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Mercury, in its various forms, has a great affinity for certain minerals, as well as protein and non-protein molecules in the body. Mercurials have a great attraction to the sulfhydryls or thiols. The mercury atom or molecule will tend to bind with any molecule present that has sulfur or a sulfur-hydrogen combination in its structure. This process of combining with a metal to form a complex in which the metallic ion is sequestered and firmly bound is called chelation. A thiol is any organic compound containing a univalent radical called a sulfhydryl and identified by the symbol -SH (sulfur-hydrogen). A thiol can attract one atom of mercury in the ionized form and have it combine with itself. Because it is a radical, it can enter into or leave this combination without any change. Mercury and lead both have a great affinity for sulfur and sulfhydryls and are capable of affecting the transsulfuration pathways in the body.
The primary sulfur-containing protein amino acids in the body are cystine, cysteine, methionine, and taurine. There is also a sulfur-containing tripeptide (having three amino acids) called glutathione that is composed of glutamic acid, cysteine, and glycine. Sulfur exists in a reduced form (-SH) in cysteine and in an oxidized form (-S-S) as the double molecule cystine. Whenever mercury binds to one of these sulfur-containing molecules, it reduces the molecule's availability for normal metabolic functions.
Sulfur is present in all proteins, which makes it universally available throughout the body for binding with mercury. Some of the important biochemical sulfur-containing compounds of the body besides glutathione are insulin, prolactin, growth hormone, and vasopressin, and science has not yet investigated the effect of mercury upon them. Mercury has a particularly high affinity for thiol groups and progressively less for other groups in the following sequence: sulfur, amides, amines, carbon, and phosphate. Because of this, mercury has the potential of binding to proteins throughout the body. Mercury compounds are formed by the binding of mercury to the biological binders albumin or cysteine.
The principal biological reaction of mercury is with thiols to form mercury mercaptides. The sulfur groups are often referred to as mercaptans because of their marked affinity for mercury. Mercaptan is defined as any compound containing reduced sulfur bound to carbon. When a metal, such as mercury, replaces the hydrogen ion of the reduced sulfur, the resulting compound is called a mercaptide. Mercury can form at least three compounds with cysteine in which all or a part of the mercury is bound firmly as a mercaptide. Mercury may cause damage, especially to the placenta, by inactivation of sulfhydryl groups in cellular enzymes. Mercury interacts with sulfhydryl groups and disulfide bonds, as a result of which specific membrane transport is blocked and selective permeability of the membrane is altered. Mercury also combines readily with phosphate and heterocyclic base groups of DNA. It also combines with other ligands: amide, amine, carboxyl and phosphoryl groups.
Glutathione is Magnesium-Dependent
Glutathione protects the cells from oxidative-stress-induced apoptosis and glutathione levels are magnesium dependent! Glutathione is a very important detoxifying agent, enabling the body to get rid of undesirable toxins and pollutants. It forms a soluble compound with the toxin that can then be excreted through the urine or the gut. The liver and kidneys contain high levels of glutathione as they have the greatest exposure to toxins. The lungs are also rich in glutathione partly for the same reason. Many cancer-producing chemicals, heavy metals, drug metabolites etc. are disposed of in this way.
Glutathione (glū'tə-thī'ōn') is a polypeptide, C10H17N3O6S, of glycine, cysteine, and glutamic acid.
Glutathione synthetase requires γ-glutamyl cysteine, glycine, ATP, and magnesium ions to form glutathione. In magnesium deficiency, the ss y-glutamyltranspeptidase is lowered. There is a direct relationship between cellular magnesium, GSH/GSSG ratios, and tissue glucose metabolism. Magnesium deficiency causes glutathione loss and this is unwelcome as the clouds of radiation are touching down across the northern hemisphere. Magnesium deficiency causes glutathione loss, which is not at all healthy because glutathione helps to defend the body against damage from cigarette smoking, exposure to radiation, cancer chemotherapy, and toxins such as alcohol and just about everything else.
According to Dr. Russell Blaylock, low magnesium is associated with dramatic increases in free radical generation as well as glutathione depletion and this is vital since glutathione is one of the few antioxidant molecules known to neutralize mercury. “For every molecule of pesticide that your body detoxifies, you throw away or use up forever a molecule of glutathione, magnesium and more,” says Dr. Sherry Rogers who goes on to say that, “Your body uses nutrients to make this glutathione and it uses up energy as well. Every time we detoxify a chemical, we use up, lose, throw away forever, a certain amount of nutrients.”
Homocysteine is a natural substance made by the body. Homocysteine functions at a metabolic crossroad that can affect all the methyl and sulfur group metabolism of key enzymes, hormones, and vital nutrients. Many people lack the ability to break it down completely, and high homocysteine levels usually occur due to the inability to clear homocysteine because of faulty methionine pathways (mercury and lead toxicity). The result is a buildup of homocysteine in the system. When it is not completely broken down, homocysteine becomes a very dangerous substance that can exert harmful effects and increase disease-causing oxidation. When it is broken down completely, it can furnish necessary substances for other beneficial reactions in the body (methyl and sulfur groups). These necessary substances provide the fuel for vital processes like liver detoxification, adrenal gland support, neurotransmitter synthesis, and joint cartilage and bone regeneration. Homocysteine is a very dangerous substance that is harmful to the arteries, which makes it a risk factor for heart disease if it is not broken down completely.
Homocysteine can cause clotting, increase harmful oxidation, and can injure the blood vessel wall (especially if already weakened by x-rays), allowing cholesterol and fat to infiltrate into the wall and cause what is known as a foam cell. This foam cell swells and protrudes into the space of the artery and obstructs the blood flow, potentially resulting in a heart attack. The artery is usually damaged and cholesterol is oxidized before infiltration into an artery and creation of a foam cell can occur, and homocysteine can damage the artery, oxidize the cholesterol, and decrease circulation, all of which increase the risk of heart disease.
The first correlation between homocysteine and disease involved cardiovascular disease, but since then, toxic effects have been revealed on other organ systems, including the liver, adrenals, joints, nerves, and general system blood vessels (inclusive of placental tearing). Neuropsychiatric conditions have also been traced to homocysteine problems, and a correctly functioning pathway is vital to neurotransmitter synthesis. Other conditions which have been linked to high homocysteine levels include neural tube defects, multiple sclerosis, rheumatoid arthritis, spontaneous abortion, placental abruption, renal failure, osteoporosis, and type II diabetes.
Homocysteine is not toxic when the pathway is functioning properly. Synergistic nutrients facilitate the homocysteine pathway, preventing toxic levels of homocysteine from accumulating, and make it possible for a functioning pathway to provide necessary methyl groups and sulfur groups for a myriad of biochemical reactions, especially those needed for detoxification and joint and cartilage repair. Nutrients which facilitate the methionine pathway and reduce homocysteine include betaine, dimethylglycine, and vitamins B6, B12, folic acid, niacinamide, choline, betaine, dimethylglycine, magnesium, and molybdenum. Homocysteine is recycled to methionine in the presence of B12, folic acid, and methyl donors such as choline or betaine (trimethylglycine). B6 (pyridoxyl-5-phosphate is the active form) and magnesium help convert homocysteine to cysteine. Molybdenum is an essential trace mineral necessary to convert the toxic sulfite molecule to the important sulfate molecule needed for many biochemical reactions.
Niacinamide, a B vitamin, can increase the activity of two crucial enzymes needed to facilitate conversion of homocysteine to non-toxic substances. Niacinamide is also necessary for steroid hormone synthesis (cortisol, estrogen, progesterone, testosterone, DHEA), and when chronic stress on the adrenals favors cortisol production, a limitation in niacinamide and/or precursors allows cortisol to be made at the expense of other steroid hormones (such as DHEA). This results in increasingly large ratios of cortisol to DHEA, leading to tissue insensitivity to insulin. All the excess cortisol will need to be conjugated (detoxed in the liver), and this happens largely through sulfur-dependent detoxification pathways in the liver. For this, the homocysteine path has to be functioning to provide the sulfur groups for liver detoxification. Providing these sulfur groups can take some of the stress off the adrenals when cortisol is excessive. Zinc, selenium and magnesium are all minerals which are important co-factors in enzyme reactions of the homocysteine pathway. Zinc and selenium are co-factors for antioxidant enzymes. Magnesium is needed to convert methionine to SAM (S-adenosylmethionine) for the end reaction which converts the toxic sulfite to the essential sulfate, and for glucose metabolism (glucose is a substrate for glucuronic acid, hyaluronic acid, N-acetyl-glucosamine, and chondroitin sulfate--all building blocks for cartilage and joint repair). Chronic mercury inhalation from mercury fillings, with its great affinity to bind to methionine and cysteine can decrease the availability of these amino acids and affect the metabolism of both vitamin B12 and folic acid.
Mercury can inhibit or modify how the body uses ATP, zinc, selenium, rubidium, vitamins A and C, and calcium. Cancer cells have altered sodium and calcium transport and reduced oxygen transport through the cell membrane. The oxygen deficiency within the cell reduces or eliminates the ability of the cell to oxidize glucose to carbon dioxide, which in turn, results in the conversion of glucose to lactic acid, lowering cellular pH into the acid range. These combined effects radically change cell metabolism and ultimately DNA replication. Mercury can alter sodium and calcium transport and also reduce the amount of oxygen transported. Mercury competes with calcium for cellular binding sites and, through this mechanism, can decrease cellular calcium or increase extracellular calcium. Mercury binds avidly to rubidium and selenium. Decreases in available selenium can also reduce available GSH-Px (glutathione peroxidase), which, in turn, causes a proliferation of free radical cellular damage. Mercury, at extremely low levels, can inhibit the respiratory burst of killer-cell leukocytes, reducing their effectiveness in controlling cancer cell proliferation.
A healthy redox balance depends on a fluid shift between glutathione synthesis and methylation, especially when responding to environmental toxins, stressors, or infections. Two B vitamins, folate and cobalamin (B12), are absolutely essential for this fluid, dynamic shift. Most important, the body must be able to adequately convert both nutrients to their active forms, so they can do their job in helping the body methylate when needed, and make more glutathione when needed.
Methyfolate is the only substance that can donate a methyl group to B12, making the all-important and highly active methylcobalamin.
Folate occurs naturally in many foods. Foods high in folate include leafy green vegetables (such as spinach, chard, turnip greens, romaine, broccoli), citrus fruits and papaya, cantaloupe, pineapple, honeydew and bananas, eggs, beans, peas, as well as beef liver. Different forms of folate—before its conversion to methylfolate—play many important roles in the body. They help regulate the healthy growth of new cells, which is especially important for an embryo and newborn. They are necessary to make both DNA and RNA, and help protect DNA from mutations that might lead to cancer.
They are crucial to making normal red blood cells (they help form heme, the iron-containing protein in hemoglobin), and it is essential for metabolizing homocysteine so that this amino acid doesn’t build up to unhealthy levels. Because folate is so important, the Food and Drug Administration published regulations in 1996 requiring that the synthetic form of folate, called folic acid, be added to breads, cereals, flours, pastas, rice and other grain products so commonly eaten by Americans. This helped prevent birth defects and miscarriage, since folate is needed during pregnancy and early life. Thus today, grains are also a source of the synthetic form of folate, folic acid.
Though folic acid is stable and has a long shelf life, the body must convert it into folate in order to use it. Studies show transformation of folic acid falls off after ingesting 200 mcg, and is saturated around 400 mcg. When it is not converted, it can remain in the bloodstream for days, even weeks at a time. In addition, there is some conflicting evidence that high-dose supplementation of folic acid may contribute to risk of certain cancers.
On the other hand, dietary folate seemed protective, although not at a rate that was statistically significant. The researchers conclude: “These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs. natural sources of folate.” However, one issue they sidestep is whether a synthetic supplement, folic acid, that has to be converted back to folate, may itself cause problems.
Genetic variations mean that some of us have trouble converting B12 to the active forms.
Although the body has many uses for folate, one is to serve as a building block for methylfolate. Methylfolate is the only substance than can donate a methyl group to B12, making the all-important and highly active methylcobalamin. Because of genetic variation, some people are less efficient at conversion, and when their bodies are stressed they may not make enough methylfolate. Then their ability to methylate and to make glutathione will be impaired, contributing to many chronic health problems. Testing can help determine if conversion capacity is low. Supplements of methylfolate are available, in a calcium salt form of 5-methyltetrahydrofolate, and in a newly available form, a glucosamine salt of 5-methyltetrahydrofolate, which has demonstrated greater solubility and bioavailability in preliminary studies. The new 5-MTHF glucosamine salt was shown to be approximately 100 times more soluble and increased plasma levels 20% higher in rats and 10% higher in humans than the calcium salt form.
Cobalamin, or B12, is a very interesting vitamin, which actually contains the mineral cobalt, giving it that lovely, striking red color. In 1934, three researchers won the Nobel Prize for the discovery that eating large amounts of raw liver, which contains high amounts of vitamin B12, could save the life of incurable patients with fatal pernicious anemia. This finding saves 10,000 lives in America each year. The vitamin itself was isolated from liver extract in 1948 and its structure was characterized 7 years later.
Deficiency of vitamin B12 impairs DNA synthesis, affecting the growth and repair of all cells. Everything from anemia to neuropathy, weakness, loss of appetite or taste and smell, irritability, memory impairment, tingling and numbness can be symptoms of Vitamin B12 deficiency.
B12 can be converted by the body to an active form known as adenosylcobalamin. This form interacts with the enzyme methylmalonyl CoA mutase and is used by the mitochondria, the energy powerhouse of the cell. Vitamin B12 can also be converted to another active form, methylcobalamin. Methycobalamin is a cofactor for the enzyme methionine synthase, and is a key nutrient in both methylation and in regulating the synthesis of glutathione. As with folic acid, supplements of B12 are often available in a synthetic form called cyanocobalamin, which has a long shelf life, but must be converted by the body back into a useable form. In addition, the body’s ability to absorb B12 from typical oral dietary supplements is limited by the capacity of something called intrinsic factor, a glycoprotein secreted by the stomach. Only about 10 mcg of a 500 mcg oral supplement is absorbed by healthy people, simply because it exceeds the ability of available intrinsic factor.
We cannot make our own B12. Bacteria in our gut can make it for us and other mammals. Naturally occurring B12 is found in animal products, including fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, but like folic acid, certain foods such as breakfast cereals are fortified with it in a cyanocobalamin form. As we age, we can have more difficulty absorbing B12 from food. In fact, many of us may be deficient in B12.
Genetic variations mean that some of us have trouble converting B12 to the active forms. Urine tests can reveal deficiencies of the active forms even when blood tests show adequate B12.
Surprising new research demonstrates that diabetic neuropathy, an extremely painful condition, may respond to supplementation with the active forms of three b vitamins: methyl B12, methylfolate, and the active form of vitamin B6 (pyridoxal-5'-phosphate). Major depression responded to methyfolate in combination with antidepressants in a 2011 study.
Methylfolate alone may sometimes be useful in clinical depression. A 2009 report and review from Harvard Medical school notes that folate is needed for the synthesis of norepinephrine, serotonin and dopamine.
Another 2011 study finds that methyl B12 rescues neurons from homocysteine-mediated cell death. Excess homocysteine is known to be toxic to neurons and can initiate cell death. Methyl B12 was able to reduce levels of an enzyme, caspase, involved in cell death. The researchers concluded that methyl B12 might be useful in treatment of late stage ALS, since homocysteine levels have been found to be increased in animal models of the disease.
Autism also responds to treatment with methycobalamin. The researchers report that there were “significant increases in cysteine, cysteinylglycine and glutathione … the oxidized disulfide form of glutathione was decreased...targeted nutritional intervention with methylcobalamin and folinic acid may be of clinical benefit in some children who have autism.”
In the simplest terms, maintaining life can be viewed as the ability to resist oxidation. Oxygen is essential to life, but oxygen is like fire. It can be very damaging and needs to be controlled by antioxidants, known as “reducing” molecules. Balancing reduction and oxidation—or redox—is the fundamental challenge of life. What’s great about that word, redox, is that it shows that they are profoundly linked and we need both. Once you understand this relationship, it leads to all kinds of new insights.
From the very moment of conception, life can be sparked by the unique redox environment created when a sperm fertilizes an egg. The sperm is extremely rich in proteins containing the mineral selenium, which is a potent reducing agent for glutathione, the most important antioxidant molecule in cells. The egg, on the other hand, is very rich in glutathione. Bring these two potent antioxidant strategies together, and you create an exceptionally reduced cell that can initiate life and promote development using the power of redox. That reducing power provides a metabolic spark as new life begins its journey, allowing the rapidly dividing cells to safely maintain a high rate of oxidation. The same metabolic challenge continues as the embryo develops. The entire nervous system and the shaping of gene activity are profoundly influenced by this redox balance as well. Aging is essentially a process of gradual oxidation, and our health as we age depends on successfully quenching that oxidation. Finally, innumerable diseases are linked to high levels of oxidation and low levels of glutathione—from schizophrenia to major depression, autism, chronic fatigue syndrome, fibromyalgia, and most chronic autoimmune and chronic inflammatory diseases.
Glutathione is made from cysteine, glycine, and glutamic acid. You can get cysteine from the diet, in meat, eggs, garlic, onions, red pepper, broccoli and other foods. Cells in the gut lining, aided by transporter molecules, will bring it into the body. Both gluten (found in grains such as wheat) and casein (milk protein) can inhibit the uptake of cysteine, which the body needs to make glutathione. So many children with autism, or adults with autoimmune disorders, do better when they eliminate wheat and milk from their diet. It’s due to a redox mechanism.
Both casein and gluten are broken down into certain peptides that are relatively stable. The protein casein is broken into casomorphins. The “morphins” are so named because, like morphine, they act on the opiate receptors. The most famous one, beta casomorphin 7 (BCM7), has seven amino acids. Our recent research shows that BCM7 first stimulates the uptake of cysteine, but then inhibits it. However, the human BCM7 is markedly different than bovine BCM7 from the cow. It turns out that the BCM7 from a cow inhibits cysteine at least twice as much as the BCM7 from a human mother. The implications for health are profound if you start thinking about formula feeding and all the dairy products from cows in our diet. Breastfeeding is clearly regulating the redox system of newborns. A diet high in dairy from cows can promote a decrease in our antioxidant capacity, our ability to make enough glutathione.
The peptide from sheep’s milk behaves more like human milk. Similarly, the protein in gluten is known as gliadin, and it also creates a seven amino acid peptide, like BCM7. We already know that gliadin can trigger celiac disease, and can also lead to gluten intolerance and sensitivity. These problems reflect the ability of gluten peptides to inhibit cysteine uptake, perhaps contributing to chronic inflammation, although we have more to learn about that. Of course, not everybody who eats diary or wheat has poor antioxidant capacity, and milk and wheat are important sources of nutrition. There are probably genetic vulnerabilities that bring some people closer to a critical point for oxidative stress, while for others it is a non-issue. Overall, though, this is an issue to consider in any chronic inflammatory disease or neuro-immune disease.
Methylation and glutathione are very tightly intertwined. There is a critical metabolic intersection—a fork in the road—where cells must decide to either make more glutathione, or support more methylation. The overall balance between these two options is crucial to health.
Your body can take homocysteine and convert it back to cysteine. Homocysteine is a metabolite of the essential amino acid methionine, and elevated levels have been associated with vascular disease. Homocysteine is created when methionine donates its methyl group to another molecule in a process known as methylation.
Methylation is a fundamental process of life which is intimately linked to redox status. In chemistry, a methyl group is a hydrocarbon molecule, or CH3. When a substance is methylated, it means that a CH3 molecule has been added to it. Methylation can regulate gene expression, protein function, even RNA metabolism. It can suppress viruses, even latent viruses or cancer viruses we are born with and can help us handle heavy metals. In the liver in particular, methylating a toxin helps change it to a form of the compound that can be more easily processed and excreted.
Methylation is an extremely broad and fundamental action that nature uses to regulate all kinds of processes. It regulates epigenetic changes—changes to gene expression that occur because of environmental factors—by affecting how DNA unravels during development. Some changes can be permanent for the whole lifespan and can even be passed down as many as three generations. That shows that the environment, through the process of methylation, can be quite a profound influence. There are 150-200 methyl transferase enzymes, and each enzyme can methylate multiple targets. So you can imagine methylation as a spider’s web within each cell, and that web branches out in many directions.
Methylation and glutathione are very tightly intertwined. There is a critical metabolic intersection—a fork in the road—where cells must decide to either make more glutathione, or support more methylation. The overall balance between these two options is crucial to health, and this occurs with homocysteine. When methionine gives away its methyl group, we’re left with homocysteine. And the body has to decide, should homocysteine be methylated, and go back into methionine, or should it be converted into cysteine, so that the body can make more of the antioxidant glutathione? This fundamental decision is made again and again by the body, and the overall balance is crucial to health. Too little glutathione and we will end up with free radical, oxidative damage. Not enough methylation, and many genes and viruses will not be properly regulated. Excess homocysteine, and the risk of vascular disease goes up.
It’s important to understand that multiple factors impinge on the same system. What’s so important here is that the glutathione antioxidant system is a common target for so many different environmental toxins and infections. Every single one of them impinges on the glutathione system. It’s not that each molecule of mercury or lead picks off one glutathione molecule. No. It’s that in general, environmental assaults inhibit the enzymes that are responsible for keeping the glutathione in its reduced antioxidant state, where it can do its job. The potent ability of mercury to inhibit selenium-containing enzymes is a good example.
Some people sail through these stressors and remain healthy, while others stumble and fall. Though many molecules and nutrients are important, the active forms of vitamin B12 (adenosylB12 and methylB12) and the active form of folate (methylfolate) are essential to this process. Once you have the raw material to make glutathione or to methylate, you need cofactors like methylfolate and methyl B12 to complete the process. If we don’t make enough of these active forms, we will not be able to smoothly and fluidly shift between methylation and glutathione.
Nature allows, and even encourages, genetic variation, and the bottom line is that some people have genetic variations that render this process less functional. Even with a less functional genetic legacy, you might be fine if you are not stressed by the environment—in particular by chronic infections or toxic assaults. Stress brings out limitations in genes that otherwise are latent and not problematic. That’s a general truth. So yes, with proper testing by a doctor to see if there is a functional deficiency, supplementation with active forms can help. For example, there is a test that measures levels of methylmalonic acid (MMA) in the urine; if the levels are high, you are not making enough of the two active forms of B12. Your serum B12 may be perfectly normal—you just aren’t converting enough of it to the active form.
We ourselves cannot make B12, also known as cobalamin. Bacteria make it for us, and since vegetables don’t carry those bacteria, vegans can be deficient in B12. B12 is such a precious material for the body that if, for instance, you eat a piece of rib eye steak, the B12 released from the proteins is instantly bound right there in the GI tract and chaperoned as if in a football handoff to be carried to cells, transported inside and then processed into the two active forms. Nature knows this is a precious material for life, and a critical indicator of cellular oxidation status.
There are several natural forms of B12 which need to be converted into the active forms, adenosylB12 and methylB12. CyanoB12, the form in most vitamin supplements, is not active and is less useful than the active forms for treating deficiency states. Glutathione itself is needed for converting other forms of B12 to the active forms. Indeed, there is a type of cobalamin called glutathionylcobalamin that is an intermediate for making the active forms.
There are two enzymes in the human body that require active B12 as a cofactor. One is called methylmalonyl CoA mutase, and it needs adenosylB12. It is an enzyme that is necessary for the mitochondria—the energy powerhouse of your cell—to function. The other enzyme that requires active B12 is the enzyme methionine synthase, which requires methyl B12.
MethylB12 is constantly recycled. It donates its methyl group to homocysteine, which then turns into methionine. Once B12 is missing its methyl group, it needs to get a fresh one. And that’s where methylfolate comes in. Methylfolate is in essence a methyl donor for methionine synthase. That’s its job in life. It is the only molecule than can donate a methyl group to B12. Once it does that, the rest of the folate is available to go out and support all kinds of other reactions in the body that need plain folate.
When your level of methylB12 is low, homocysteine builds up and this can have adverse health effects. High homocysteine levels in the blood reflect low activity of the enzyme methionine synthase, and this has been linked to an increased risk of atherosclerosis and coronary artery disease. It is also well known that homocysteine levels are increased in Alzheimer’s disease, which suggests a role for impaired methylation in this neurodegenerative disorder. Of course low B12 levels are classically associated with pernicious anemia and with peripheral neuropathy.
Low levels of folate are also classically associated with anemia, heart disease, fetal abnormalities such as spina bifida, as well as neuropathies and these have been specifically linked to a deficiency in methylfolate. In addition, recognition of the important role of methylfolate and vitamin B12 in supporting D4 dopamine receptor methylation links their deficiency to impaired attention such as attention-deficit hyperactivity disorder (ADHD). People with genetic polymorphisms in the enzyme that makes methylfolate are particularly vulnerable to a deficiency.
Some research has shown that synthetic folic acid can build up when supplemented, and a few studies have suggested this may even be linked to cancer in high doses.
In addition to vitamin B12 and methylfolate, there are several other nutritional supplements whose actions are critical for redox and methylation pathways. Vitamin B6 (pyridoxal-5-phosphate or P5P) is an essential cofactor for the two enzymes that sequentially convert homocysteine to cysteine, namely cystathionine-beta-synthase and cystathionine-gamma-lyase. Together these two B6-dependent enzymes comprise the transsulfuration pathway that promotes glutathione synthesis. The common supplement form of vitamin B6, pyridoxine, must be converted to the active form, and in some disorders, such as autism, this conversion is impaired, so the P5P form may be more effective. N-acetylcysteine (NAC) provides a supplementary source of cysteine. NAC can cross into the cell cytoplasm where the cysteine is released and allowed to promote glutathione synthesis. SAMe is an active, methyl-donating derivative of the essential amino acid methionine, and during oxidative conditions its levels may be low, due to low methionine synthase activity. SAMe has shown particular benefit in treating depression.
These examples of the interrelationship between oxidation and methylation are just the tip of the redox iceberg. Nature has learned to harness the power of oxidation as a signaling mechanism to control cellular activity. When more antioxidant is made available, cells can safely undertake a higher level of metabolic activity. There is a lot more to learn, and the real challenge will be to convert this evolving knowledge about redox and methylation into new, more effective treatment strategies.
Cysteine (sis-tee-in) is a unique amino acid, largely by virtue of its sulfhydryl group. It is an important constituent of proteins, being largely responsible for their molecular configuration, either by forming disulfide bonds with other cysteine molecules incorporated into the same protein or by forming disulfide bonds with free cysteine. It can link together a number of separate proteins or polypeptides by forming disulfide bonds between cysteine residues in different molecules. Cysteine is made from two other amino acids, methionine and serine. Methionine furnishes the sulfur atom and serine furnishes the carbon skeleton in the synthesis of cysteine. Cysteine is produced by enzymatic or acid hydrolysis of proteins. Cysteine can be oxidized to cystine (sis-tin), which is rather insoluble in water. Sometimes it can be found in the urine and in the bladder in a crystal form where it will form cystine calculus (stones) in the kidneys or bladder. Cystine is the main sulfur-containing compound of the protein molecule. Upon reduction, cystine produces two molecules of cysteine. Heavy metals catalyze the oxidation of cysteine to cystine and also react with cysteine to form mercaptides. Cysteine is very soluble in water and therefore can be easily eliminated via the urine.
However, cysteine can be oxidized to cystine, which can then present the potential of stone problems. If an adequate supply of vitamin C is available, it will help keep cysteine in its reduced and soluble form, thereby preventing the formation of stones. The ratio of vitamin C to cysteine should be three-to-one. Cystathionase, an enzyme that is necessary to change cystathionine into cysteine, and which is present in humans postnatally, is not present in human fetal liver or brain. Cysteine is not considered an essential amino acid in adults. Cysteine is an essential amino acid for the human fetus, and for prematurely born and full term infants for a short period after birth. Its concentration in maternal plasma is greater than or equal to that in fetal plasma. Cystathionine, which is present in human brain in large concentrations, may not be needed until some time after birth.
Methionine is one of the essential amino acids required in the diet, whereas cysteine is considered to be non-essential. Eighty to 90% of the daily requirement can be replaced by cystine. The ability for one sulfur to replace another is called transsulfuration and represents an important route for either cysteine or cystine. Plasma levels of taurine, serine, methionine, and threonine have been found to be significantly lower in patients with essential hypertension (high blood pressure). The levels of these four amino acids, as well as total sulfur amino acids, correlated inversely with systolic blood pressure. Individuals with mercury amalgam dental fillings could have low plasma sulfur amino acids, leading to high blood pressure. Mercury has been shown to affect methionine use.
Taurine is a sulfur-containing amino acid that the body makes from cysteine. Methionine is a precursor for cysteine and taurine biosynthesis. There are two primary bile acids needed to break down fats; one of them, taurocholic acid, cannot be produced without taurine. Taurine is concentrated in the brain where it functions as a neurotransmitter and/or as a modulator of neurotransmission, preventing excess electrical activity, such as that occurring during epileptic episodes. Taurine plays a major role in the transport regulation of blood electrolytes (calcium and potassium) and may affect in the cardiovascular system. Excretion in pregnant women falls dramatically starting at week-9 of pregnancy. Reserves of taurine are increased for use during the latter phases of pregnancy. Concentrations are higher in the fetal liver and brain and some believe that it plays a role in brain development and also functions as a growth modulator. Both mercury and lead have a great affinity for the sulfur atom. Mercury can serously interfere in the transsulfuration pathway at many different locations, ultimately leading to a deficiency or reduction in available taurine.
Glutathione is present in almost all cells in the body in rather high concentrations. Glutathione serves as a storage and transport form of cysteine and also as a respiratory carrier of oxygen, both extremely important metabolic functions. Within the cell itself, it has some very important metabolic functions such as protecting the cells against damage that can be caused by free radicals and hydrogen peroxide. In the liver, glutathione is a reservoir of cysteine which is utilized for protein synthesis. Glutathione can also replace cysteine derived from methionine, thus exerting a methionine sparing action. Vitamins C and E are two key nutrients that go through this recycling process. Once they have performed their function as an antioxidant, scavenging free radicals, they are reduced to an inactive state and must be regenerated to their original form. This process requires an adequate supply of reduced glutathione. Reduced glutathione (GSH) is present in red blood cells where it is functionally associated with the enzyme glucose-6-phosphate dehydrogenase (G6PD) and the coenzyme reduced nicotinamide-adenine dinucleotide phosphate (NADPH). Both G6PD and NADPH are needed to maintain red blood cell integrity.
Glutathione also plays a part in how our immune systems function. When the supply of glutathione is low, or has been depleted, this can inhibit the activation of lymphocytes, and may also have a bearing on the response of cytotoxic T-lymphocytes. The ability of mercury to affect the available supply of glutathione also affects these same lymphocyte functions. Mercury also inactivates G6PD, which results in altered red blood cell membrane permeability and blocking of active glucose transport into cells. Mercury itself increases red blood cell membrane permeability. The altered membrane permeability, in turn, disrupts a large number of essential membrane functions, ultimately leading to cell death. Glutathione peroxidase (GSH-Px) activity in the liver, kidneys, testes, and erythrocytes is significantly depressed by silver and mercuric chloride.
The antioxidant glutathione, known as GSH, is arguably the most important antioxidant the body makes, and most certainly the most powerful intracellular antioxidant. In its reduced form it plays a pivotal role in DNA repair, immunity, flushing of toxins, removal of heavy metals, quenching of free radicals, and recycling of other antioxidants such as vitamins C and E. Glutathione supports detoxification in the lining fluid of the lung and intestines, enhances macrophage function, and slows virus production.
Low levels of glutathione are associated with an astonishing range of diseases, from diabetes to Parkinson’s to asthma to kidney problems, and many other conditions. Unfortunately, oral supplementation of glutathione has proven tricky and sometimes ineffective, since the molecule, when taken orally, is not able to effectively reach and be absorbed into the intracellular space where it is needed. Optimal exposure to the potential benefits linked to GSH have been achieved with IV therapy but it is expensive and inconvenient, and has only short-term benefits, and so needs to be repeated frequently.
The contribution of GSH deficiency in many pathologies has stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. One novel formulation of the molecule, S-acetylglutathione (S-GSH), is surprisingly well absorbed by cells and of great potential benefit. It crosses the cell membrane more easily than GSH itself, and is easily de-acetylated in the cell, becoming active GSH. S-GSH can be effectively absorbed by cells after an oral dose and has great potential in comparison to IV therapy.
S-GSH proved a significant anti-viral agent both in vitro and in animal studies in a 2005 study from Johann Wolfgang Goethe University Hospital in Germany. Remarkably, it was stable in plasma and taken up directly by cells with subsequent conversion to GSH (the active, reduced form). In cell culture, S-GSH efficiently restored intracellular glutathione, and in mice, S-GSH but not plain glutathione, significantly decreased virally induced mortality. This novel form of glutathione was active and stable.
S-GSH has also been shown to cause the death of certain cancer cells. In a study in the International Journal of Oncology, S-GSH induced significant cell death in three human lymphoma cell lines. It did not have the same effect on normal lymphocytes. The researchers concluded that “S-acetyl glutathione specifically activates programmed cell death in lymphoma cells.” In fact, their analysis showed that this form of glutathione depleted intracellular glutathione in the cancer cells, in a selective effect that was the opposite of its action in normal cells.
Finally, in mice infected with a viral complex, S-GSH was able to reduce spleen viral content by 70% and lymph node viral content by 30%--and to do so at half the concentration of GSH. As the Italian researchers note in Molecules, glutathione analogues such as S-GSH “may offer a promising therapeutic alternative for reducing the GSH functional loss related to many human diseases.”
Glutathione peroxidase protects the human brain. When polyunsaturated fatty acids, which are located primarily in the brain, are oxidized, organic hydroperoxides are formed that can only be reduced by GSH-Px. Alterations in GSH-Px activity and tissue damage caused by peroxide accumulation is of significance in the development of senility and degenerative neurological diseases. One of the primary ways the body gets rid of metal compounds is through a pathway that goes from the liver into the bile where they are then transported to the small intestine and excreted in the feces. Inorganic mercury is complexed with glutathione in the bile, suggesting that glutathione status is a major consideration in the biliary secretion of mercury. This same pathway is affected by a mercury induced reduction of available taurine needed to produce bile acid (taurocholic acid).
When the microflora of the intestine have been reduced through stress, poor diet, use of antibiotics and other drugs, fecal content of mercury is greatly reduced. Instead of being excreted in the feces, the mercury gets recirculated back to the liver. The person who is under stress, eating a poor diet, and/or taking antibiotics will tend to maintain a higher body burden of mercury derived from dietary sources--especially if they are eating fish.