Sulfur Part II: Sulfur and Sulfur Compounds in the Human Body

Transcription

1 Sulfur Part II: Sulfur and Sulfur Compounds in the Human Body by Mark J. Donohue Introduction Sulfur is an element of the earth and is vital to the human body, without it we would not survive. Sulfur is the sixth most abundant macro-mineral in human breast milk and the eight most abundant mineral in the body. Sulfur is an essential nutrient and therefore cannot be synthesize by the human body and instead must be obtained from the diet. Sulfur is not present as an isolated element in the body, but in combination with other elements and complex molecules (compounds). The primary placement of sulfur in the human body is in the sulfur-containing amino acids (SAA): methionine, cysteine and taurine. The human body is composed of % sulfur: Liver to p.p.m. Muscle to p.p.m. Bone to 2400 p.p.m. Blood 1800 mg/dm -3 Sulfur is found in every cell in the human body and is involved in a wide range of biochemical functions. Sulfur s involvement in the human body ranges from: Cellular energy production / metabolism. Maintaining blood glucose levels. Protects nerve tissue synthesizes neurotransmitters, improves memory and dampens excessive firing. Antioxidant protection - scavenges or neutralizes free radicals and recycles oxidized antioxidants. Blood flow produces both blood clotting factors as well as anticoagulants. Joint Health production of glycosaminoglycans (GAGS), chondroitin sulfate and hyaluronic acid. Detoxification by means of conjugation and chelation. Regulation of DNA replication and transcription. Digestion production of hydrochloric acid. Supports healthy lipoprotein balance cholesterol, LDL, and HDL. Adrenal gland support and hormone production cortisol, aldosterone, testosterone, etc. Proper immune response enhancing proliferation of lymphocytes, cytotoxic T cells and NK cells. Lungs protects against mucous formation in lungs. Eyes - decreases cataract development. Formation of skin, hair and nails. Luckily, sulfur and sulfur compounds are ubiquitous. They are found naturally occurring in the soil, plants, animals and atmosphere and easily gain entry to the human body. Unfortunately, as mentioned in the previous report many toxic sulfur compounds exist in our environment as man-made by-products (pollutants) which also gain easy access to the human body.

2 Natural of Sulfur and Sulfur Compounds in the Human Body The human body is a carbon based (organic) organism. Therefore, compounds in humans that contain sulfur are referred to as organic sulfur compounds or commonly known as organosulfur compounds. More specifically, it is the sulfur containing functional group within a compound that defines it as an organosulfur compound. A functional group is a group of atoms that reacts as a single unit and determines the properties and structure of a class of compounds. There are several dozen organosulfur compounds, all classified according to their sulfur-containing functional group. Listing and describing all of them is beyond the scope of this report. Rather, we will focus on a select few, their sulfur content and their function in the body as well as their sources. A list of the organosulfur functional groups which pertain to this report are (* R- usually denotes carbon side chain): Thiol or Sulfhydryl or Mercaptan (R-SH) is a compound that contains the functional group composed of a sulfur-hydrogen bond. Many, but not all, thiols have strong odors resembling that of garlic. Examples of thiols are the amino acids cysteine and glutathione, as well as coenzyme A. Sulfide or Thioether (R-S-R) form when two organic groups are bonded to a sulfur atom. Many fungicides and herbicides incorporate organically bound sulfide sulfur. Disulfide and Polysulfide (R-S-S-R) a unique property of sulfur is the ability to form chains of sulfur atoms (from 2 20) with organic groups at either end. Cystine is an example of a disulfide. Sulfoxide or Sulfinyl (R 2-S=O) is an organic compound containing sulfur and oxygen. The best known sulfoxide is dimethyl sulfoxide (DMSO). Sulfones or Sulfonyl (R 2-SO 2) is an organic sulfur compound attached to two oxygen atoms and two carbon atoms. Several drugs are manufactured with this functional group. Sulfonic Acid or Sulfo (R-SO 3H) is an organic acid where R is usually attached to a hydrocarbon (hydrogen-carbon compound) side chain. Sulfonic acids and their salts sulfonates (R-SO 2O-), and their amides sulfonamide (R-SO 2NH 2) are used extensively in a diverse list of products such as detergents, dyes, antibacterial drugs and sulfa drugs. Isothiocyanate (R-N=C=S) - cruciferous vegetables are rich sources of sulfur-containing compounds called glucosinolates. Isothiocyanates are biologically active hydrolysis (breakdown) products of glucosinolates. Cruciferous vegetables contain a variety of glucosinolates, each of which forms a different isothiocyanate when hydrolyzed.

3 Food The main source of organosulfur compounds in humans comes from food. Organosulfur compounds occur in the bodies of all living creatures in the form of certain essential amino acids, enzymes, coenzymes, vitamins, and hormones. Foods containing high amounts of organosulfur compounds are: Protein: Meat Fish Eggs (T) Milk (T) Cheese-all (T) Whey (T) Dairy-all (T) Soy-all (T) Vegetables: Arugula Asparagus (T) Artichokes (T) Broccoli (T, I) Bean Sprouts (T) Brussels Sprouts (T, I) Bok Choy (T, I) Chive (T) Cauliflower (T, I) Cabbage (T, I) Collard Greens (T) Daikon (T) Garlic (T) Green Beans (T) Greens (T) Horseradish (T, I) Kale (T, I) Leek (T) Mustard Green (I) Mustard (I) Mushrooms Onion (T) Peas (T) Radish (T, I) Rutabaga (T) Red Peppers (T) Shallots (T) Sauerkraut (T) Spinach (T) Split Peas (T) Swiss Chard Turmeric (raises T) Turnips (T, I) Truffle Watercress (I) Beans: Beans-all (T) Lentils-all (T) Grains: Oats (T) Wheat Germ (T) Fruit: Pineapple (T) Papaya (T) Nuts: Peanuts (T) Misc.: Coffee (T) Carob (T) Chocolate (T) ** T indicates high level of Thiol content, I indicates high level of Isothiocyanate content. From the list above the most important source of organosulfur compounds in the human diet is from proteins. The organosulfur compounds found in protein come from the sulfur containing amino acids methionine and cysteine. Sulfuramino acids (SAAs) are the primary source of sulfur in the human diet. The average person takes in (dietary intake) around mg. of sulfur per day, mainly in the form of protein. Nutritional supplements are commonly taken today and therefore can also be considered as a source of organosulfur compounds. One intention for taking nutritional supplements is to provide nutrients (vitamins, minerals, amino acids, etc.) that are missing or are not consumed in sufficient quantity in a person s diet. Another intention is to reinforce or increase the effectiveness of certain body compounds, by consuming like compounds. The remainder of this report lists and details some of the more common organosulfur compounds that are either: a) Naturally synthesized by the body. b) Found in food c) Taken as a nutritional supplement

4 Biotin, Thiamine (B1), Pantethine Biotin (C 10H 16N 2O 3S) also known as vitamin B7, is a water-soluble B- complex vitamin. A vitamin is an organic compound required as a nutrient in tiny amounts with the B-complex vitamins (8 of them) playing important roles in cell metabolism. Biotin is attached, as a cofactor/ coenzyme (enzyme helper) at the active site of several enzymes known as carboxylases. Each carboxylase catalyzes an essential metabolic reaction, for example: Acetyl-CoA carboxylase I and II are required for the synthesis of fatty acids. Pyruvate carboxylase is a critical enzyme in gluconeogenesis (glucose from amino acids) Methylcrotonyl-CoA carboxylase is involved in the breakdown of leucine (amino acid) Propionyl-CoA carboxylase is involved in the metabolism of certain amino acids, cholesterol and fatty acids. Biotin is synthesized by bacteria that normally colonize the small and large intestine. However, whether biotin is released and absorbed in meaningful amounts remains unknown. Biotin is found in many foods, but generally in lower amounts than other water-soluble vitamins. Found in microgram (mcg) dosages, the richest sources of biotin are from liver, egg, yeast, salmon and pork. Biotin is also manufactured as a nutritional supplement. Thiamine (B1) (C 12H 17N 4OS) is a water soluble B-complex vitamin. Thiamine is synthesized in bacteria, fungi and plants but not in animals or humans. Therefore, thiamine must be obtained from foods. a) Thiamine is essential for energy-yielding metabolism, especially carbohydrate metabolism via the coenzyme thiamine pyrophosphate (TPP). b) Thiamine is important to the health of nerves and the nervous

5 system, possibly because of its role in the synthesis of acetylcholine (neurotransmitter). With a lack of thiamine, the nerves are more sensitive to inflammation. c) Thiamine is involved in the production of hydrochloric acid in the stomach. All plant and animal foods have thiamine though at low concentrations. Higher levels of thiamine are found in many nuts, seeds, brown rice, seafood, and whole-grain products. Sunflower seeds are a particularly good source. Thiamine is destroyed by prolonged high temperatures and ultraviolet light, but not by freezing. Because there is very little thiamine stored in the body, depletion can occur as quickly as within 14 days. Thiamine is also manufactured as a nutritional supplement. Pantethine (C 22H 42N 4O 8S 2) is the biologically active form of pantothenic acid (B5), another water-soluble B- complex vitamin. Though pantethine is not to be confused with pantothenic acid (B5). Rather, the making of pantethine is the very reason the body needs pantothenic acid (B5) in the first place. That is, pantothenic acid s (B5) whole purpose in the body is to serve as a raw material for the synthesis of pantethine. While pantothenic acid is a single molecule, pantethine is composed of two molecules of pantothenic acid (B5) linked by cysteamine (sulfur) bridge group. a) Cysteamine is theorized to bind to and thus inactivate sulfur-containing amino acids in liver enzymes involved in the production of cholesterol and triglycerides. Therefore, as a supplement, pantethine is used to support healthy levels of blood lipids and lipoproteins such as cholesterol, triglycerides, low density lipoprotein (LDL the bad cholesterol), and high-density lipoprotein (HDL the good cholesterol). It is important to note - pantothenic acid (B5) does not have these cholesterol-balancing effects. b) Pantethine serves as the precursor for synthesis of coenzyme A (CoA), a critical factor in cellular energy production. c) The adrenal glands require CoA for the synthesis of the powerful hormones through which the body adapts to stress. Stress can therefore seriously deplete the body of pantothenic acid (B5) and supplemental pantothenic acid (B5) can help correct for this stress-induced deficiency. However, pantethine provides much more powerful support for adrenal function than does pantothenic acid (B5).

6 d) One important subfamily of the detoxification phase II enzyme family is the group that conjugates toxins using acetyl groups (C 2H 3O + ) a process which requires CoA. It is therefore not surprising that pantethine supplements, by boosting CoA levels, support the detoxification of a variety of toxic molecules and protect the liver from many damaging chemicals. For instance, pantethine supplementation reduces the formation of the toxic alcohol byproduct acetaldehyde. Pantethine is naturally synthesized by the body from pantothenic acid (B5). Pantothenic acid (B5) is found in most foods, while pantethine is not found in any foods. Both pantothenic acid (B5) and pantethine are manufactured as nutritional supplements. Though pantethine is the more biologically active form it is less stable and decomposes over time if not kept refrigerated. Coenzyme A, Acetyl-CoA Coenzyme A (C 21H 36N 7O 16P 3S) (THIOL) also referred to as CoA, is a coenzyme / cofactor found in every cell in the body and is one of the most important substances involved in cellular metabolism. a) CoA is required to metabolize the three major forms of energy (fat, carbohydrates, and protein). As the initiator of the body's energy cycle (known variously as the TCA, Kreb or citric acid cycle), it produces more than 90% of the energy the body requires to sustain life. It is specifically involved in the conversion of pyruvate into acetyl-coa via the enzyme pyruvate dehydrogenase. b) CoA is also required to initiate the chemical reactions required by the human body to utilize Coenzyme Q10, Coenzyme 1 (NADH) and many of the other nutrients the body needs to stay healthy. c) CoA is also involved in a variety of other functions in the body such as: the synthesis of the acetylcholine, the steroid hormones and the sex hormones. It supports immune function, including the repair of DNA and RNA, plus healing from physical injury. It facilitates the manufacture of important components of connective

7 tissue necessary to joint health, particularly chondroitin sulfate and hyaluronic acid. Coenzyme-A also enhances physical performance and prevents sore, stiff muscles by reducing the buildup of lactic acid during physical activity. Coenzyme A is constantly expended by the metabolic processes in the body and constantly needs replenishing. CoA is synthesized in the body from pantethine, cysteine and adenosine triphosphate (ATP). CoA is not found in foods, but it is manufactured as a nutritional supplement. Acetyl-CoA (C 23H 38N 7O 17P 3S) is formed as a result of an acetyl group (C 2H 3O) attaching to coenzyme A s sulfur molecule. This takes place during the first step of the Kreb / citric acid cycle which occurs in the matrix of the mitochondria (cell s power plant). It is here where pyruvate, the end product of glycolysis (glucose to pyruvate), is acted upon by pyruvate dehydrogenase and coenzyme A to form acetyl-coa. a) Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. b) Acetyl -CoA forms the basis from which steroids are synthesized. c) Acetyl-CoA is also an important component in the synthesis of the neurotransmitter acetylcholine. Choline, in combination with Acetyl-CoA, is catalyzed by the choline acetyltransferase to produce acetylcholine. Acetyl-CoA is not found in foods nor is it manufactured as a nutritional supplement. Acetyl-CoA can only be found as a naturally synthesized compound in the body.

8 Methionine, S-Adenosylmethionine (SAM-e), Homocysteine Methionine (C 5H 11NO 2S) is an essential amino acid and is the body s primary source of sulfur. a) Methionine is necessary for the synthesis of proteins and is an important methyl group donor (-CH 3). b) Methionine helps prevent fatty liver through its ability to form choline. Methionine can also lower acetaldehyde levels after alcohol ingestion. c) Methionine is converted into S-adenosyl methinonne (SAMe), by the enzyme methionine adenosyltransferase. SAMe also serves as a methyl group donor. Because methionine is an essential amino acid, this means the body does not synthesize it and therefore methionine must come from the intake of foods. High levels of methionine can be found in sesame seeds, brazil nuts, fish, meats, and dairy products. Most legumes, fruits and vegetables contain very little methionine. Methionine is also manufactured as a nutritional supplement. S-Adenosyl methionine (SAM-e) (C 15H 22N 6O 5S+) is a naturally occurring compound that is found in almost every tissue and fluid in the body, though most SAM-e is produced and consumed in the liver. a) SAMe has a fundamental role in transmethylation (the transfer of a methyl group from one compound to another). This process is mandatory for the synthesis of phospholipids and the maintenance of membrane fluidity. b) SAMe is involved in producing neurotransmitters such as serotonin, melatonin and dopamine. Indicating possible value in supplementation for depression.

9 c) SAMe exerts analgesic effects and stimulates the synthesis of proteoglycans (a protein with a high polysaccharide content) by articular chondrocytes (cartilage cells), with minimal or absent side effects on the gastrointestinal tract and other organs. d) SAMe is involved in producing cartilage components such as glycosaminoglaycans (GAGS). e) SAMe improves and normalizes liver function: In ethanol-fed baboons, SAMe prevents depletion of glutathione levels, normalizes mitochondrial enzymes, and results in histological improvement of hepatic lesions. In healthy human volunteers it was demonstrated that, after ethanol ingestion, SAMe significantly lowered plasma concentration of ethanol and acetaldehyde. SAMe was tested in patients with alcoholic cirrhosis. A 47-percent lower rate of death or need for liver transplantation was noted compared to controls. Patients took 1,200 mg SAMe/ day. In people with less severe cirrhosis, the results were even more impressive. SAMe is naturally synthesized by the body from ATP and the amino acid methionine. SAMe is not found in food however, it is manufacture as a nutritional supplement. Homocysteine (C 4H 9NO 2S) is a non-essential amino acid biosynthesized in the body from methionine via SAMe. a) Homocysteine can be recycled back into methionine with the aid of B- vitamins thus creating additional methyl group donors. b) Homocysteine can be converted into cysteine which is further used in the detoxification of toxins. Homocysteine is naturally synthesized in the body from methionine. Homocysteine is not obtained in the diet from foods, nor is it manufactured as a nutritional supplement.

10 Cysteine, Cystine, N-Acetyl-Cysteine, Metallothionein Cysteine (C 3H 7NO 2S) (THIOL) is a non-essential amino acid biosynthesized in the body. a) Cysteine has antioxidant properties which are typically expressed in the tripeptide glutathione and is the rate-limiting precursor to the production of taurine as well as glutathione. b) Cysteine is critical to the metabolism of a number of essential biochemical compounds such as biotin and coenzyme A. c) The thiol group also has a high affinity for heavy metals and will tightly bind with metals such as mercury, lead and cadmium. d) Cysteine counteracts the poisonous effects of acetaldehyde by supporting the next step in metabolism, which turns acetaldehyde into the relatively harmless acetic acid. e) Cysteine also has the ability to breakdown proteins found in mucous that settles in the lungs. As a result it may be useful in the treatment of bronchitis and other respiratory problems. f) Large amounts of cysteine are found in keratin, the protein that makes up fingernails, skin and hair. Human hair is approximately 14% cysteine. Cysteine naturally occurs in the body and is synthesized from homocysteine and serine (amino acid). Cysteine is found in most high-protein foods such as pork, sausage meat, chicken, turkey, duck, eggs, milk, whey protein, ricotta, cottage cheese, and yogurt. Non-protein sources include red peppers, garlic, onions, broccoli, brussel sprouts, oats, granola, wheat germ. Cysteine is also manufactured as a nutritional supplement. CAUTION: High levels of Cysteine are potentially toxic. Cysteine is a brain excito-toxin that can cause damage to brain cells in susceptible individuals. Cystine (C 6H 12N 2O 4S 2) (Disulfide) is an amino acid formed by the linkage of two cysteine molecules which covalently link to make a disulfide bond. The disulfide link is readily reduced to make two corresponding cysteine molecules. In fact, both amino acids can be converted into the other as needed.

11 For this reason, the nutritional benefits and sources of cystine are identical to those for the more common cysteine. Cysteine is more easily absorbable than cystine, therefore most supplements contain cysteine. CAUTION: Too much cystine in the body can cause cystinosis, a rare disease that can cause cystine crystals to form in the body and produce bladder or kidney stones. This side effect has not been associated with cysteine. However, cysteine is unstable and is readily converted to cystine. N-Acetyl-Cysteine (NAC) (C 5H 9NO 3S) (THIOL) NAC is a metabolite of cysteine where an acetyl group is attached to the nitrogen atom. a) NAC is often used as a cough medicine because it breaks up the disulfide bonds in the mucus and thus liquefies it, making it easier to cough up. It is also this action of breaking disulfide bonds that makes it useful in thinning the abnormally thick mucus in Cystic Fibrosis patients. b) NAC is also used as a specific antidote in cases of acetaminophen overdose. c) NAC is rapidly metabolized to intracellular glutathione. d) Heavy metals like lead, mercury and arsenic are detoxified and removed from the body by NAC. It also increases the excretion of zinc and other essential minerals when taken over an extended period. e) NAC has been shown to reduce the proliferation of certain cells lining the colon and may reduce the risk of colon cancer in people with recurrent polyps in the colon. Its action as an antioxidant and a glutathione precursor may also contribute to a protective effect against cancer. NAC is naturally synthesized in the body from cysteine. Thought cysteine is found in a variety of foods, NAC is not found in any foods. NAC is also manufactured as a nutritional supplement. FURTHER RESEARCH: There are conflicting reports that indicate NAC does not raise cysteine levels in the brain. This would be a way to obtain additional cysteine while eliminating the neurotoxic effects in the brain. However, there are other reports indicating that NAC does raise cysteine levels in the brain. Additionally, there are reports that NAC may be a preferred delivery system for cysteine because cysteine readily absorbs moisture and oxidizes. As well as being more stable and may be better absorbed. Yet other reports indicate NAC is not an ideal source since it is catabolized (broken down) in the gut. Also, IV administration is preferable for poisoning, since NAC may cause nausea and vomiting thereby reducing the effectiveness of oral therapy.

12 Metallothionein (MT) is a family of cysteine-rich low molecular weight proteins. Cysteine residues represent about 30% of the amino acid content of MTs. MTs form complexes with heavy metal ions. The binding occurs via the thiol groups of the cysteine residues. a) MTs function is not clear, but experimental data suggest MTs may provide protection against metal toxicity (cadmium, mercury, silver), be involved in regulation of physiological metals (zinc, copper, selenium) and provide protection against oxidative stress. b) Other possible functions of MTs are: development and continued functioning of the immune system, development and pruning of brain cells (neurons), prevention of yeast overgrowth in the intestines, production of enzymes that break down casein and gluten, production of hydrochloric acid by stomach cells, taste and texture discrimination by the tongue, behavior control and development of memory and social skills. Metallothionein is naturally synthesized primarily in the liver and kidneys. Its production is dependent on availability of the dietary minerals zinc, copper, selenium and the amino acids histidine and cysteine. MT is not found in foods nor is it manufactured as a dietary supplement. Alpha-Lipoic Acid, Glutathione, Taurine Alpha-Lipoic Acid (C 8H 14O 2S 2) (THIOL) is a naturally occurring fatty acid found inside every cell in the body. Most intracellular ALA is not free rather it is covalently bound to specific proteins. What free ALA that does exist is converted to and exists in the reduced form as dihydrolipoic acid (DHLA), which is rapidly exported from the cell. a) Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive compounds (a.k.a. free radicals) with the potential to damage DNA, proteins and lipids in cell membranes. Both ALA and DHLA can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube. However, free ALA is rapidly eliminated from cells, so any increases in direct radical scavenging activity by DHLA are unlikely to be sustained. b) In test tubes DHLA has been found to be a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including glutathione, CoQ10, vitamin C and E. In other words DHLA recycles these antioxidants after they have been used thereby maintaining their levels.

13 c) ALA has been shown in cell culture experiments to increase cellular uptake of glucose by recruiting the glucose transporter GLUT4 to the cell membrane, suggesting its use in diabetes. d) ALA easily crosses the blood brain barrier and enters the brain producing protective effects on nerve tissue. Studies of rat aging have suggested that the use of ALA results in improved memory performance and delayed structural mitochondrial decay suggesting its use for people with Alzheimer s or Parkinson s. e) Owing to the presence of two thiol groups it is a chelating agent and has significantly enhance biliary excretion of inorganic mercury in rat experiments. f) One of the most visible roles of ALA is as an essential cofactor for several mitochondrial enzyme complexes that catalyze critical reactions related to energy production specifically pyruvate dehydrogenase. Alpha-Lipoic Acid is naturally synthesized in the body. It can also be found in small amounts in almost all foods, but slightly more so in kidney, heart, liver, peas, spinach, broccoli, and yeast extract. However, naturally occurring ALA is always covalently bound and not immediately available from dietary sources. This is probably why consumption of ALA from foods has not yet been found to result in detectable increases of free ALA in human plasma cell. ALA is also manufactured as a nutritional supplement. And in contrast to foods, high oral doses of free ALA (50 mg or more) result in significant but transient increases in free ALA in plasma and cells. Studies in humans have found that about 30-40% of an oral dose of ALA is absorbed. Oral ALA supplements are better absorbed on an empty stomach than with food. Plasma ALA concentrations generally peak in one hour or less and decline rapidly because free ALA is quickly reduced to DHLA and excreted. CAUTION: The chemical structure of biotin is similar to that of ALA and there is some evidence that high concentrations of ALA can compete with biotin for transport across cell membranes. Glutathione (C 10H 17N 3O 6S) (THIOL) is a tripeptide made up of the amino acids glycine, cysteine and glutamic acid and is found inside every cell in the body. Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent to other unstable molecules, such as reactive oxygen species (free radicals). In donating an electron, glutathione itself becomes reactive, but readily reacts with another reactive glutathione to form glutathione disulfide (GSSG). Such a reaction is possible due to the relatively high concentration of glutathione in cells (especially the liver). GSH can be regenerated from GSSG by the enzyme glutathione reductase. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.

14 a) It is the major endogenous antioxidant produced by the cell, participating directly in the neutralization of free radicals / reactive oxygen compounds. b) Glutathione is a reducing agent which maintains exogenous antioxidants such as vitamins C and E. c) Through direct conjugation, it detoxifies xenobiotics (foreign compounds) and carcinogens, both organic and inorganic. Unfortunately, hepatic (liver) glutathione can be depleted very quickly, resulting in less glutathione being available for the conjugation of other toxic substances. d) Glutathione is essential for the immune system to exert its full potential by: Modulating antigen presentation to lymphocytes, thereby influencing cytokine production. Enhancing proliferation of lymphocytes thereby increasing magnitude of response. Enhancing killing activity of cytotoxic T cells and natural killer cells. Regulating apoptosis, (cell death) thereby maintaining control of the immune response. e) Glutathione plays a fundamental role in numerous metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport and enzyme activation. f) Low GSH levels in elderly subjects have been theorized to accelerate the aging process. Glutathione is naturally synthesized in the body from the amino acids -cysteine, glycine and glutamic acid. Glutathione also occurs naturally in most foods, but occurs in highest amounts in fresh (uncooked) meats. It can also be found in moderate amounts in certain raw fruits and vegetables and is absent or found only in small amounts in grains and pasteurized dairy products. Dietary forms of glutathione are efficiently absorbed into the blood, though heat or cooking greatly decreases glutathione concentrations. Glutathione is also manufactured as a nutritional supplement. FURTHER RESEARCH: There is conflicting reports on glutathione s absorbability. While some research suggests that glutathione taken orally, as a supplement, is not well absorbed across the GI tract other research has shown administration of oral glutathione increases hepatic GSH levels in rats. Though in the later, it is not completely clear whether the increase in GSH is from direct absorption of the oral GSH or because GSH contains cysteine, the key precursor. Regardless, plasma and liver glutathione concentrations maybe raised by oral administration of glutathione precursors - SAMe, NAC, undenatured whey protein, and alpha lipoic acid. Melatonin (hormone) has been shown to stimulate a

15 related enzyme glutathione peroxidase. And the herb silymarin or milk thistle has demonstrated an ability to replenish glutathione levels. Researchers also found that blood glutathione levels rose nearly 50% in healthy individuals taking 500 mg of vitamin C daily. Vitamin C facilitates an increase in blood glutathione levels by supplying the body with a nutrient that is critical to the manufacture of it. Taurine (C 2H 7NO 3S) Taurine often referred to as an amino acid, is not part of the human body s structural proteins. Instead, taurine remains free in the tissues and bloodstream. In fact, taurine is one of the most abundant free amino-acid-like compounds found in the heart, the skeletal muscles and the nervous system. Also, technically speaking, taurine is NOT an amino acid as it lacks a carboxyl group. Amino acids are molecules containing an amine group (contain nitrogen N) and a carboxylic acid group (organic acids/carbon - COOH) attached to a side chain. However, taurine does contain a sulfonate group and may be called an amino sulfonic acid. a) Taurine functions in electrically active tissues such as the brain and heart to help stabilize cell membranes. This in turn can depress the firing of brain cells and cause a dampening of nerve cell action of the excitatory amino acids - glutamate & aspartate. Thus protecting against excito-toxicity. b) Taurine aids the movement of potassium, sodium, calcium, and magnesium in and out of cells and helps generate nerve impulses. This has everything to do with the electrical activity of the cells and subsequent communication between cells. c) Taurine functions with glycine and GABA as an inhibitory neurotransmitter. d) Taurine plays an important role in bile metabolism. e) Taurine is involved in detoxification by conjugating with various toxins. f) Taurine acts as an important antioxidant improving superoxide dismutase (SOD) and glutathione peroxidase activities and improved mitochondrial membrane injury. g) Taurine has been shown to boost white blood cell counts. Taurine is also known to re-invigorate the natural killer cells of in the immune system. h) Taurine plays a role in decreasing cataract development.

16 Taurine is naturally synthesized in the body from cysteine when adequate levels of vitamin B6 are available. Taurine is found in high protein foods such as dairy products, meat, poultry, eggs and fish. Taurine is also manufactured as a nutritional supplement. CAUTION: Taurine affects the hypothalamus which regulates body temperature. High doses can decrease body temperature and create chilliness. Sulfite and Sulfate Sulfite (SO 3 2- ) is an intermediate compound formed in the body during the metabolism of sulfur-containing amino acids and other sulfur-containing compounds. This takes place via the detoxification pathway called sulfoxidation. The function of sulfites in the body is unknown other than as a toxic metabolite. Sulfites can react with a variety of humoral (immune) and cellular components (i.e. proteins, lipids, DNA, etc.) potentially having neuro-toxic effects on brain tissue. Sulfites can also inhibit 90% of lung ATP energy production, can impair liver cell ATP energy production, and can deplete glutathione. Because of sulfites potential damaging effect to cells (toxicity) it must be converted and detoxified via the enzyme sulfite oxidase into the safer compound - sulfate. Sulfite oxidase is found in high concentrations in the liver and lungs. Mutations to the genes that code for sulfite oxidase are quite rare because they are usually fatal. A more common problem has to do with one of the components of this enzyme, the molybdenum cofactor. Molybdenum is a trace element that occurs in very low amounts in our soil and food supply. In fact, the published minimum daily requirement for molybdenum is just 75 micrograms. Anything that disables the molybdenum cofactor, such as lead and mercury can reduce a person s ability to process sulfite. Persons with a deficiency of or a poorly functioning sulfite oxidase are usually sensitive to sulfites. In such cases measures need to be made to improve the conversion of sulfites to sulfates, as well as avoiding sources of sulfites. The symptoms related to sulfite sensitivity are many, but the best documented cases report breathing problems that lead to asthma attacks.

17 Sulfites are formed as a natural by-product of sulfur metabolism in the human body. Sulfites are also a naturally occurring compound that nature uses to prevent microbial growth. They are found naturally on grapes, onions, garlic, and on many other growing plants. Sulfites are also found naturally occurring in some foods undergoing fermentation (i.e. beer and wine). However, one of the main sources of sulfites in the human body comes from the addition of sulfites and sulfur dioxide to many food products. This is done to preserve food and will be discussed below under man-made sources of sulfur. Sulfate (SO 4) a heavily oxidized sulfur compound, sulfate is an extremely important end product of sulfur metabolism. a) One of the important roles for sulfate is in the biosynthesis of 3 -phosphoadenosine-5 -phosphosulfate (PAPS). Catalyzed by the enzyme PAPS synthetase (PAPSS), inorganic sulfate along with adenosine triphosphate (ATP) is required in controlling the rate of PAPS formation. PAPS is also known as active sulfate. Sulfate conjugation or sulfation (the addition of a sulfate group to a substrate) is an important detoxification pathway in the metabolism of many drugs, xenobiotics, neurotransmitters and hormones. Sulfation also takes place in the formation of glycosylaminoglycans (GAGs). PAPS is the high-energy sulfate donor co-substrate for the sulfotransferase (SULT) enzymes that catalyze these reactions. The highest concentrations of PAPS is found in the liver, followed by the kidney, then the lungs, intestines and brain. b) Sulfate is also an essential component of key membrane-associated PAPS macromolecules - glycosaminoglycans (GAGs). GAGs are long, unbranched

18 heteropolysaccharide chains(long molecules composed of repeating carbohydrate/sugar structures). More specifically, GAGs are composed of repeating disaccharide units (acidic sugar amino sugar). The amino sugar is either D-glucosamine or D-galactosamine. The acidic sugar is either D-glucuronic acid or L-iduronic acid and together with sulfate give GAGs their strongly negative nature. GAGs are generally associated with a small amount of protein, forming proteoglycans. Sulfation of the carbohydrate chain occurs after the monosaccharide to be sulfated had been incorporated into the growing carbohydrate chain. The source of the sulfate is 3 -phosphoadenosyl-5 -phosphosulfate (PAPS). Sulfotransferases causes the sulfation of the carbohydrate chain at specific sites. GAG synthesis occurs, in the endoplasmic reticulum and the goigi, rather than the cystosol. GAGs are then transferred to and located on the surface of cells and in the extracellular matrix (ECM). The extracellular matrix is the non-cellular component of connective tissues surrounding all cells. Cartilage is the primary example of extracellular matrix in joints. There are eight major classes of GAGs 1. Chondroitin 4- and 6- sulfates are the most abundant GAGs in the body. Found in cartilage, tendons, ligaments and aorta. 2. Keratin sulfates I and II KS I is found in cornea. KS II is found in loose connective tissue with chondroitin sulfate. 3. Dermatan sulfate found in skin, blood vessels and heart valves. 4. Heparan sulfate extracellular GAG, found in basement membrane (a thin, delicate layer of connective tissue underlying the epithelium of many organs) and as a ubiquitous component of cell surfaces. 5. Heprin unlike other GAGs that are extracellular compounds, heparin is an intracellular component of mast cells that line arteries, liver, lungs and skin. 6. Hyaluronic acid is different from other GAGs as it is unsulfated, not covalently attached to protein and the only GAG not limited to animal tissue also found in bacteria. Hyaluronic acid is found in synovial fluid of joints, eyes, umbilical cord, loose connective tissue and cartilage. With the exception of keratin sulfate, which has a half-life of greater than 120 days, the GAGs have a relatively short half-life, ranging from about three days for hyaluronic acid to ten days for chondroitin and dermatan sulfate. The two main characteristics of sulfated GAGs is in their ability to maintain a negative charge on cell membranes and serve also as hydration sites which maintain the properties of mucous membranes. Meaning, GAGs have the special ability to bind large amounts of water, thereby producing the gel-like matrix that forms the basis of the body s ground substance or extracellular matrix.

19 Image: Glycsaminoglycans (GAGs) Because of sulfated GAGs large number of negative charges they tend to be extended in solution. They repel each other and are surrounded by a shell of water molecules. When brought together, they slip past each other. This produces a slippery consistency of mucous secretions and synovial fluid. When a solution of sulfated GAGs is compressed, the water is squeezed out and the sulfated GAGs are forced to occupy a smaller volume. When the compression is released, the GAGs, spring back to their original hydrated volume. These characteristics of sulfated GAGs allow them to be involved in numerous functions in the body such as: Act as structural components of the extracellular membrane. Act as a sieve in the extracellular membrane. In cartilage, they bind collagen and hold fibres in a tight, strong network. Are used to synthesize the chondroitin matrix of cartilage. Have role in compressibility of cartilage by acting as lubricants and shock absorbers. Contribute to the turgor (hydration) of various tissues. In the eye they play a role in corneal transparency and have a structural role in the sclera (white part). Act as anticoagulant. Facilitate cell migration - tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations. Are essential components of cell surfaces and play an important role in mediating cell- cell signalling and adhesion. Are components of synaptic vesicles. Are widely distributed within the intestine.

20 The major source of sulfate (64%) is produced in the body from the conversion of organic sulfur to inorganic sulfate. Methionine and cysteine in food proteins, glutathione in both animal and vegetable products, taurine in animal-source foods and sulfated GAGs in both plant-and animal-derived foods are the primary contributors of organosulfur compounds. Other organosulfur compounds, ingested for a variety of reasons, which are converted and contribute to the inorganic sulfate pool are listed in this report (N-acetyl-L-cysteine, S-methylmethionine, chondroitin sulfate, glucosamine sulfate, methylsulfonylmethane, etc.). Approximately 19% of total sulfate comes from the direct ingestion of inorganic sulfate from foods. The inorganic sulfate content of few foods is: Food Mean Sulfate Content (mg/g) Almonds 0.9 Bread (brown) 1.5 Bread (white) 1.3 Broccoli 0.9 Brussel sprouts 0.9 Cabbage 0.8 Cauliflower 0.5 Dates 1.1 Dried apples 4.9 Dried apricosts 3.0 Pasta, durum wheat 0.3 Peanuts 0.7 Prunes 1.0 Raisins 1.3 Sunflower seeds 0.6 The inorganic sulfate contained in water and beverages, account for 17% of the sulfate found in the body. Most public water supplies contain sulfate concentrations of less than 500 mg/l. Sulfate levels in water around 250 mg/l and above are detectable due to an off odor and taste, and this generally causes those exposed to water with higher concentrations of sulfate to switch to bottled water sources for drinking. The inorganic sulfate content of a few beverages is: Beverage Mean Sulfate Content (mg/l) Beer 260 Cider 270 Coconut milk 500 Cola 80 Juice, apple 70 Juice, grape 200 Juice, tomato 250 Milk, cow 100 Milk, human 5 Wine, red 380 Wine, white 300

21 Sulfate ingestion from drinking water is highly variable and depends on the area of the country from which the water is obtained. Some well water in rural areas of the United States has been known to contain upwards of 500 mg/l and some of the mineral waters sold with health claims have been reported to exceed this level. Distilled water contains very little, if any, sulfate, and de-ionized water contains no sulfate. Gastrointestinal absorption of sulfate can occur in the stomach, small intestine, and colon. Absorption is a sodium-dependent active process. When soluble sulfate salts (e.g., potassium sulfate or sodium sulfate) are consumed, more than 80 percent of oral sulfate doses are absorbed. With insoluble sulfate salts, such as barium sulfate, almost no absorption occurs. When magnesium sulfate is used what sulfate that is not absorbed in the upper gastrointestinal tract passes to the large intestine and colon, where it is either excreted in the feces, reabsorbed or reduced by anaerobic bacteria to metabolites, such as hydrogen sulfide. The major pathway of excretion for sulfur consumed as both organic sulfur (amino acids, compounds) and as inorganic sulfur (sulfites, sulfates) is via urine. A study found that fecal sulfate was not a major pathway of sulfur excretion. NOTE: Sulfate is the rate limiting factor in the production of PAPS and GAGs. Meaning sulfate depletion inhibits PAPS and GAGs synthesis. The depletion of sulfate is problematic because the extracellular sulfate pool in humans is among the smallest of animal species. Researchers have found that human cartilage especially GAG reproduction suffers significant deterioration with an even slight decrease in serum sulfate. A reduction in the sulfate concentration from 0.3 mm to 0.2mM resulted in a 33% reduction in human GAG synthesis. If the sulfate pool is depleted it will lead to a vicious cycle of degenerating cartilage/extracellular matrix reproduction and eventually proceeding to effects of arthritis. Unfortunately, there are several possible causes for sulfate depletion, some of which are: Old age Low protein or vegetarian diet can lead to a deficient intake of dietary sulfur. Mineral deficiency - molybdenum is needed for sulfite oxidase. Poor sulfoxidizers due to genetic weakness in sulfoxidation pathway. Heavy metal toxicity (e.g. mercury). Too much detoxification. Infection tumor necrosis factor (TNF) (a cytokine involved in systemic inflammation) blocks sulfite oxidase which converts cysteine to sulfate. Poor renal re-absorption an important factor in the homeostasis of sulfate is its renal re-absorption. Chemicals can have a direct effect on sulfate re-absorption. For example salicylic acid found in many over-the-counter medications as well as fruits and vegetables - increases the renal clearance of inorganic sulfate. Use of sulfate reducing drugs researchers have found that GAG synthesis in human cartilage appears to be very sensitive to the potential sulfate-depleting effects of drugs used in the treatment of rheumatoid arthritis and osteoarthritis, namely - non-steroidal anti-inflammatory drugs (NSAIDs ). It has been shown that NSAIDs

22 are detoxified via the sulfation pathway, thereby promptly reducing circulating sulfate concentrations for the creation of PAPS. They also act by directly inhibiting GAG synthesis in human joint cartilage. FURTHER RESEARCH: There are conflicting reports on sulfates role in the gastrointestinal tract. There are some reports which make a correlation between low levels of sulfated GAGs in the GI tract with irritable bowel diseases. While other reports indicate that sulfate and undigested sulfur compounds are implicated in the etiology of ulcerative colitis. The specific agent is thought to be the bacterial toxin - hydrogen sulfide, which is produced in the colon from sulfate by sulfate-reducing bacteria. Sulfate-reducing bacteria convert either sulfate or sulfite to sulfide and release it into the lumen (intestinal cavity) where it is further converted to hydrogen sulfide gas (H 2S). Excess luminal sulfide is thought to overburden mucosal detoxification systems, resulting in impaired butyrate oxidation and colonic epithelial inflammation. Also sodium sulfate supplementation has been demonstrated to stimulate the growth of sulfate-reducing bacteria in the colon of humans. Chondroitin Sulfate, Glucosamine Sulfate Chondroitin Sulfate as mentioned above, chondroitin sulfate is a large molecule and a member of the polysaccharides called glycosaminoglycans (GAGs). A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. These chains consist of unbranched polysaccharides of variable length containing two alternating monosaccharides: D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc). a) Chondroitin sulfate is a major component of extracellular matrix cartilage, lumbar disc, bone, skin, cornea and the arterial wall and is important in maintaining the structural integrity of these tissues. When administered, chondroitin sulfate exhibits an affinity for these sulfated GAG-rich tissues. b) In cartilage, chondroitin sulfate provides structure by holding water and nutrients and allowing other molecules to move through cartilage an important property, as there is no blood supply to cartilage. The tightly packed and highly charged sulfate groups of chondroitin sulfate generate electrostatic repulsion that provides much of the resistance of cartilage to compression. c) Chondroitin sulfate increases synovial fluid viscosity by increasing the amount of hyaluronic acid in the joints. Hyaluronic acid, another GAG, is a protective fluid that keeps the joints lubricated.

23 d) Chondroitin sulfate inhibits extracellular proteases (enzymes) involved in cartilage degradation. e) Chondroitin sulfate also blocks the TNF-alpha receptor - a cytokine involved in cartilage degradation. f) Chondroitin sulfate has an anti-inflammatory effect which protects cartilage matrix against damage from free radicals. g) In bones chondoitin sulfate increases the calcium pool and increases the rate of bone repair. Chondrotin sulfate is naturally synthesized in the body. Chondroitin sulfate is not found in foods, but is manufactured as a nutritional supplement from extracted animal cartilage, such as bovine tracheas or shark cartilage. It can also be produced by synthetic means. FURTHER RESEARCH: Despite its use as a nutritional supplement only limited evidence supports its efficacy as a therapeutic supplement for joint health. According to one authoritative study, pooled literature on chondroitin sulfate biochemistry offers enough information to assert that chondroitin sulfate is not absorbed by the human gastrointestinal tract. Therefore, any direct action of orally administered chondroitin sulfate on cartilage and chondrocytes is not possible. However, in 1995 researchers found evidence that up to 15 percent of chondroitin is absorbed intact, even though it is a large molecule with molecular weight ranging from 5,000 50,000 daltons. Lower molecular weight chondroitin (less than 17,000 daltons) appear to be absorbed completely intact. CAUTION: Unfortunately, chondroitin sulfate appears to play a major role in cancer biology and using it may be risky. When the joint is damaged (as it is in osteoarthritis), the joint cartilage responds by producing an array of chondroitin-containing proteins in an attempt to heal. One of the proteins produced in the arthritic joint is the chondroitin binding protein versican. You can find versican on the surface of a wide range of cancer cell types. In general, the greater the amount of chondroitin-containing versican bound to the cancer cell, the more likely it is that the cancer cell will be able to spread widely throughout the body. There is sufficient documentation of this effect of versican for prostate cancer, melanoma, some brain tumors, and a range of other cancers. Glucosamine Sulfate is an amino acid-monosaccharide (a combination of glutamine and glucose) combined with a sulfate group. Glucosamine is a natural compound that is found in healthy cartilage. a) There are two main components of ligaments, cartilage, tendons and spinal discs tissues. The first is collagen the second is sulfated glycosaminoglycans (GAGs). GAGs are the tissue frame work that collagen holds onto. Glucosamine is concentrated in joint cartilage where it is a substrate for cartilage GAG synthesis.

24 b) Glucosamine sulfate decreases the catabolic activity of chondrocytes by inhibiting the synthesis of protease enzymes and other substances that contribute to the damage of the cartilage matrix. c) Whereas glucosamine sulfate is thought to promote the formation and repair of cartilage, chondroitin sulfate is beleived to promote water retention and elasticity in cartilage. Glucosamine sulfate is naturally synthesized by the body from glucose and glutamine. Glucosamine sulfate is not found in foods, but is manufactured as a nutritional supplement. Raw material for supplementation comes from the shells of shellfish and animal bones and bone marrow. It can also be produced by synthetic means. FURTHER RESEARCH: Exactly how glucosamine works is not fully understood. About 90 percent of orally administered glucosamine gets absorbed, although a significant portion is catabolized during first pass metabolism and free glucosamine is not detectable in the serum after oral intake (possibly because it is bound to plasma proteins). This has led some researchers to speculate it is the sulfate rather than the glucosamine that is the active constituent. This is one reason why researchers believe that glucosamine sulfate might work better than other forms of glucosamine such as glucosamine hydrochloride or N-acetyl glucosamine. Methylsulfonylmethane (MSM), Methanethiol Methylsulfonylmethane (MSM) (C 2H 6O 2S) (THIOL) MSM is composed of 34% elemental sulfur and is one of the least toxic substances in biology, similar in toxicity to water. Because MSM provides such a high level of elemental sulfur, the claimed attributes of MSM are similar to the functions listed for sulfur in the introduction to this report. MSM is not produced by the body but is found in small amounts in many foods such as - cow s milk, meat, seafood, fruits and alfalfa, corn, tomatoes and in human milk and urine. However, MSM is easily destroyed by heat or processing. The half-life of MSM is only 12 hours when consumed within the body. MSM is also manufactured as a nutritional supplement. According to research done at the MSM clinic at the Oregon Health Sciences University, long-term use of MSM at a dose greater than 2 grams per day is well tolerated, producing no adverse effects.

25 FURTHER RESEARCH: There are conflicting reports about the utilization of MSM in humans. A 1975 study found recovery of MSM administered orally to humans was only three percent, suggesting some type of utilization or modification in the gut or liver. Yet another study (1986) of radio-labeled MSM was administered to guinea pigs and incorporation of sulfur into methionine and cysteine was measured. One percent of the radioactivity was incorporated into serum methionine and cysteine, none was found in the feces and most was excreted in the urine. CAUTION: MSM is sometimes incorrectly referred to as dimethyl sulfoxide (DMSO) (C 2H 6OS). Though MSM is structurally related to DMSO due to it being an oxidized metabolite of DMSO, their behaviors differ. As a matter of fact when DMSO enters the body approximately 15% is converted to MSM. The mistake comes from the fact that MSM is also known as DMSO2 because MSM/DMSO2 (C 2H 6O 2S) has one more additional oxygen (O) molecule than DMSO. DMSO is described below. Methanethiol (CH 4S) (THIOL) also known as methyl mercaptan is a colorless gas with a smell like rotten cabbage. It is a natural substance found in the blood, brain, and other tissues of humans. Produced by bacteria, methyl mercaptan is always present in your body and in your urine and feces. It is also one of the main chemicals responsible for bad breath and the smell of flatus a) Methyl mercaptan is a by-product of bacterial metabolism in the human gut and currently it is unknown if it serves any biochemical function in humans. b) Methyl mercaptan is manufactured for use in making the nutritional supplement - methionine. It is also used in industry to produce pesticides, as a jet fuel additive and in the plastics industry. c) It has also been approved for use as a food additive, but because of its unpleasant smell, very little can be used. Methyl mercaptan is naturally synthesized in the human body. Methyl mercaptan can be obtained through the diet as it occurs naturally in certain foods such as some nuts (filberts) and cheese (Beaufort). Methyl mercaptan is not manufactured as a nutritional supplement. Methyl mercaptan is also released from decaying organic matter in marshes and in surface seawater, where it is the primary breakdown product of algae. It also originates from man-made sources such as pulp mills and sewage treatment plants. Therefore, methyl mercaptan can be inhaled through the lungs upon exposures to these sources.

26 Fibrinogen, Heparin, Insulin Fibrinogen is a blood plasma protein produced by the liver. Fibrinogen plays an important role in blood coagulation. Blood coagulation is a process in which several components of the blood form a clot. When blood escapes from a rupture in a blood vessel several proteins, called coagulation factors, go into action to produce thrombin. The thrombin then converts fibrinogen to fibrin. Fibrin produced from fibrinogen is the main protein in a blood clot. It surrounds the cells in the blood and plasma and helps form the clot. Fibrinogen is found strictly as a synthesized protein in the body. Fibrinogen is not found in foods nor is it manufactured as a nutritional supplement. CAUTION: Increased levels of fibrinogen are a risk factor for heart disease and stroke. Heparin (C 12H 19NO 20S 3) a highly sulfated glycosaminoglycan (GAG). Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed, it allows the body's natural clot mechanisms to work normally to break down clots that have not yet formed. Heparin is naturally synthesized in the body from basophiles and mast cells (immune cells). Heparin is not found in foods nor is it manufactured as a nutritional supplement. However, heparin is produced by pharmaceutical companies where it is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung. Pharmaceutical grade heparin is administered via injection.

27 Insulin is a natural hormone and protein made by the pancreas. Insulin controls the level of sugar glucose in the blood. Insulin permits cells to use glucose for energy. Cells cannot utilize glucose without insulin. Insulin is synthesized in the body by the pancreas. Insulin is not found in foods nor is it manufactured as a nutritional supplement. However, insulin is produced by pharmaceutical companies for the purpose of injections in treating diabetes. Allicin, Acidophilus, Chlorella Allicin (C 6H 10OS 2) is an oily, yellow liquid, which gives garlic its characteristic odor. Allicin is produced when garlic is crushed or bruised. The reaction is catalyzed by the enzyme allicinase. Allicin is not bioavailable and will not get absorbed in the blood, even after ingesting large amounts. However, the allicin remaining in the gut exhibits antibacterial and anti-fungal properties. For example: studies have confirmed that allicin has inhibitory activity on Helicobacter pylori - a bacteria responsible for the development of gastric ulcers. The sensitivity might also explain the lower risk of stomach cancer in people with high garlic intake. Allicin is not synthesized by the body. Allicin is found primarily in garlic and onions. Allicin is also manufactured as a nutritional supplement. Acidophilus (dairy) (THIOL) also known as lactobacillus acidophilus is a probiotic. Probiotics (friendly bacteria) are live microbial organisms that are naturally present in the digestive tract. a) Acidophilus can help protect the body against harmful bacteria, parasites, and other organisms. As it breaks down, it releases hydrogen peroxide which creates a toxic environment for unhealthy creatures in the body, helping to drive them out.

28 b) Acidophilus plays an important role in digestion, helping to produce a number of chemicals which aid in the digestion process. c) Acidophilus is thought to help boost the immune system and produce vitamin K. Acidophilus is not synthesized by the body, rather acidophilus can be found in cultured dairy products such as yogurt or kefir. Fermented foods such as sauerkraut also contain acidophilus. Acidophilus is also manufactured as a nutritional supplement. Chlorella (THIOL) - is a single celled green algae. Chlorella contains the green photosynthetic pigments chlorophyll. It is also an attractive food source because it is high in protein (SAA s) and other essential nutrients. Clinical studies on chlorella suggest effects including: detoxification of dioxin (highly toxic chemicals in the environment that do not break down), healing from radiation exposure, the ability to reduce high blood pressure, lower serum cholesterol levels, accelerate wound healing, and enhance immune functions in humans. Chlorella is not synthesized by the body. Chlorella is grown in lake farms or outdoor ponds and then processed as a nutritional supplement. However, studies have shown that chlorella actually loses most of its nutritional value when altered or processed in any way. Compiled Chart: Organosulfur Compounds (both exogenous and endogenous, that the human body either inhales, ingest or biosynthesizes)

29 Organosulfur Compounds Found in Food Man-Made Produced in Body (organic sulfur compounds) (supplements) Biotin (C10H16N2O3S) X X - Thiamine(B1) (C 12H 17N 4OS) X X - Pantethine (C22H42N4O8S2) - X X Coenzyme A (C23H38N7O17P3S) - X X Acetyl-CoA (C23H38N7O17P3S) - - X Methionine (C5H11NO2S) X X - S-Adenosylmethionine (C15H22N6O5S+) - X X Homocysteine (C4H9NO2S) - - X Cysteine (C3H7NO2S) X X X Cystine (C6H12N2O4S2) X - X N-Acetyl-Cysteine (C5H9NO3S) - X X Metallothionein - - X Alpha-Lipoic Acid (C8H14O2S2) X X X Glutathione (C10H17N3O6S) X X X Taurine (C2H7NO3S) X X X PAPS (C10H15N5O13P2S) - - X Chondroitin Sulfate - X X Glucosamine Sulfate - X X Methslsulfonylmethane (MSM) (C2H6O2S) X X - Methanethiol/Methyl Mercaptan (CH4S) X - X Fibrinogen - - X Heparin (C12H19NO20S3) - X X Insulin - X X Allicin (C6H10OS2) X X - Acidophilus X X - Chlorella X X - DMPS (C3H8O3S3) - X - DMSA (C4H6O4S2) - X - DMSO (C2H6OS) - X -

30 Man-Made of Sulfur and Sulfur Compounds in the Human Body In the previous report Sulfur and Sulfur Compounds in the Environment - the topic of man-made sources of sulfur is discussed in detail. Below is a description of how some of them gain entry into the human body. Elemental Sulfur (S) Sulfur dust is used as a pesticide and can be inhaled, absorbed through contact with the skin, eyes or mucous membranes and can be unintentionally swallowed. Additionally, people may be exposed to small amounts of sulfur through the food supply as pesticide residue. However, EPA does not believe that the ingested sulfur is harmful in any amount and therefore has not established limits for residues of sulfur in or on food. Elemental sulfur is considered, by the EPA, to be non-toxic. However, many sulfur derivatives such as sulfur dioxide and hydrogen sulfide are considered to be highly toxic. Sulfur Dioxide (SO2) Is a toxic, non-flammable, colorless gas that has a strong pungent, irritating odor familiar to the smell of a just struck match. Sulfur dioxide is the result of sulfur being burned. When carbon is burned the well known carbon dioxide (CO 2) is produced. When sulfur is burned, sulfur dioxide (SO 2) is produced. Sulfur dioxide is released into the atmosphere from a variety of natural sources such as hot springs, volcanoes, decay of vegetation and forest fires. Man-made sources of sulfur dioxide result from the burning of sulfur and sulfur compounds found in fossil fuels by way of - vehicle exhaust, power plants, pulp mills, homes burning oil for heat, etc. In humans, sulfur dioxide irritates eyes and the respiratory systems. High concentrations are associated with a number of lung problems, and even low concentrations can cause asthmatic subjects to experience severe bronchial constriction during exercise. Sulfur dioxide can even react with moisture in the lungs to form sulfurous acid which in sufficient quantities may harm the lungs, eyes or other tissues. Inhalation of sulfur dioxide is dangerous however, they claim ingestion of sulfur dioxide and sulfites is harmless, hence their use in the food industry as food preservatives.

31 Sulfite (SO3 2- ) It was determined earlier that sulfites are a naturally occurring compound in the human body. However, it was also determined that they served no function and were toxic intermediates that need to be immediately detoxified. Yet, a major source of sulfites to humans comes from the sulfite and sulfur dioxide additives found in many food products. Sulfites and sulfur dioxide are strong antioxidants that are added to foods for the control of enzymatic and non-enzymatic browning as well as for their antimicrobial action. For example: In 'fresh' food products sulfites prevent discoloration and oxidation (breakdown) of the food. On grapes sulfites are used as a fungicide. In wines sulfites kill certain unwanted bacteria and assist in the aging process. In packaged processed food sulfites are a preservative. Sulfites are used as a bleaching agent for food starches. Sulfites are used as a strengthener in dough conditioners. Sulfites can even be found in herbs because sulfur treatment is sometimes used to prevent herbs from deteriorating. This is usually done by placing the herbs on a screen and having sulfur vapors (from burning sulfur) briefly flow from below the screen, which could leave traces of sulfur dioxide. Sulfites are also frequently used in pharmaceutical drugs as a preservative and stabilizer. A list of the different types of sulfites used in foods and medicines are: Sulfite Sulfur Dioxide Sodium Sulfite Sodium Bisulfite Sodium Metabisulfite Calcium Bisulfite Calcium Metabisulfite Potassium Bisulfite Potassium Metabisulfie It should be noted sulfur dioxide (a gas), strictly speaking is not a sulfite. However, the human response to sulfur dioxide mimics the response to sulfites, probably because it may be oxidized to become a sulfite. Sulfur dioxide gas is used to prevent discoloration, for example in the drying of fruit. In the process, sulfur dioxide is trapped and bound to the fruit and the concentration can be quite high. Since ancient times, burning sulfur has been used to temper the fermentation of wine. Most modern wine makers today use the sulfite salts directly, but the result is the same. Sulfur dioxide can also be dissolved in water to have a softening effect on fibers and other organic structures. This effect is used in the corn refining process that produces corn starches and syrups. Since corn refining starts with a two day soak in hot water laced with sulfur dioxide (called steeping), all corn starches and syrups wind up with a sulfur content. Corn starches and syrups such as - baking powder, caramel, dextrin, maltodextrin, dextrose, fructose, etc. are the most common sulfured ingredients in modern foods.

32 It should also be noted that sensitivity to sulfites is a different condition compared to a sulfa drug allergy. Some patients will have allergic reactions to sulfur containing medications or sulfa antibiotics. This is a very different condition than sulfite sensitivity. Those allergic to sulfites are often not at increased risk of sulfa drug allergy, and vice versa. Hydrogen Sulfide (H2S) Hydrogen sulfide is a colorless, flammable, extremely hazardous gas with a rotten egg smell which occurs when water (H 2O) mixes with sulfur(s). Natural sources come from natural gas, hot springs, swamps, shallow lakes, plumbing systems, water heaters, etc. Man-made sources of hydrogen sulfide come from pulp mills, waste water treatment plants, refineries, etc. Hydrogen sulfide is readily absorbed in the lung and by the alimentary canal (entire digestive system mouth to anus). At levels of only 5ppm hydrogen sulfide can cause irritation of the conjunctiva and bronchial mucus. At 100 ppm it can cause asphyxia, nausea, cerebral excitement, narcosis and after an hour death ppm leads to immediate paralysis and death. Though elemental sulfur is considered to be non-toxic, doses of over 10 grams will can cause headache, vomiting and intestinal pain. These toxic effects are caused by sulfur mixing with water in the intestines to create hydrogen sulfide which can be noticed on the breath. Pharmaceutical Drugs The amount of pharmaceutical drugs consumed in the US and worldwide is staggering. Many of these drugs are manufactured with the element of sulfur and therefore must also be considered as a source of sulfur intake. The chemical compounds found in pharmaceutical drugs are manufactured synthetic compounds. Below is a partial list of the more common sulfur containing pharmaceutical drugs. 2,3-Dimercapto-1-Propanesulfonic Acid (DMPS) (C 3H 8O 3S 3) (THIOL) is a chelating agent used as an antidote to heavy metals poisoning (mercury, arsenic, lead). Chelating agents are chemical compounds that have the ability to bind strongly with metal ions. DMPS is administered via injection. Dimercaptosuccinic Acid (DMSA) (C 4H 6O 4S 2)(Di-THIOL) is a water-soluble, sulfhydryl-containing organic compound that is FDA approved as a chelating agent for the treatment of lead (Pb)and mercury (Hg) toxicity. DMSA is administered orally and although it is sold as a prescription drug, it is also available as a nutritional supplement. Animal studies show DMSA to be almost 3 times more effective than DMPS in removing mercury from the brain. DMSA has the added advantage that it is taken by mouth in capsule form, whereas DMPS must be given by injection. DMPS is also 3 times more toxic than DMSA, based on its LD-50 (the dose at which 50 percent of lab animals die).

33 Dimethyl Sulfoxide (DMSO) (C 2H 6OS) (THIOL) is a by-product of the wood industry and has been in use as a commercial solvent for decades. In the medical field DMSO is predominantly used as a topical analgesic (relieves pain), a vehicle for topical application of pharmaceuticals, as an anti-inflammatory and an antioxidant. Because DMSO passes through membranes easily it increases the rate of absorption of some compounds through organic tissues including skin, it can be used as a drug delivery system. It is frequently compounded with antifungal medications, enabling them to penetrate not just skin but also toe and fingernails. It penetrates the skin so rapidly one can taste it soon after it comes into contact with the skin. Additionally, DMSO has demonstrated that it can exert a protective effect on the GAG - hyaluronic acid. Sulfonamides or Sulfa Drugs (H 2NO 2S) in chemistry sulfonamide is another sulfur containing functional group which is made up of a sulfonyl group S(=O) 2 connected to an amine group (NH 2). Attached to sulfonamide group is an organic group which is produced by a pharmaceutical company. There are several sulfonamide-based groups of drugs. The original sulfonamides (called sulfa drugs) contained antibacterial/antimicrobial properties. These drugs have the marked ability to halt the growth of bacteria in the body. Antibiotic sulfonamides were the first antibiotics used to treat infections. However, today sulfa drugs are used much less frequently. Below is a partial list of antibiotic/antimicrobial sulfonamides/sulfa drugs (generic names): Antibiotic/Antimicrobial Sulfonamides Sulfa-benzamide Sulfa-isodimidine Sulfa-cetamide Sulfa-methoxazole Sulfa-diazine Sulfa-methoxypyridazine Sulfa-dimethoxine Sulfa-nilamides Sulfa-doxine Sulfa-thiazole There are also non-antibiotic sulfonamides which are devoid of antibacterial activity. Most non-antibiotic sulfonamides are prescribed as diuretics (increase the excretion of water from the body via urination) and anticonvulsants (used for epileptic seizures by suppressing the rapid and excessive firing of neurons). Below is a partial list of diuretic and anticonvulsant sulfonamide drugs (generic names): Diuretic Sulfonamides Acetazolamide Ethoxzolamide Chlorthalidone Clopamide Furosemide Hydrochlorothiazide Indapamide Mefruside Metolazone Xipamide