by Dr. Eric Braveman as "the brain’s three musketeers," GAM, GA, and GABA are close in name and category but quite different in function. In the brain, GABA serves as an inhibiting (calming) neurotransmitter, GA as an excitatory neurotransmitter and GAM mainly as an energy source and mediator of both GA and GABA. Some proponents of glutamine have referred to it as "brain fuel". These three amino acids usually fall into the same discussion because they have the ability to metabolize into one another. For example, if the brain senses a lack of glutamic acid it may draw glutamine from the muscles into the bloodstream, pass it through the blood-brain barrier and transform it into glutamic acid or glutamate. Nitrogen is a critical component of all amino acids and is often released when they are broken down. Unfortunately this free nitrogen is easily converted to ammonia – especially toxic to nerve tissue and the brain. The liver must work hard to convert nitrogen into urea so it can be excreted in the urine. On the other hand, nitrogen may also attach itself to glutamic acid, forming glutamine. Because glutamine is unique among amino acids – the only one with two nitrogen molecules – glutamic acid serves as a "sink" to collect free nitrogen, protecting many tissues from harm. Glutamine is crucial to the metabolism and maintenance of muscle. It is also the primary nutrient for cells lining the intestinal tract. In periods of stress or severe illness, glutamine levels may fall. That’s why it is such a useful supplement for athletes, surgical patients, those suffering from the muscle wasting of AIDS or cancer and for various gastrointestinal disorders. Glutamine can also boost the immune system, act as a cancer preventative and treatment, detoxify the body and support liver metabolism. Dr. Ronald Klatz of the American Academy of Anti-Aging Medicine (A4M) describes glutamine as a ‘growth-hormone releaser’ and an anti-aging agent. The overlap of the possible clinical applications of glutamine and glutathione is no coincidence. Glutamine supplies the body with glutamate (glutamic acid), the second most important component of GSH after cysteine. Whether taken orally or intravenously, glutamine supplementation raises glutathione concentrations. T.R. Harward in Florida and M. Basoglu in Turkey conducted similar studies to measure the fortifying effect of glutamine on GSH levels in the gut. Levels of lipid peroxidation and oxidative stress both fell in these experiments. Y. Cao in Arkansas found a three-fold increase in intestinal GSH after glutamine supplementation. R. Denno and J.D. Rounds of Harvard University conducted a study on parenteral nutrition – nutrients delivered by routes other than the stomach and gut. This is very important during long surgery and under other special circumstances. They showed that when glutamine was included, plasma glutathione levels rose significantly and supported liver functions. R.W. Hong from the same team showed that glutamine supplementation improved survival odds against such toxic threats as acetaminophen overdose by preserving glutathione stores in the liver. Glutamine also plays a role in cancer therapy. Tumor cells often act as a trap, stealing glutamine from other parts of the body and leading to muscle wasting and atrophy. For this reason, many cancer therapists avoided glutamine in the past, fearing they would be feeding the cancer. It is now known that just the opposite is true. Glutamine promotes GSH production, heightening the immune system’s defense against tumor cells and making it easier for normal tissue to tolerate chemotherapy and radiotherapy. Another University of Arkansas study led by Dr. K. Rouse showed how oral glutamine supplementation could lower glutathione in tumors – making them more susceptible to chemotherapy – and raise glutathione in healthy cells – making them more resistant to chemotherapy. S. Yoshida and A. Kaibara conducted similar experiments in Japan and concluded that glutamine supplementation prevents deficiencies of glutamine and glutathione and improves protein metabolism in cancer victims. Glutamine is found in many plant and animal food sources but is easily destroyed by cooking. Raw spinach and parsley are good sources. Chicken, fish, pork and beef are high in glutamine. However, eating raw meats carries certain health risks. Braver individuals may eat sushi, carpaccio, kibbi, or steak tartar – all uncooked animal products. Glutamine is being widely researched as a nutritional supplement for certain hospitalized patients. More research is still needed and the appropriate dosage for various scenarios is still unclear. The amount demanded by the body during periods of physical stress is still unknown. Store-bought tablets contain as little as 0.5 grams (500 mg). It also comes in powder form – often taken in daily doses of 4 or 5 grams. In extreme situations – following a bone marrow transplant, for example – doses as high as 40 grams per day have been given. Supplemental glutamine must be kept absolutely dry or it will degrade into ammonia. Completely healthy individuals don’t need supplemental glutamine. It can provoke such side effects as gastrointestinal upset. Older people and patients with impaired kidney and liver failure should be cautious. Any serious use of this supplement should be monitored by a health professional. LIPOIC ACID Also called alpha-lipoic acid or thioctic acid, lipoic acid is a disulfide compound that acts as an effective antioxidant, a neutralizer of various toxins including some heavy metals, and an important co-enzyme for recycling other antioxidants including vitamin C, vitamin E and glutathione. Lipoic acid occurs naturally in your body but has also recently appeared on the shelves of health food stores. It is being actively investigated by the scientific community for its medical merits. Research has revealed the benefits of lipoic acid for such conditions as diabetes, HIV infection and AIDS, liver disease, lead and cadmium toxicities, cataracts, poisoning by amanita mushrooms, reperfusion injury (following stroke and heart attack) and vitamin E deficiencies. It also extends the endurance of body builders and their recovery time from injury. You may notice that its advantages entirely overlap those of glutathione. Lipoic acid is vital for converting glutathione back and forth from its oxidized (GSSG) to its reduced (GSH) form (see figure 6, chapter 1). It regenerates vitamin C, vitamin E and coenzyme Q10. It can also provide reduction redox support to other sulfur groups and NADPH energy reactions. Although lipoic acid has been described by many researchers as an antioxidant in its own right, scientists such as H. Bast and G.R. Haenen from the Department of Pharmacochemistry in the Netherlands believe that lipoic acid actually protects against lipid peroxidation by keeping GSH in its reduced (non-oxidized) state, and that GSH is the active antioxidant in this scenario. In fact, they showed that lipoic acid in the absence of glutathione actually promotes oxidation. One reason glutathione has been called the "master antioxidant" is because its critical enzyme glutathione-reductase maintains lipoic acid in its reduced (non-oxidative) state. The ability of lipoic acid to enhance GSH function has been demonstrated by other scientists. E. Buses in Germany established that the protection offered by lipoic acid against radiation damage results from improved cell viability due to elevated glutathione levels. Some leading American researchers in lipoic acid work at the University of California in Berkeley, led by L. Packer. They describe lipoic acid as providing intact cystine, which makes cysteine available to the cells. It is clinically significant that lipoic acid helps restore glutathione when it is deficient. Recommended dosages range from 100 to 200 mg per day. SILYMARIN (MILK THISTLE) The milk thistle plant, known scientifically as Silybum marianum has been used by herbalists for centuries to treat a variety of liver disorders, including hepatitis, alcoholic cirrhosis, jaundice and gallbladder disease, and to fight a number of toxins, including amanita poison mushrooms. The active ingredient of milk thistle is silymarin, a compound made up of the flavonoids silybin, silydianin, and silychristin and found in the seeds. Many clinicians have studied this herbal extract and its use in toxicology and liver disease. It seems to stimulate the growth and regeneration of injured liver cells. However, its bioflavonoids seems to act primarily as free radical scavengers and to support detoxification enzyme pathways. Further studies describing this action have demonstrated silymarin’s impressive ability to promote glutathione production. It clearly prevents lipid peroxidation and maintains GSH levels. Silybin has a protective effect on acetaminophen overdoses – traditionally treated with the drug NAC. Silymarin can increase GSH by as much as 35% in certain glutathione – deficient states and accelerates detoxification of xenobiotics accordingly. Recommended doses vary greatly, from 50 to 500 milligrams three times a day. Toxic reactions can include gas, cramps and diarrhea. Liver diseases should never be treated without the advice of a health professional. WHEY PROTEINS Whey, a large group of proteins, is a constituent of milk from all mammals, including human beings. The most commonly available whey comes from cow’s milk. Raw milk contains 5 to 10% protein, of which 80% is casein and 20% whey. Casein is a mainstay of cheese production. For a long time whey was treated as an insignificant byproduct of the dairy industry but its advantages as a nutritional supplement are now creating a new surge of interest. Many milk derivatives and whey products are marketed to health-conscious people. These products are extremely variable in their protein content, their concentration, the forms of proteins present, and other factors which determine the bio-effectiveness of the product, including the level of protein denaturation. Denaturation refers to a breakdown in the protein structure that may not affect its food value but that can affect is biological action (bioactivity) in the body. Many nutritionists point out that the fat or lactose content of milk products may still be high enough to cause concern. Others have reservations about the milk industry and its liberal use of antibiotics and steroids to boost product. And we cannot ignore the very real issue of fat-soluble and water-soluble environmental toxins passing into the milk. Fresh milk whey contains potent GSH precursors such as lactoferrin, beta-lactalbumin, and serum albumin that are easily denatured. When consumed intact they are easily digestible and their constituent breakdown products pass readily into the bloodstream, serving as cysteine and cystine delivery systems. From there they are taken to individual cells, where these precursors are transported through the cell wall and metabolized into GSH.
These precursors are fragile and easily denatured. They contain thermolabile components that are easily disturbed by heating and a mechanical shape that is quickly broken down by physical stresses such as shaking or churning. By the time most milk products reach your table their bioactivity is entirely lost, although their food value remains. Milk products are usually pasteurized several times to guard against bacterial contamination. This almost inevitably destroys their usefulness as glutathione precursors. In order to maintain these precursors in a bioactive form, special means must be designed and used to extract whey proteins from milk and the process must be carefully monitored. Concentrations of protein in whey products range from as little as 20% to over 90%. They vary greatly in their make-up, as well as to the extent which GSH precursors are denatured or broken down. Some are bioactive. Most are not. BIOACTIVE WHEY PROTEINS (IMMUNOCAL) Bioactive whey proteins contain high levels of non-denatured protein. In scientific terms, they preserve the original bioactivity of the thermolabile components and mechanical shape of the proteins, guaranteeing the highest level of GSH-promoting activity. Our knowledge of the GSH-sustaining effect of dietary whey proteins is the result of research begun at McGill University in Montreal in the early 1980’s. Dr. Gustavo Bounous was studying protein supplementation when by chance he discovered the bioactive potential of whey protein. He investigated this protein’s effect on the immune system and published some exciting results. His findings encouraged many other scientific teams to study these GSH-enhancing qualities in tests on a wide variety of diseases. Dr. Bounous and his team went on to develop Immunocal – a whey protein made under conditions that maximize the protein’s bioactivity. Immunocal has been patented for its immuno-sustaining and GSH-enhancing effects. It is extracted exclusively from milk produced without antibiotics or steroids. The process produces 90%-pure whey protein and has received a patent for its method of use. It has also been recently granted a USA patent as a chemotherapeutic agent. It is the first natural supplement to receive such recognition. Its history is backed up by phase I, II and III clinical trails including research into infectious disease (HIV/AIDS, hepatitis, Lyme disease, bacterial infections), cancer therapy, pulmonary disease, chronic fatigue syndrome and other disorders associated with high oxidative stress and low glutathione activity. It has been sold in Europe and the Orient by pharmaceutical distributors. In North America this all-natural product is available without prescription, although certain governmental agencies and insurance companies will reimburse patients with a physician’s prescription. Undenatured whey protein is a natural extract of milk and an ideal solution – a safe, dependable, effective way to raise and sustain GSH levels. CO-FACTORS FOR GSH PRODUCTION SELENIUM Selenium is a trace element. It functions principally as an antioxidant but does other things too. It is involved in protein synthesis and other metabolic processes and acts synergistically (hand-in-hand) with other antioxidants – in particular vitamin E. Its clinical applications have received a great deal of attention and we are about to see an increase in the number of clinical trials using this mineral. Plants absorb sodium selenite – an inorganic compound in the soil – and convert it into organic seleno-methionine. When we eat these plants the seleno-methionine is either used to make protein or converted once again, this time into seleno-cysteine. The cysteine portion of this molecule contributes to GSH production. The selenium portion is an essential component of the critically important enzyme glutathione peroxidase. Browsing through a list of selenium research and clinical trials, one is reminded of GSH research and clinical trials. Both deal with the same types of disease, clinical symptoms and outcome. Selenium has been linked with heart disease and atherosclerosis, cancer treatment and prevention, liver and pancreatic function, detoxification of heavy metals, immune support, male infertility, AIDS, Crohn’s disease, pancreatitis, cystic fibrosis and multiple sclerosis – a reflection of the contents of this book on GSH. Most scientists agree that the principle way in which selenium fights these diseases is by elevating levels of glutathione peroxidase, the only known metabolically active form of selenium in the body. A recent study sponsored by the National Cancer Institute (USA) caused quite a stir. Having examined favorable reports about selenium being cancer-preventive, it began a study on skin cancer. Patients were given either selenium or a placebo, and monitored for eight years for any recurrence of their skin lesions. Initial results were disappointing – there was no evidence that selenium protects against skin cancer recurrences. However, they were startled to find that their test group suffered significantly lower rates of other cancers, including lung, prostate and colon cancers (see chapters 5, 14 and 15). These unexpected findings rolled over into a host of new studies, some of which are still in progress. Selenium is found abundantly in foods grown in selenium-rich soil and from the meat and dairy products of animals who have been raised on those plants. The suggested daily intake is 40 to 70 micrograms (mcg) – an amount found in normal diets and not requiring supplementation. Be careful – too much selenium has a well-known toxicity and some individuals suffer ill effects at doses as low as 205 mcg/day. At 1,000 mcg/day, many symptoms become apparent. Selenium is usually sold in doses ranging from 25 to 200 mcg. It may be a natural food supplement but it must be approached with caution. People in good health with a reasonable diet should take no more than 25 to 50 mcg/day. VITAMINS B1, B2 The water-soluble vitamins B1 (thiamine) and B2 (riboflavin) were two of the first vitamins discovered back in the 1920’ and 30’s. They each perform several important functions in our body. Vitamin B1 is essential for carbohydrate metabolism and energy production. It also helps conversion of fatty acids into steroid hormones. Vitamin B2 is just as involved in energy production and hormone regulation and helps combine individual amino acids into larger proteins, glutathione being one of them. Vitamins B1 and B2 maintain glutathione and its related enzymes in their active forms, enabling GSH to function at its optimum capacity. They are integral constituents of coenzymes that product glutathione reductase and NADPH – essential for recycling oxidized glutathione (GSSG) back to reduced glutathione (GSH), the active form. The currently recommended daily intake of these two vitamins is 1 to 2 milligrams. Most clinicians believe that these values are far too low and it’s just a matter of time before they are raised. Doses of 50 to 150 mg are not uncommon and many feel that the optimum level lies between 25 and 300 mg/day. It is apparently not toxic – these higher doses have revealed no adverse effects. Nutritionists at times prescribe 500 mg/day for some conditions, but for most near-normal states 10 to 50 mg/day should suffice. VITAMINS B6, B12, & FOLIC ACID Like their cousins B1 and B2, vitamins B6 (pyridoxine) and B12 (cobalamin) are also water soluble. Both play an indirect but important role in glutathione metabolism. Vitamin B6 is one of the most widely used vitamins in our body and contributes to over sixty enzyme systems. It is crucial for the metabolism and function of many amino acids and essential fatty acids, so the majority of our tissues depend on it. Vitamin B12 acts as a coenzyme in the production and regulation of red blood cells, myelin and other neurological tissues. It is prone to depletion in various diseases including malabsorption, alcoholism, pernicious anemia and the complications of strict vegetarianism. Folic acid – also known as folate or folacin – takes part in a number of various processes including DNA synthesis and neurotransmission. It works together with vitamin B12 in amino acid metabolism and protein synthesis. Its role in cardiovascular disease has been recently highlighted – it lowers elevated homocysteine levels, a serious risk for cardiovascular disease. Folate tends to shunt cysteine preferentially towards glutathione production rather than homocysteine production. North American recommended daily dietary allowances for vitamins B6, B12 and folate are 0.5 to 2 mg, 1 to 2 mcg, and 105 to 250 mcg respectively. Some nutritionists may recommend as much as 50 to 500 mg of vitamin B6, 100 to 500 mcg of vitamin B12, and 400 to 2,000 mcg of folic acid. Vitamin B12 has negligible toxicity but vitamin B6 can be neurotoxic at higher doses. Folic acid is relatively safe unless taken alone by someone deficient in certain B-vitamins, particularly B12. Under normal circumstances we recommend a maximum 10 to 50 mg of B5, 10 to 50 mc of B12, and 400 mcg of folic acid per day. VITAMIN C The water-soluble vitamin C has various names, including ascorbate and ascorbic acid. It has been a focus for antioxidant research longer than any other antioxidant. Linus Pauling, the foremost researcher in vitamin C is considered by many to be the grandfather of free radical biology. He blazed the trail along which this and many other books have evolved. Thousands of articles have been written about it and research is still going strong. Yet even after all this time the topic of vitamin C in health and disease is still fraught with controversy. The classic disease of vitamin C deficiency is scurvy. More recently, the use of vitamin C has been studied in cancer, anti-aging medicine, cardiovascular disorders, emotional or physical stress, and of course in immunology and infectious disease. It is an antioxidant but performs many other functions in our body. It is involved in bone, cartilage and soft tissue repair, support of various biologic systems including the recycling of B-vitamins, folic acid and other antioxidants, iron storage and a list of other life-sustaining functions far too long and involved for us to discuss in this book. It is mentioned here because of its important links with glutathione metabolism. It is intimately involved in the GSH-driven glutathione-transhydrogenase enzyme system which keeps GSH, vitamin C, vitamin E and other antioxidants in their reduced (non-oxidized) state. Numerous studies have demonstrated the ability of vitamin C to support glutathione levels and activity. C.S. Johnston, C.G. Meyer and J.C. Srilakshmi from Arizona State University conducted a double blind study comparing the GSSH levels of three groups – one ate a low-vitamin C diet, another ate vitamin C at 500 mg/day, and the third received 2,000 mg/day. Those taking the vitamin had significantly higher GSH red blood cell counts than the no-vitamin C group. There was little difference in glutathione level between the two groups taking vitamin C. The converse is equally true. Vitamin C is far les effective and rapidly depleted without adequate glutathione. When a vitamin C molecule mops up a free radical, it effectively neutralizes it. However, the vitamin C complex is now tied up. It is either ejected from the cell and eliminated by the body, or it is recycled to go back and do more work. In the latter case, glutathione is the recycling agent. GSH and GSH enzymes accept the free radical from the vitamin C complex and free it up to get back to work. This cycle drives antioxidant function in our bodies (see figure 6, chapter 1). S. Mendiratta, J.M. May, and Z.C. Qu of Vanderbilt University in Nashville carried out a persuasive study demonstrating this phenomenon in human plasma and red blood cells. When GSH content was intentionally depleted with the chemical diamide, vitamin C was either eventually lost from the plasma or severely functionally impaired in the red blood cells, remaining in its oxidized state (dehydro-ascorbate). Glutathione enabled its transformation back into the functional form, ascorbate. There is still much dissent over the appropriate dosage of vitamin C. Although both the American and Canadian recommended daily allowances of vitamin are in the range of 30 to 60 mg/day, many scientists and nutritionists feel that this figure is far too low. Advocates of megadosing with vitamin C are not adverse to taking 10, 20, or 30 thousand mg/day. It is well documented that supplies of vitamin C beyond a certain threshold are eliminated from the body, often accompanied by cramps and diarrhea. Other researchers feel that vitamin C is potentially harmful at high doses. It may serve as a pro-oxidant, and also strongly competes with other antioxidants, occasionally impairing their function. E.W. Flagg and her team at Emory University in Atlanta showed that high levels of vitamin C intake corresponded to lowered GSH levels. If glutathione levels are adequate, no more than 200 to 1,000 mg/day of vitamin C is necessary. VITAMIN E The fat-soluble vitamin E is America’s second most popular supplement next to vitamin C. Given the wealth of information and positive clinical studies done on this vitamin, its popularity will probably continue to grow. Some have estimated that if all North Americans took adequate vitamin E supplements, health-care costs could be reduced by billions of dollars. Studies have shown benefits in cancer prevention and therapy, cardiovascular disease, diseases of aging, wound healing, neurodegenerative disease and many other states of health. Besides it clearly defined role as an antioxidant, it plays a part in detoxification of many compounds and in the immune system. Like vitamin C, vitamin E has an important role in the GSH-driven glutathione-transhydrogenase enzyme system which keeps GSH, vitamin C, vitamin E and other antioxidants in their reduced (non-oxidized) state (see figure 6, chapter 1). Studies with GSH and vitamin E resemble those with GSH and vitamin C because these antioxidants depend on each other for proper function and recycling. The synergistic effect of vitamin E and glutathione can be attributed to vitamin E’s ability to help GSH with antioxidation, and to its direct modulation of glutathione-related enzymes. Vitamin E comes in several forms, natural and synthetic. This vitamin actually represents different substances of which alpha-, beta-, delta-, and gamma-tocopherols are the most active. The natural form of tocopherol most often found is D-alpha-tocopherol, which is more potent and bioavailable than the synthetic DL-alpha-tocopherol. The daily-recommended allowances range from 25 to 50 IU (international units), however studies hint that most of us would experience more benefit at much higher doses. Popular regimens use doses from 100 to 1200 IU/day. With adequate GSH levels, it is unlikely that one needs more than 400 IU/day. At excessive levels, vitamin E is toxic and can provoke gastrointestinal, cardiovascular and neurological side-effects. OTHER MICRONUTRIENTS Magnesium deficiency can lead to impairment of the enzyme gamma glutamyl transpeptidase, which is important in the synthesis of glutathione. Vanadium is a trace element that depends on glutathione to remain in a reduced (non-oxidized) state and to increase its bioavailability. Under certain conditions, vanadium may recycle GSH. However, vanadium in high concentrations is toxic and may deplete glutathione. Zinc deficiency is also detrimental to glutathione metabolism, reducing GSH concentration, especially in red blood cells. Zinc also carries a certain toxicity, and may reduce GSH at high levels. CONCLUSION For our bodies to sustain healthy glutathione levels, the limiting factor in our daily intake of food is usually the amino acid cysteine. It must be in a form that can survive the trip from our mouths to our cells. Unfortunately, merely eating either glutathione or the free amino acid cysteine does not give the cell what it needs to manufacture glutathione. Several drugs and natural products can do this efficiently. NAC (N-acetyl-cysteine) is a powerful drug that is commonly used in critical care medicine, toxicology, and pulmonary medicine. It has been the most researched of all the GSH-promoting modalities, and newer clinical applications are being developed all the time. Many natural products exert some of their positive effects by supporting or directly raising glutathione levels. Undenatured whey proteins are an exciting development. A whey protein isolate, Immunocal, has recently been patented to augment glutathione levels and enhance immune function. Ongoing clinical trials are underway to test it with a number of different medical conditions. REFERENCES TO CHAPTER 4 RAISING GSH LEVELS
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