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wellbeing. Most vitamins are not made in the body, or only in insufficient amounts, and are mainly obtained through food. When their intake is inadequate, vitamin deficiency disorders are the consequence. Vitamins are present in food in minute quantities compared to the macronutrients protein, carbohydrates and fat. The average adult in industrialised countries eats about 600g of food per day on a dry-weight basis, of which less than 1 gram consists of vitamins. No single food contains all of the vitamins and, therefore, a balanced and varied diet is necessary for an adequate intake. Each of the 13 vitamins known today has specific functions in the body, which makes every one of them unique and irreplaceable. Vitamins are essential for life! Of the 13 vitamins, 4 are fat-soluble, namely vitamins A, D, E and K. The other vitamins are water-soluble: vitamin C and the B-complex, consisting of vitamins B1, B2, B6, B12, folic acid, biotin, pantothenic acid and niacin. The history of vitamins can be divided into five periods. 1. The empirical healing of diseases, now associated with vitamin deficiency, through consumption of particular foods. An example is the use of liver to treat night blindness (vitamin A deficiency) by the Egyptians (Papyrus Ebers 1550-1570 BC), Assyrians, Chinese, Japanese, Greeks, Romans, Persians and Arabs.
The second phase was characterised by the ability to induce a deficiency disease in animals, which started with the classical studies of Lunin and Eijkman around 1890. The ability to produce deficiency diseases, such as beriberi in animals, led to Hopkins’ concept that small amounts of “accessory growth factors” are necessary for growth and life, and the coining of the term “vitamine” in 1912 by the Polish-American scientist, Funk. The third phase consisted in seven decades of exciting research involving the discovery, isolation, structure elucidation and synthesis of all the vitamins, and culminating in the synthesis of vitamin B12 in 1972. Most scientists think that the discovery of any new vitamin is quite unlikely, although efforts are still continuing in that quest. Many of the researchers involved in this golden age of the vitamins received a Nobel prize in recognition of their great achievements (Table 2) During the era of discovery, a fourth period began which was concerned with the biochemical functions, establishment of dietary requirements and commercial production. In the early 1930s it was realised that riboflavin (vitamin B2) was part of the “yellow enzyme”, which in time led to the elucidation of the role of the Bvitamins as coenzymes. The subsequent identification of most of the B-vitamins as coenzymes remained a central theme, defining their function for many decades. The first commercial synthesis of vitamin C by Reichstein in 1933 was the start of a successful industrial effort that led to the availability of relatively inexpensive vitamins for research
and use in animal feedstuffs, for the fortification of food products, and for supplements. The accumulation of reports of health benefits beyond preventing deficiencies and exciting new biochemical functions of vitamins ushered in a fifth period, starting with the report in 1955 of the cholesterol-lowering effect of niacin (1). This is now a well accepted effect of the vitamin, which has nothing at all to do with its classical coenzyme role, and is a clear health effect beyond preventing the deficiency disease pellagra. Finally, work on the biochemical function of vitamins in the last three decades has considerably expanded our concept of how vitamins function in the body and has helped provide a chemical basis for the in vivo observation of their health effects (Table 3).
Table 1: The History of Vitamins
Table 2: Vitamin-Related Nobel Prize Winners
Table 3: Biochemical Function of Vitamins
Vitamin B complex
You would not be able to even type ABC into your browser without ATP. In fact, within a few seconds death would wrought its ugly head had this source of energy ceased to be produced. Think
logically for a moment; if this complex molecule is of such importance, then its optimization must be of prime significance if one is to train at full capacity--enter the B-Complex. It is integral to almost every step of cellular respiration (energy production). Can you afford a deficiency in this area? The answer is a clear no. I must warn you, however, the body’s ability to form energy is indeed complex beyond the readers wildest imaginations. It will therefore be no easy task to understand all the mechanisms capable of enhancing it. Today, however, you will take one giant Leap forward--that is a guarantee.
Vitamins can be defined as essential organic compounds required in minuscule amounts (referred to as micronutrients). Vitamins mainly function as catalysts for reactions within the body. They contain no useful energy, but as catalysts, they serve as essential links and regulators in metabolic reactions that release energy from food. Vitamins also control the processes of tissue synthesis and aid in protecting the integrity of the cells' plasma membrane; they also assist growth, maintenance of health, metabolism and much more. To refresh your memory, a catalyst is a substance that allows a chemical reaction to occur using less energy and less time than it would take under normal conditions. If these catalysts are missing, as in a vitamin deficiency, normal bodily functions can break down hindering athletic performance, and rendering a person susceptible to disease . In the early part of the twentieth century, vitamins--then known as "accessory growth factors,"--were discovered. The word 'vitamin'
is derived from the combination of words ‘vital amine’ and was conceived by Polish chemist Casimir Funk in 1912. Funk isolated vitamin B1 (thiamine) from rice . However, vitamins achieved importance centuries before scientists isolated and classified them. The Greek physician Hippocrates (discussed in President Wilson’s suburb article, Hippocrates - Was He Hardcore? ) advocated ingesting liver to cure night blindness. While he did not know the reason for the cure, we now know that vitamin A, which helps to prevent night blindness, occurs plentifully in this meat. In 1897, a Dutch physician in Java observed that a regular diet of polished rice caused beriberi in fowl, while adding rice polishings (thiaminerich) to table scraps cured the disease. A most famous discovery was found in the early 19th century, when it was observed that adding oranges and lemons to the diet of British sailors paved the way for eradicating the dreaded disease scurvy, because of the protective effects of the vitamin C contained in the fruits. Not until 1932, however, did ascorbic acid (vitamin C) become isolated from lemon juice . The formal discovery of vitamins revealed that these organic substances were needed by the body in minute amounts. Vitamins, their amine role having been discredited, have no particular chemical structure in common, and are often considered accessory nutrients because they neither supply energy, nor contribute substantially to body mass. Finally, with the exception of vitamin D, which is formed with the help of ultraviolet radiation, or sunshine, and some K and B vitamins, which are produced by bacteria within our intestines, the body cannot
manufacture vitamins; hence, diet and or supplementation must supply them [37,28].
Vitamins are classified as either fat-soluble or water-soluble. The fat-soluble vitamins (vitamins that can mix with fat, but usually not with water) are vitamins A, D, E, and K; the water-soluble vitamins (can be dissolved/mixed in water) are vitamin C and the Bcomplex vitamins (based on their common source distribution and common functional relationships). Today we will narrow in on the later group. Water-soluble vitamins, with the exception of vitamin C, are members of the B complex. Most of the B-complex group can be further divided according to general function: energy releasing, hematopoietic (refers to an agent or process that affects or promotes the formation of blood cells) and others. Other vitamins cannot be classified this narrowly because of their wide range of functions . The water-soluble vitamins act largely as coenzymes, with small molecules combing with a larger protein compound (apoenzyme) to form an active enzyme that accelerates the interconversion of chemical compounds. Coenzymes participate directly in chemical reactions; when the reaction runs its course, coenzymes remain intact and participate in additional reactions. Water-soluble vitamins, similar to their fat-soluble counterparts, consist of carbon, hydrogen, and oxygen atoms. They also contain nitrogen
and metal ions including iron, molybdenum, copper, sulfur, and cobalt. Because of their solubility in water, water-soluble vitamins disperse in the body fluids without being stored to any appreciable extent. If the diet regularly contains less than 50% of the recommended values for water-soluble vitamins, marginal deficiencies may develop within 4 weeks [89,88,90,12,13].
Water-soluble vitamins are absorbed into portal blood; furthermore, with the exception of cyanocobalamin (vitamin B12), they cannot be retained for long periods by the body. Any storage occurring results from their binding to enzymes and transport proteins. Generally, an excess intake of water-soluble vitamins becomes voided in the urine. Water-soluble vitamins exert their influence for 8 to 14 hours after ingestion; thereafter, their potency begins to decrease. For maximum benefit of, for example, vitamin C supplements, they should be consumed at least every 12 hours. Sweating during extreme physical activity can produce negligible losses of the water-soluble vitamins as well [3,5]. Finally, let us venture into today’s subject, the water-soluble substances known collectively as, ‘Vitamin B complex.’
Vitamin B complex
B-complex consists of eight different vitamins, which include thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), piroxidine (B6), folic acid (B9), cyanocobalamin (B12), and biotin. All of the above are
water soluble, and play a key role in several bodily functions, such as protein, fat, carbohydrate, and mitochondrial energy metabolism; maintenance of the liver, skin, hair, mouth, and eyes; plus so much more, which will be covered thoroughly within the following paragraphs. As mentioned above, vitamin b complex can be further broken down in to 3 general categories; that is, energy releasing, hematopoietic, or other. And some fit in both categories. Here is a list [7,12]: Energy releasing- Thiamine (B1), Riboflavin (B2), Niacin (B3), Pantothenic acid (B5), Piroxidine (B6), and Biotin. Hematopoietic- Folic acid (B9), Cyanocobalamin (B12), Pantothenic acid (B5), and Piroxidine (B6). Other- Thiamine (B1), Niacin (B3), Piroxidine (B6), Folic acid (B9), and Cyanocobalamin (B12). All of these factors will be understood, after this article. Before we begin, here is an outline of what will be covered on each of these 8 powerhouses. · Description- the chemical makeup and structure of each vitamin · Digestion- how these micronutrients are digested in the human body. · Function- A complete dissection of the process by which they benefit the body · Deficiency- the problems caused by a deficit in any of the B-complexes · Recommendation- within I will list food sources that contain them, recommended doses, toxicity levels, and much more.
For full comprehension of this article, I would highly recommend you read last month’s issue of hyperplasia, as many of the terms and physiological occurrences are discussed therein.
The first aspect of the B-complex we will cover is Vitamin B1. The first to publish a correct formula and synthesis for this vitamin was Dr. Robert R. Williams in 1936. Synonyms for it are thiamine, thiamin and aneurin. Chemically, Thiamine consists of a pyrimidine ring and a thiazole moiety (or one of two parts) linked by a methylene (CH2) bridge. As stated above, it is water-soluble [63,44].
Thiamin can travel by both active (through plasma membrane, requires metabolic energy to “power” the exchange of materials) and passive (through plasma membrane, requires no energy) transport, depending on the amount of the vitamin presented in the intestine for absorption. At low physiological concentrations, thiamin absorption is active and sodium-dependent (type of active transport). Absorption occurs primarily in the upper jejunum but can occur in the duodenum and ileum (portions of the small intestine). When intakes of thiamin are high, absorption is predominantly passive [101, 88, 83]. Transport of thiamin into red blood cells is thought to occur by facilitated diffusion (diffusion that is assisted by protein
transporters). Only free thiamin or thiamin-monophosphate (TMP) is thought to be able to cross cell membranes. In red blood cells, most thiamin exists as thiamin-diphosphate (TDP) with smaller amounts of free thiamin and TMP. The human body contains approximately 30 mg of thiamin, with relatively high but still small concentrators found in the skeletal muscles, heart, liver, kidney, and brain. In fact, skeletal muscles are thought to contain about half of the body's thiamin . Following absorption, most free thiamin is taken up by the liver and converted to its coenzyme form, thiamin-diphosphate (TDP). Conversion of thiamin to TDP requires adenosine triphosphate (ATP) and thiamin pyropbospbokinase, an enzyme found in the liver, brain, as well as other tissues. About 80% of total thiamin in the body exists as TDP, 10% as TTP (thiamin triphospate), and the rest is TMP, which is inactive [88, 83, 2]. To understand transport systems, as well as more information on the digestion track, it would behoove the reader to study the following articles: Sodium - A comprehensive Analysis & Fiber Dynamics Part I. Next, we will show how Vitamin b1 functions in the body, and its many beneficial traits.
Vitamin b1 is absolutely essential to several bodily functions. We will break them down into 2 categories consisting of: • Energy metabolism • Nervous system
The Krebs cycle (also called the citric acid cycle and the tricarboxylic acid cycle) is extremely important in extracting energy from fuel molecules. Consequently, the process is thiamin dependent. TDP functions as a coenzyme (binds with certain protein molecules to form active enzymes) necessary for the oxidative decarboxylation of both pyruvate and a-ketoglutarate. These reactions are instrumental in generating energy (ATP). Inhibition of these decarboxylation reactions prevents synthesis of ATP, and of acetyl CoA needed for the synthesis of, for example, fatty acids, cholesterol, and other important compounds, and results in the accumulation of pyruvate, lactate, and a-ketoglutarate in the blood [35,26,25]. Failure to oxidize the molecules listed above (and several others), results in the accumulation of both the branchedchain amino acids and their a-keto acids in blood and other body fluids. This is characteristic of maple syrup urine disease (MSUD). MSUD results from a genetic (inborn error of metabolism) absence or insufficient activity of the branched-chain a-keto acid dehydrogenase enzyme complex. People with MSUD must avoid meat, poultry,
fish, and dairy products to limit intakes. But in short, thiamin is vital for energy conversions, and if lacking in your diet and supplementation, can induce serious health problems, and inefficiencies in the iron jungle. Concerning this topic, Sanz Paris A et. al states, “In thiamine deficiency, the Krebs cycle slows large quantities of pyruvate are diverted to lactate production and anaerobic metabolism begins .” Timm DE et. al states, “Thiamine is essential for central metabolic processes, including the formation of acetyl CoA from glucose and the Krebs cycle. Deficiencies in human thiamin metabolism result in beriberi and Wernicke encephalopathy.” Thiamin assists many other bodily functions, such as synthesis of pentose, NADPH, and additional molecules. All of which are essential for fatty acid synthesis, cell replication and much more. Here is an additional quote form La Selva M et. al , “Thiamine restores cell replication, decreases the glycolytic flux and prevents fluorescent AGE formation in endothelial cells cultured in high glucose”
It is apparent from several neurological disorder studies concerning thiamine deficiency, and taking into account where thiamine is found (in both the nerves and brain), that this vitamin plays a vital role in nerve function. Ke ZJ et al. states , “results indicate that TD [thiamine deficiency] induces alterations in neurons, endothelial cells, and microglia contemporaneously. This model provides a unique paradigm for elucidating the molecular
mechanisms involved in neuronal commitment to neuronal death cascades and contributory microglial activity.” What the exact role is has yet to be determined. But there are many viable theories currently being investigated. One theory is that thiamine triphosphate helps regulate nerve impulses, via the Na+ and K+ gradient. And other important channels, helping to regulate functions through many reactions. Also, it is thought to act as a coenzyme in the production of neurotransmitters (chemical messengers between nerve fibers). Either way, results have consistently revealed that being deficient in this vitamin is highly detrimental to the function of your nervous system, making this a vital supplement [55,46,17,16,].
Deficiency of aneurin can cause serious ailments. One of the first symptoms of thiamin deficiency is a loss of appetite (anorexia) and thus weight. As deficiency worsens, cardiovascular system involvement (such as hypertrophy and altered heart rate) and neurological symptoms appear. One major symptom of B1 deficiency is an ailment called, ‘beriberi’. There are three types of beriberi classified today: • Dry beriberi- found predominantly in older adults; it is thought to result from a chronic low thiamin intake especially if coupled with a high carbohydrate intake. Dry beriberi is characterized by muscle weakness and wasting, especially in the lower extremities
• Wet beriberi- results in more extensive cardiovascular system involvement than dry beriberi; right-side heart failure leads to respiratory involvement with edema. • Acute beriberi- seen mostly in infants has been documented in countries such as Japan. In the United States and in Western countries, thiamin deficiency associated with alcoholism is common and is referred to as 'Wernicke's encephalopathy' or 'Wernicke-Korsakoffa syndrome'. Individuals with dependency on alcohol are particularly prone to thiamin deficiency because of: • Decreased intake of the vitamin due to decreased food consumption. • An increased requirement in the case of liver damage (decreased liver function impairs mp formation and, consequently, vitamin use); and • Decreased thiamin absorption Wernicke's encephalopathy, often manifested in those with a history of alcohol abuse, is characterized by ophthalmoplegia (paralysis of eye muscles), nystagmus (involuntary, rapid, rhythmic movement of eyeball), ataxia (Failure of muscular coordination, irregularity of muscular action), loss of recent memory, and confusion. Treatment consists of therapeutic doses (at least 100 mg) of thiamin [112,101,100].
Because of thiamin’s importance in energy metabolism, needed intake varies according to energy (caloric) intake. The RDA for adults is 0.5 mg/ 1000 kcal; however, an intake of no less than 1 mg/day is advised. The 1998 Dietary Reference Intakes RDA for individual intake for thiamin for adult men aged 19 years and older is 1.2 mg/day and for adult women aged 19 years and older 1.1 mg daily. Thiamin in-takes with pregnancy and lactation (secreting milk) are increased to 1.4 and 1.5 mg/day, respectively [113,47]. As far as over consumption is concerned, there appears to be little danger of thiamin toxicity associated with oral intake of large amounts (500 mg daily for 1 month) of thiamin. Pharmacological levels of thiamin are used in the treatment of certain inborn errors of metabolism. One variant form of MSUD has been shown to respond to oral thiamin supplements (up to 500 mg daily). Other metabolic diseases that may respond to large doses of the vitamin are thiamin-responsive megaloblastic anemia id and thiamin-responsive lactic acidosis. In the latter condition, large doses of thiamin can increase the activity of pyruvate dehydrogenase in the liver, thereby decreasing the level of lactic acid, as more pyruvate is decarboxylated for entry into the Krebs cycle . Finally, thiamin is widely distributed in foods, including meat (especially pork), legumes, and whole or enriched grain products. Yeast and wheat germ also contain significant amounts of this vitamin [110,98].
B2, known as Riboflavin, is constructed of flavine (a ring, acts as a covalent link), which is attached to a sugar alcohol, formed by the reduction of ribose called ribitol. And once again, it is a watersoluble vitamin.
Riboflavin is primarily absorbed in the proximal small intestine by a sodium dependent carrier. Within cells, b2 is converted to its coenzyme forms, regulated by hormones, such as the thyroid hormone. These coenzymes, than bind to apoenzymes (an enzyme, which needs a co-enzyme to be activated) forming what is called a flavoprotein (discussed below) [62,61,60,59].
FMN and FAD (flavoproteins) are the principle forms of riboflavin. They are coenzymes, and used in several actions, particularly in the oxidation (reactant that accepts electrons from another reactant) of agents, vital for many process to occur. Here is a list of the many uses of vitamin b 2 [111,79,59,29]: • Like thiamin, it acts as a coenzyme in the breakdown of fats, proteins, carbs, and other nutrients.
• Helps fatty acid reduction. CoA needs FAD to accomplish this. • Assists choline catabolism. • Required for neurotransmitter (such as dopamine, and others) oxidation. • Necessary for catabolism of nutrients in the liver. • Helps b6 (discusses shortly) in many reactions, as it is often FMN dependent. • Assists eye and skin maintenance.
There is no exact understood mechanism for disease related to b2 deficiency; however, clinical symptoms of deficiency after almost four months of inadequate intake have shown inflammation of the tongue, loss of function on the outside of the lips and at the sides of the mouth, sore throat, a red or bloody/puffy mouth, inflammation of skin, eyes become light sensitive, and nerve dysfunction, to name a few. Extreme lack of riboflavin may slow the synthesis of the coenzyme form of vitamin B6 and niacin synthesis (later discussed within this article). Conditions and populations associated with increased need for riboflavin intake are many. Deficiency often occurs with heart disease, some cancers, thyroid disease, and excess alcohol intake. Women on pregnancy pills
are also more likely to develop deficiency than women not taking these drugs. Concerning this topic, Wacker J et. al states : “Riboflavin deficiency should be considered a possible risk factor for preeclampsia. Insufficient concentrations of the riboflavin-derived cofactors flavin adenine dinucleotide and flavin adenine mononucleotide could contribute to the established pathophysiologic changes including mitochondrial dysfunction, enhanced oxidative stress, and disturbances in nitric oxide release.” Finally, have you ever noticed when taking a multi vitamin, or perhaps a vitamin b supplementation pill, your urine-changed color? This is due to riboflavin. Riboflavin is a fluorescent yellow compound. Ingestion of this will most likely induce a change in urine color, to light yellow/bright orange. Also, small amounts of vitamin b2 are secreted in the feces, causing a yellowish color. This side effect is harmless though, so you can put your mind at ease when this occurs [113,59,32]. Recommendation The 1989 RDA for riboflavin is given in milligrams per 1,000 kcal. The recommended allowance for people of all ages is 0.6 mg/ l,000 kcal with a minimum intake of 1.2 mg for persons whose caloric intake may be more than 2,000 kcal. Through the years, the recommended allowances for riboflavin have been calculated in relation to:
• Protein requirement, • Energy intake • Metabolic body size. Because of the interdependence of these three variables, allowances calculated by the various methods have not differed significantly. The 1998 DRI RDA for individual intake for riboflavin is similar to the 1989 RDA. The DRI RDA for adult men and women aged 19 years and older for individual intake for riboflavin is 1.3 and 1.1 mg/day, respectively. With pregnancy and lactation the DRI for daily riboflavin intake increases to 1.4 and 1.6 mg, respectively. Toxicity associated with large oral doses of riboflavin has not been reported. Good sources of Vitamin B2 are eggs, meat, legumes, milk, and milk products such as cheese [80,67].
Niacin, also known as nicotinic acid nicotinamide, and vitamin b 3, is a water-soluble vitamin, and apart of the b-complex. Digestion In the human body, niacin is broken down to Nicotinamide adenine dinucleotide phosphate (NADP), and nicotinamide adenine dinucleotide (NAD). These are the primary forms which niacin functions within the body. In the intestine, NAD and NADP may be hydrolyzed to release free nicotinamide. This can be absorbed in the stomach, but
primarily in the small intestine. In low concentrations, free nicotinamide is absorbed by a sodium dependent carrier. In high concentrations, it uses passive diffusion. Most of the niacin in the blood is found as nicotinamide, a small amount of the time as nicotinic acid. From here, they move through the cell via a sodium dependent carrier system [107,85,57,56,15] Function Almost 200 enzymes require NAD and NADP to function. To name a few B3 functions, NAD helps glycolysis, oxidation of pyruvate, acetyl CoA by the kreb cycle, and fatty acids. NADP assists with fatty acid synthesis, cholesterols and steroid synthesis, oxidation of glutamate, and DNA synthesis. Some enzymes which require NADP are glutathione reductase, dihydrofolate, and tetrahydrofolate [107,56,43,33]. For much more on NAD in relation to energy metabolism, read, Energetic Transference Occurring in the Biosphere Part II: Anaerobic Energy Pathways. Deficiency Deficiency of niacin often results in a condition known as pellagra. The side effects are known as four d’s; dermatitis (inflammation of skin), dementia (a mental disorder characterized by a general loss of intellectual abilities involving impairment of memory, judgment and abstract thinking as well as changes in personality), diarrhea,
and death. Dermatitis is much like a sunburn at first and appears on areas exposed to sun such as the face and neck and on the extremities such as the back of the hands, wrists, elbows, knees, and feet. Some neurological problems are paralysis of extremities, and dementia (the second D) or delirium. Several gastrointestinal problems may occur such as nausea, vomiting, and diarrhea (the third D). Ultimately, if this problem is not treated, death occurs. A poor diet, and excess alcohol leads to increased niacin needs; as does stress, trauma, and prolonged fevers [64,30,3]. Concerning this topic, Spronck JC and Kirkland JB, said this : “These data show that niacin is required for the maintenance of chromosomal stability and may facilitate DNA repair in vivo, in a tissue that is sensitive to niacin depletion and impaired pADPr metabolism. Pharmacological intakes of niacin do not appear to be further protective compared to adequate intakes. Niacin supplementation may help to protect the bone marrow cells of cancer patients with compromised nutritional status from the side effects of genotoxic chemotherapy drugs.” Recommendation The 1989 RDA for adults is 6.6 mg of niacin per 1,000 cals consumed. The DRI RDA recommends at least 16 mg per day. For pregnancy and lactation, the DRI RDA recommends 18 mg a day. Up to 35 mg a day has been suggested. For high cholesterol, up to 3 g of nicotinic acid per day has been applied. The
mechanism of action for lowered cholesterol is not clearly understood; it is proposed that nicotinic acid decreases the levels of camp in the adipocytes, thereby decreasing lipase activity. Decreased lipase activity results in a decreased mobilization of fatty acids from the adipocytes and, therefore, a decreased substrate for synthesis of very low-density lipoproteins (VLDLs) in the liver. Decreased production of VLDLs lowers triacylglycerollevels, because VLDLs contain relatively high amounts of triacylglycerols. Furthermore, with decreased VLDLs there is less synthesis of LDL (bad cholesterol) and thus lower serum cholesterol levels. An increase in the HDL (good cholesterol) appears to be due to a decrease in their breakdown within the liver [113,107,70]. Concerning mega doses, consuming 1g and above may induce [67,54]: • Release of histamine, which causes flushing and is bad for people with asthma. Sometimes this may occur with as little as 10 mg. • Raises acidic levels in body. • Induces itching. • Raises glucose levels • May injure liver by obstructing flow of nutrients to the small intestine.
Up to 500 mg of niacin appears to give relatively no adverse effects. Niacin may be found in dairy products, poultry, fish, lean meats, nuts, and eggs. Legumes and enriched breads and cereals as well .
Pantothenic acid (B5)
Pantothenic acid is derived from the Greek word "pántothen", meaning "from all quarters," and as its name depicts, it is found present in virtually all plants and animal foods, hence, deficiency is not likely. It is part of the chemical makeup of Coenzyme A. It is also known in other forms -Calcium Pantothenate, Pantothenate, and Panthenol [74,63]. Digestion This vitamin occurs mainly as coenzyme A. It is primarily absorbed in the small intestine via passive diffusion. Transportation in the heart, muscles, and liver cells is done by a sodium active transport. Within the central nervous system, adipose, and renal uptake, facilitative diffusion is used [74,42,12]. Function Synthesis of CoA is dependant on Pantothenic acid. As discussed throughout this article, CoA is used in many reactions, such as the kreb cycle, and production of energy from carbohydrates, proteins, and lipids. It also assists metabolism of certain drugs, skin, and steroids. Studies have show than Vitamin b5 may accelerate the normal healing process after surgery [78,76,75]. Here is one study by Taherzadeh MJ  “Physiological effects of deficiency of pantothenate, a necessary precursor in the
synthesis of coenzyme A, were studied… the time required for complete conversion of the glucose decreased by 40%. Acetate addition affected the acetate and glycerol yields in a similar way in pantothenate-rich medium” Deficiency Deficiency usually occurs with people who are severally malnutritioned, along with alcoholics, diabetics, and certain bowel diseases. Side effects are vomiting, fatigue, weakness, and a burning feet syndrome, characterized by abnormal skin sensations [33,7,6,69]. Recommendation The DRI recommends 5 mg a day for adults. For certain conditions such as pregnancy, 7 mg’s a day is recommended. Concerning side effects, intakes of 100 mg a day for Vitamin b 5 may increase niacin excretion. 10 g a day (besides niacin excretion) has exhibited no side effects. 20 g a day may cause some intestinal distress, and diarrhea. Pantothenic acid can be found in egg yokes, legumes, whole grains, mushrooms, broccoli, avocados, and several plants and meats [113,77,69,7,6].
The b-complex Pyridoxine, is a water-soluble vitamin. It was discovered in 1934 by P. Gyorgy. Its composition is complex;
made of several vitamers (one of two or more similar compounds capable of fulfilling a specific vitamin function in the body) its 3 major forms are pyridoxine (PN), pyridoxal (PL), and pyridoxamine (PM). These vitamers are comparable in function, and quite often interchangeable within a given reaction . Digestion For digestion to occur, vitamin b must be broken down, and separated into its 3 main components pyridoxine, pyridoxal, and pyridoxamine. This occurs in the intestinal brush border, via enzymatic reactions. Absorption occurs primarily in the jejunum (middle portion of small intestine, connects with the duodenum (first portion) and the ileum (last portion) of the small intestine) by passive diffusion. In the intestine, PN is converted to pyridoxine phosphate (PNP), PL is converted to pyridoxal phosphate (PLP), and PNP is often converted to PLP, while PM remains the same, and composes about 15% of the vitamers in the blood. 60% of vitamin b 6 found in the blood is PLP. In order for PLP to cross the cell membrane it must be broken down to PL. The liver stores approximately 10% of vitamin b 6, while muscles store the most at 80%. Other storage houses are the kidneys, brain, and red blood cells . Function B6 acts as a coenzyme for approximately 100 essential chemical reactions. These include protein and glycogen metabolism, proper action of steroid hormones, pyruvate production, production of red blood cells and much more. It assists in many decarboxylation
reactions (removal of carboxyl group) for the production of several compounds such as glutamate (major neurotransmitter of the central nervous system). It also is of great use to the immune system in that it helps hemoglobin production and increases the amount of O2 carried by it. Also, it assists white blood cell production, all of which is vital for your health. Ortiz A et. al reports that , “Vitamin B6 is essential for cellular functions and growth due to its involvement in important metabolic reactions.” Pyridoxine is additionally responsible for the synthesis of many compounds. For example, niacin depends on a PLP dependant reaction to be broken down. Others required by Pyridoxine for synthesis are amino acid histidine, carnitine, nitrogen containing compounds, CoA and glycine taurine, dopamine, and helps regulate neurotransmitters, playing a major role in the nervous system. Finally, it appears PLP helps glycogen degradation. This theory is in its infancy, but studies show that it acts as a protein buffer to help maintain the compound, and promote covalent bonds to form glucose [102,97,7]. Deficiency Signs of deficiency are fatigue, glossitis (sore tongue) sleepiness, dermatitis (skin inflammation), neurological problems, eye problems, seizers, kidney and heart diseases, and convulsions in infants. Tryptophan and niacin synthesis will be slowed as well.
People more likely to be deficient in this are infants, old people, excessive alcohol consumption, those on a variety of drugs, and certain medical conditions. High protein intake and stress may inhibit this as well. Also, a deficiency in B6 has been shown to increase the amino acid homocysteine found in the blood. Studies have shown that an excess of this protein can inflict blood clotting, and promote heart disease/strokes [53,36,31]. Recommendation B6 consumption is based on protein intake, the RDA recommends .0016 mg of Vitamin b6 per 1 gram of protein. The DRI RDA recommends at least 1.3 mg for young male adults, and 1.7 for those 50 and over. For female adults and those over 50, they recommend 1.3 and 1.5 g respectively [87,86]. 100 mg per day is the upper intake for adults. Many doctors suggest 100-200 mg a day of b6 to treat carpal tunnel disease (A condition where there is a disturbance of median nerve function in the wrist as the nerve passes through the carpal tunnel.). There have been innumerable studies, which show its effectiveness. Ellis JM et. al states the following from two scientific journals [105, 102],: “It is concluded that patients with a severe syndrome including the carpal tunnel defect have a deficiency of vitamin B6, and that both the syndrome and the deficiency are relived by therapy with pyridoxine.”
“ In my practice, vitamin B6 (pyridoxine) therapy (100 to 200 mg daily for 12 weeks) has proved curative for a large percentage of patients having carpal tunnel syndrome (CTS). Laboratory determination of the vitamin B6 status has been useful in diagnosing deficiency and in making decisions relative to surgery. This paper directs particular attention to prevention of CTS during pregnancy and discusses changes in symptoms during the course of treatment of CTS with vitamin B6.” Scientist Laso Guzman FJ had this to say from his experiment : “Twelve patients with carpal tunnel syndrome were studied. Clinical and electrophysiological data were obtained and an estimation of vitamin B6 (pyridoxine) status by an assay of erythrocyte aspartate aminotransferase and coenzyme stimulation assay were done. None of the patients was found to have vitamin B6 deficiency. Patients were treated with 150 mg of pyridoxine daily for 3 months. Erythrocyte aspartate aminotransferase increased significantly (p less than 0.001) in all the patients. In 6 patients there were clinical and electrophysiological improvement and erythrocyte aspartate aminotransferase increased more than in the other 6 patients. The data obtained appear to indicate that although vitamin B6 deficiency is not common in carpal tunnel syndrome patients, pyridoxine supplementation can be recommended as adjuvant treatment in those patients undergoing surgery.”
Here is an excellent quote from Folkers K et. al, who makes a very bold claim : “Blood samples from four patients at the time of surgery to relieve the compression of the carpal tunnel syndrome, which was diagnosed by clinical and electromyographic evaluation, were differentially assayed to determine the specific activities and the % deficiencies of the erythrocyte glutamic oxaloacetic transaminase (EGOT). The data from these assays revealed that these four patients had a severe deficiency of vitamin B6. These data, in conjunction with previous biochemical and clinical results over five years, underscore the desirability, and even necessity, of testing by the EGOT analysis for the presence of a severe deficiency of vitamin B6 in all such patients before surgery. Treatment with vitamin B6 (pyridoxine) for a minimum period of 12 weeks, depending upon the duration and severity of the symptoms, has been effective without exception.” Kasdan ML et. al came to the same conclusion : “We reviewed 1075 patients presenting over a 12-year period with symptoms of carpal tunnel syndrome. A total of 994 had a final diagnosis of carpal tunnel syndrome. There were 444 male and 550 female patients with a mean age of 42 years. Three-hundred and ninety-five related symptoms to their job. Surgery
was performed in 27 percent of the total diagnosed cases with approximately 97 percent relief of symptoms. Satisfactory alleviation of symptoms was obtained in 14.3 percent of patients treated conservatively prior to 1980, with one or a combination of splinting anti-inflammatory agents, job or activity change, and steroid injections. In 1980, vitamin B6 (pyridoxine) was added as a method of conservative treatment. Satisfactory improvement was obtained in 68 percent of 494 patients treated with a controlled dosage (100 mg b.i.d.). While our findings were not the result of a controlled scientific study, we feel they suggest that regulated use of vitamin B6 may be helpful in treating many cases of carpal tunnel syndrome.” In conclusion, though the exact mechanism has not yet been determined, it is clear through hundreds of experiments that pyridoxine plays a significant role in the treatment of carpal tunnel syndrome. Another, similar problem known as Tarsal Tunnel Syndrome (Compression of the posterior tibial nerve caused by thickening of the laciniate leading to symptoms of pain or paresthesia over the sole of the foot) is also often treated with B6. Finally, due to its wide variety of functions in the nervous system, such as production of neurotransmitters dopamine, serotonin, supplementation of this vitamin is often suggested for treating abnormal nerve sensations in the legs, arms, and other bodily functions. Along with headaches, and states of depression [103,81,66,67,24,23,22,21,20].
Concerning overdoses, 200 mg a day appears to have no adverse effects. But 500 mg inflicts some neuro toxicity. And 1-6 grams daily has been shown to result in several side effects such as ensory and peripheral neuropathy (dysfunctions in nervous system) including numbness of the feet and hands, unsteady movement, abnormal sensations of the dorsal root ganglia (group of nerves) in the spinal cord, impaired tendon reflexes, and degeneration of sensory fibers. Pyridoxine is found in poultry, fish, pork, eggs, soybeans, oats, whole-grain products, nuts, seeds and bananas [66,53,36,31].
Folic acid (B9)
Folic acid is named after the Latin word, “folium” for leaf. This vitamin was discovered by DR. Lucy Wills, while researching how to prevent anemia (loss of red blood cells) during pregnancy. Synonyms for folic acid are vitamin B9, folacin, Pteroylglutamate, Pteroylmonoglutamate, and folate. B9 is composed of 3 parts; pteridine connected to paraaminobenzoic acid (PABA), which forms Pteroic acid. Finally, Pteroic acid is connected to glutamic acid to form folic acid. These compounds must be present for activation of vitamin B9 [68,63]. Digestion
To be absorbed, B9 must be broken down to monoglutamate. This occurs in the small intestine by the enzyme conjugase. This process is zinc dependent--a deficiency in zinc will inhibit this process. Absorption primarily occurs in the jejunum of the small intestine, and is sodium dependent. In the blood, folate is primarily found as monoglutamate. Throughout the body, B9 is reduced to several forms such as THF, N5/N10 Methyl THF, among others. The liver stores the majority of folic acid [108,91,52,18,9,]. Function Health News stated , “Folate delivers head-to-toe health advantages.” Lets see what exactly these are. Folate helps in the metabolism of several amino acids such as histidine, glycine, serine, and methionine. These processes will be discussed subsequently [92,71,8,7].
Histidine (an amino acid) can be broken down to uronic acid; this can further be reduced to formiminoglutamate (FIGLU). This with the help of THF can further be broken down to glutamic acid. When deficient in Pteroylglutamate, FIGLU accumulates, instead of being converted, and used as glutamate (as stated early, this is vital for nervous function).
Glycine and Serine
Folate in the form of N5 and N10 (discussed above) is necessary for both glycine, and serine synthesis (valuable amino acids used in the metabolism of fats, carbs, muscular growth, immune system, and much more) and degradation. It also helps activate enzymes such as pyridoxal phosphate (PLP) to complete the reactions.
THF is required for breakdown of homocysteine to methionine. Tying the article together, folate, vitamin B 12 (discussed next), and B6, all show to play a role in this process. Research shows that high homocysteine concentrations promotes heart disease. An experiment revealed supplementing with these 3 vitamins reduced homocysteine concentrations by 50%! Other Folic acid is essential for cell division, production of DNA and RNA, and assists the prevention of changes in DNA, which may lead to cancer. Deficiency Deficiency of folic results in anemia, depression, dementia, increased rate of heart disease and cancer, loss of appetite, weight loss, to name a few. People with increased folate needs are the elderly, alcoholics, bowel diseases, pregnant and lactating (secretion of milk) women, and the ingestion of certain drugs [68-
70]. Additionally, Rami;rez T et. al states , “Deficiencies of folic acid and methionine, two of the major components of the methyl metabolism, correlate with an increment of chromosome breaks and micronuclei.” Recommendation The DRI RDA recommends 400 ug for adults. With an additional 200 and 100 ug for pregnancy lactation respectively. Concerning side effects, studies suggest no side effects of consuming 400 mg of folate per day. However, some studies are contradictory to this, showing 15 mg of folate daily induce insomnia, irritability, diminished zinc status, and gastrointestinal distress. Toxicity for oral supplementation has not been reported. 5,000 ug of folate a day can mask B12 deficiency. Alleviating anemia, but at the same time, masking neurological inflictions that are due to B12 deficiency. It is recommended that if you are 50 years old, to ask a doctor to monitor your B12 level. But in short, make sure you are consuming proper amounts of B12, and these problems will not exist. Sources of folic acid include mushrooms, green vegetables such as broccoli, spinach and asparagus, as well as fruits grains, and legumes (particularly lima beans) [68,34].
Vitamin B12, also called cobalamin, and cyanocobalamin, is an active coenzyme, vital for many reactions, discussed shortly. Digestion First, B12 is acted upon by a salivary enzyme in the stomach. It then proceeds to combine with a protein known as ‘R-protein’ called intrinsic factor before entering the small intestine. After this, a pancreatic enzyme called trypsin separates it from the protein. Then, it is combined with another protein, and from there the ileum absorbs 70% of it, mainly by passive diffusion. After absorption, B12 is binded to one of 3 R proteins called TCI, TCII, or TCIII in the blood. About 90% of cyanocobalamin found in the body is bound to TCI. Contrary to other water-soluble vitamins, B12 can be stored in the body for extended amounts of time, even for years. It is primarily stored in the liver; other places are the heart, spleen, brain, kidneys, bones, and muscles [94,93 ,49]. Function As discussed previously, B12 plays a large part in the conversion of homocysteine to methionine, which helps protect the heart from disease. It assists conversion of THF into any of its coenzyme forms, when deficient in B12, folate is trapped in its methyl form. Cobalamin helps oxidation of several compounds. CoA and the kreb cycle are also dependent on B12. It helps nerve cells, red blood cells, and the manufacturing/repair of DNA. It is vital for
processing carbohydrates, proteins and fats, which help make all of the blood cells in our bodies. It also assists memory [7,66,41].
Deficiency Lack of B12 results in anemia, constipation, heart disease, depression, weakness, neurological failures, permanent nerve damage, nausea, flatulence (gas), loss of appetite, confusion, weight loss, numbness/tingling in hands and feat, difficulty in maintaining balance, memory loss, and soreness of the mouth or tongue. Here is another interesting study by Petchkrua W : “Vitamin B12 (or cobalamin) deficiency is well known in geriatric patients, but not in those with spinal cord injury (SCI). This retrospective study describes vitamin B12 deficiency in SCI… CONCLUSION It is recommended that physicians consider vitamin B12 deficiency in their patients with SCI, particularly in those with neurologic and/or psychiatric symptoms. These symptoms often are reversible if treatment is initiated early.” Recommendation
The DRI RDA recommends 2.4 ug of vitamin B12 per day for adults age 19 and up. With an increase of .2 and .4ug for pregnancy and lactation accordingly. No toxicity has been reported for massive doses of vitamin B12. Those with greater needs of Cobalamin are elderly people, those with gastrointestinal disorders, vegetarians, and those with pernicious anemia, which causes the absence of intrinsic factor, inhibiting cyanocobalamin absorption. Great sources are meats such as fish, shellfish, poultry, eggs (especially the yoke) and dairy products. They are rarely contained in plants [49-52,66].
Biotin is also known as vitamin H and coenzyme R. It was isolated in 1936 when researchers showed consumption of raw eggs caused a deficiency. Uncooked egg whites contain a protein called avidin, which strongly binds to biotin in the intestinal tract and inhibits absorption. Thankfully, cooking eggs effectively destroys this protein. It is water soluble, and considered to be apart of the B-complex. It is made of two rings, an ureido ring, connected to a thiophene ring, with an additional valeric acid side chain . Digestion Biotin connected to proteins must be digested by enzymes prior to absorption. It is broken down to free biotin, biotoinyl peptides, or
biocytin. There is still little information concerning the absorption of biotin in the human body. But it is believed to occur in the upper one-third to one-half of the small intestine. Absorption within the duodenum is thought to be higher than in the jejunum, and that is thought to be higher than the ileum. This may occur via a sodium dependent mechanism, or by passive diffusion. Little biotin is absorbed in the colon. Biotin is stored in minute quantities of the muscles, liver, and brain. Lastly, intestinal bacteria can manufacture small amounts of biotin, making this vitamin unique to most other vitamins, which cannot be made from natural process [40,7]. Function Biotin acts when covalently bound to biotin dependent enzymes (biotin also assists cell growth and replication). These include Bmethylcrotonyl CoA carboxylase, Propionyl CoA carboxylase, Pyruvate carboxylase, and Acetyl CoA carboxylase. We will discuss these 4 reactions next [58,65]. B-methylcrotonyl CoA carboxylase This enzyme is vital for the catabolism of the amino acid leucine (the most abundant amino acid found in proteins). Bmethylcrotonyl CoA carboxylase is formed during leucine catabolism. This is a biotin dependent reaction, and further changed to B-methylglutaconyl CoA carboxylase, which is broken down to form acetoacetate and acetyl CoA. Propionyl CoA carboxylase
Propionyl CoA carboxylase is important for the breakdown of isoleucine, threonine, and methoinine, all of which help make propionyl CoA. Propionyl CoA carboxylase assists other catabolization reactions. Tests show a biotin deficiency decreases the activity of this enzyme. Pyruvate carboxylase A lack of biotin shows to inhibit pyruvate activity. Pyruvate carboxylase is necessary for gluconeogenesis (synthesis of glucose, from non-carbohydrate), and helps replenish oxalocetate for the Krebs cycle. Acetyl CoA carboxylase For malonyl CoA to form Acetyl CoA carboxylase needs biotin. This reaction provides a mechanics for digestion of several amino acids, and chained fatty acids. Succinate formed, enters the kreb cycle. Jitrapakdee S and Wallace JC elaborate further on this discussion : ”The biotin carboxylase family is comprised of a group of enzymes that utilize a covalently bound prosthetic group, biotin, as a cofactor. These enzymes, which include acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, geranoyl-CoA carboxylase, oxaloacetate
decarboxylase, methylmalonyl-CoA decarboxylase, transcarboxylase and urea amidolyase, are found in diverse biosynthetic pathways in both pro-karyotes and eukaryotes…Further comparisons of biotin-dependent carboxylases with other groups of enzymes in the protein data bank reveal that this family of biotin enzymes has strong similarities in specific domains to a number of ATP-utilizing enzymes and to the lipoylcontaining enzymes.” Deficiency Lack of this vitamin may induce hair loss, rashes around the openings of the eyes, nose, mouth ect., central nervous system abnormalities such as depression, lethargy, hallucinations, and paresthesias (tingling, numbness, ect.). dermatitis, muscle pain, loss of appetite, slight anemia, an inflamed tongue, and weakness. Excess alcohol intake, bowel diseases, ingestion of raw eggs, and certain drugs, will induce greater biotin needs [114,109,66]. Furthermore, Bender DA. States , “Biotin deficiency leads to impaired glucose tolerance” Recommendation Because of the uncertain use of biotin in the intestine, It is hard to conclude an exact consumption rate. The 1989 RDA recommended 30-100 mg of biotin per day for children of 11 years of age, to adults. Another suggests is 30 ug a day for adults, and 35 ug for women. Toxicity of biotin has not been reported.
Sources for biotin are liver, brewer's yeast, egg yolk, soybeans, peanuts, cauliflower, mushrooms, and legumes [71,72,11].
As clearly displayed, Vitamin B-complex is absolutely essential for the bodybuilding life style. So the question is, what do you do from here? Obtaining B-Vitamins from food is possible, but can be very difficult, especially if you are on restricted calories. As such, I would highly recommend you purchase a B-Complex supplement. Furthermore, taking into account that it is virtually impossible to consume too much of these water-soluble beasts, and that as athletes, we are more susceptible to losing vitamins through loss of water from animalistic training sessions, there is no reason why you wouldn’t. But be sure to study this article thoroughly, consume the proper servings as recommended, and avoid harmful products such as alcohol, which promote deficiencies, and contribute nothing but harm to your body. Finally, results show that consuming vitamin b with a meal enhances absorption, and avoids gastrointestinal distress, which is often induced if consumed on an empty stomach. From there, enjoy your gains [67,29,28,7,9].
20 Wisdom crieth without; she uttereth her voice in the streets: 21 She crieth in the chief place of concourse, in the openings of the gates: in the city she uttereth her words, saying, 22 How long, ye simple ones, will ye love simplicity? and the scorners delight in
their scorning, and fools hate knowledge? 23 Turn you at my reproof: behold, I will pour out my spirit unto you, I will make known my words unto you. Proverbs 1:20-23  These are exciting times my friends. The Lord Jesus has blessed Abcbodybuilding with an abundance of innovation. My final suggestion to our fellow hyperplasia viewers is to take advantage of this opportunity. Knowledge is literally knocking at your door--all you have to do is open up.
Call unto me, and I will answer thee, and show thee great and mighty things, which thou knowest not. - Jeremiah 33:3 
Keep it Hardcore
A carrier-mediated mechanism for pyridoxine uptake by human intestinal epithelial Caco-2 cells: Regulation by a PKA-mediated pathway. Am J Physiol Cell Physiol. 2003 Jul 16 [Epub ahead of print] 2. Ariaey-Nejad MR, Balaghi M, Baker EM, Sauberlich HE. Thiamin metabolism in man. AmJ Clin Nutr1970;23:764- '78. 3. Alhadeff L, Gualtieri C, Lipton M. Toxic effects of watersoluble vitamins. Nutr Rev 1984;42:33-40. 4. Annous K, Song w: Pantothenic acid uptake and metabolism by red blood cells of rats. J Nutr 1995; 125:2586-93. 5. Athadeff L, Gualtieri C, Lipton M. Toxic effects of watersoluble vitamins. Nutr Rev 1984;42:33-40. 6. Aprahamian M, Dentinger A, Stock-Damge C, KouassiH J, Grenier J. Effects of supplemental pantothenic acid on wound healing: Experimental study in rabbit. Am J Clin Nutr 1985;41:578-89. 7. Bender D. Nutritional Biochemistry of the Vitamins. New York: Cambridge University Press, 1992:269-317. 8. Boushey C, Beresford S, Omenn G, Motulsky A. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of in- creasing folic acid intakes. JAMA 1995;274:1049-57. 9. Brody T. Folic acid. In: Machlin L J., ed. Handbook of Vitamins, 2nd ed. New York: Dekker, 1991:453-89. 10.Optimum nutrition: thiamin, biotin and pantothenate. Bender DA. 11. Bonjour J. Biotin. In: Machlin L J., ed., Handbook of Vitamins,2nd ed. New York: Dekker, 1991:393-427. 12.Bender D. Nutritional Biochemistry of the Vitamins. New York: Cambridge University Press, 1994:318-40. 13.Bender D. Nutritional Biochemistry of the Vitamins. New York: Cambridge University Press, 1992:341-59.
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A, Lambeth J, Edmondson D, et al. Formation and mode offlavoproteins. Ann Rev Nutr 1981;1: 281-317. 62.McCormick D. Riboflavin. In: Shils ME, Young VR, eds. Modem Nutrition in Diet and Disease, 7th ed. Philadelphia: Lea and Febiger, 1988:362-9. 63.McCollum EV.A History of Nutrition. Boston: Houghton Mifflin 1957. 64.McKenney J, Proctor J, Harris S, Chiitchili v: A comparison of the efficacy and toxic effects of sustained vs immediaterelease niacin in hypercholesterolemic patients.J AMA 1994;271:672-7. 65. Mock D, Lankford G, Cazin J. Biotin and biotin analogs in human urine: biotin accounts for only half of the total.J Nutr 1993;123:1844-51. 66.National Research Council. Recommended Dietary Allowances, l0th ed. Washington,D.C.:National Academy Press, 1989;158-65 67. National Research Council. Recommended Dietary Allowances, l0th ed. Washington, D.C.:National Academy Press, 1989;150-8. 68.National Research Council. Recommended Dietary Allowances, loth ed. Washington, D.C.: National Academy Press, 1989:165-9. 69. National Research Council. Recommended Dietary Allowances, loth ed. Washington, D.C.: National AcademyPress,1989:169-73. 70.National Research Council. Recommended Dietary Allowances, loth ed. Washington, D.C.: National Academy Press, 1989:137-42. 71. National Research Council. Recommended Dietary Allowances, loth ed. Washington, D.C.: National AcademyPress,1989:132-7.
Research Council. Recommended Dietary Allowances, loth ed. Washington,D.C.: National Academy Press, 1989:125-32. 73.The biotin enzyme family: conserved structural motifs and domain rearrangements Jitrapakdee S, Wallace JC. 74. Olson R. Pantothenic acid. In: Brown ML, ed. Present Knowledge in Nutrition,6th ed. Washington, D.C.:The Nutrition Foundation, 1990:208-11. 75.Plesofsky-Vig, N. Pantothenic acid and coenzyme A. In: Shils ME, Olson J A, Shike M., eds. Modern Nutrition in Health and Disease, 8th ed. Philadelphia: Lea arid Febiger,1994:395-401. 76. Plesofsky-Vig N, Brambl R. Pantothenic acid and coenzyme A in cellular modification of proteins. Ann Rev Nutr 1988;8:461-82. 77. Pike RL, Brown ML. Nutrition: An Integrated Approach, 3rd ed. New York: Wiley, 1984: 92-97. 78. Robishaw J, Neely J. Coenzyme A metabolism. Am J PhysioI1985;248:EI-E9. 79.Rivlin R. Riboflavin. Nutrition Reviews' Present Knowledge in Nutrition, 5th ed. Washington, D.C.: The Nutrition Foundation, 1984:285-302. 80.Riboflavin deficiency and preeclampsia. Wacker J, Fruhauf J, Schulz M, Chiwora FM, Volz J, Becker K. 81.Successful therapy with vitamin B6 and vitamin B2 of the carpal tunnel syndrome and need for determination of the RDAs for vitamins B6 and B2 for disease states. Ann N Y Acad Sci. 82. S-adenosyl-L-methionine is able to reverse micronucleus formation induced by sodium arsenite and other cytoskeleton disrupting agents in cultured human cells. Mutat Res. 2003 Jul 25;528(1-2):61-74. Rami;rez T, Garci;aMontalvo V, Wise C, Cea-Olivares R, Poirier LA, Herrera LA.
HE. Bioavailability of vitamins. Prog Food Nutr Sci 1985;9:1-33. 84. Sauberlich H. Vitamins-how much is for keeps? Nutr Today 1987;22:20-28. 85. Sauberlich H. Bioavailability of vitamins. Prog Food Nutr Sci 1985;10-11. 86.Shibata K, Matsuo H. Effect of supplementing low protein diets with the limiting amino acids on the excretion of N' methylnicotinamide and its pyridones in the rat.J Nutr 1989;119:896-901. 87. Sauberlich H. Bioavailability of vitamins. Prog Food Nutr Sci 1985;9:1-33. 88. Sauberlich H. Vitamins-how much is for keeps? Nutr Today 1987;22:20-28. 89. Sauberlich H. Bioavailability of vitamins. Prog Food Nutr Sci 1985;9:1-33. 90. Sauberlich H. Vitamins-how much is for keeps? Nutr Today 1987;22:20-28. 91. Steinberg S. Mechanisms of folate homeostasis. Am J PhysioI1984;246:G319-24. 92. Shimakawa T, Nieto I'; Malinow M, Chambless L, Schreiner P; Szklo M. Vitamin intake: a possible determinant of plasma homocyst( e )ine among middle-aged adults. Ann EpidemioI1997;7:285-93. 93. Seatharam B, Alpers D. Absorption and transport of cobalamin (vitamin B12). Ann Rev Nutr 1982;2:343-69. 94. Sandberg D, Begley J, Hall C. The content, binding and forms of vitamin B12 in milk. Am J Clin Nutr 1981;34:171724. 95. Sauberlich H. Bioavailability of vitamins. Prog Food Nutr Sci 1985;9:1-¥.
H. Vitamins-how much is for keeps? Nutr Today 1987;22:20-28. 97. Tarr J, Tamura T, Stokstad E. Availability of vitamin B6 and pantothenate in an average American diet in man. AmJ Clin Nutr 1981;34:1328-37. 98.Tanphaichitr I; Wood B. Thiamin. In: Olson RE, Broquist HP, Chichester CO, Darby WJ, Kolbye A, Stalvey R. Present Knowledge in Nutrition, 5th ed. Washington, D.C.: The Nutrition Foundation, 1984:273-84. . 99.Thiamine deficiency associated with parenteral nutrition: Sanz Paris A, Albero Gamoa R, Acha Perez FJ, Playan Uson J, Casamayor Peris L, Celaya Perez S. apropos of a new case Nutr Hosp. 1994 Mar-Apr;9(2):110-3. Spanish. 100.Thiamine corrects delayed replication and decreases production of lactate and advanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions. La Selva M, Beltramo E, Pagnozzi F, Bena E, Molinatti PA, Molinatti GM, Porta M. Diabetologia. 1996 Nov;39(11):1263-8. 101.Tanphaichitr 1: Thiamin. In: Shils ME, Olson ]A, Shike M., eds. Modem Nutrition in Health and Disease. 8th ed. Philadelphia: Lea and Febiger, 1994:359-65 102.Treatment of carpal tunnel syndrome with vitamin B6. South Med J. 1987 Jul;80(7):882-4. Ellis JM. 103.Therapy with vitamin B6 with and without surgery for treatment of patients having the idiopathic carpal tunnel syndrome. Res Commun Chem Pathol Pharmacol. 1981 Aug;33(2):331-44. Ellis J, Folkers K, Levy M, Takemura K,
Shizukuishi S, Ulrich R, Harrison P.
B6 deficiency in patients with a clinical syndrome including the carpal tunnel defect. Biochemical and clinical response to therapy with pyridoxine. Res Commun Chem Pathol Pharmacol. 1976 Apr;13(4):743-57.
B6 (pyridoxine) therapy for carpal tunnel syndrome. Hand Clin. 1996 May;12(2):253-7. Review. Ellis JM, Kishi T, Azuma J, Folkers K. 106.Vitamin therapy helps fight CTS. Occup Health Saf. 1987 Feb;56(2):67. No abstract available. 107.van Eys J. Niacin. In: Machlin L J, ed., Handbook of Vitamins, 2nd ed. New York: Dekker, 1991:311-40. 108.Wagner C. Cellular folate binding proteins: function and significance. Ann Rev Nutr 1982;2:229-48. 109.Wolf B, Heard G, McVoy J, Grier R. Biotinidase deficiency. Ann NY Acad Sci 1985;447:252-62. 110.Warnock L, Prudhonme C, Wagner C. The determination of thiamin pyrophosphate in blood and other tissues, and its correlation with erythrocyte transketolase activity. J Nutr 1979;108:421-7. 111.White H, Merril1 A. Riboflavin-binding proteins. Ann Rev Nutr 1988;8:279-99. 112.Wood B, Currie J. Presentation of acute Wernicke's encephalopathy and treatment with thiamine. Metab Brain Dis 1995;10:57- 71. 113.Yates A, Schlicker S, Suitor C. Dietary reference in- takes: the new basis for recommendations for calcium and related nutrients, B vitamins and choline. J Am Diet Assoc 1998;98:699- 706 114. Zempleni J, McCormick D, Mock D. Identification of biotin sulfone, bisnorbiotin methyl ketone, and tetranorbiotin-1sulfoxide in human urine. Am J Clin Nutr 1997;65:508-11.
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Table of contents Introduction Conclusion
Biochemistry of the Water Soluble Vitamins: A Lecture for First Year Pharmacy Students
Michael G. Bartlett, PhD1
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602-2352
Keywords: biochemistry, vitamins
This manuscript describes the lecture on vitamins contained in the core course entitled, “The Biochemical Basis of Drugs and Diseases” (Pharmacy 3050). In the first year, our curriculum is designed to focus on systems and diseases. As such, this course acts in concert with both the Anatomy & Physiology course and the Pathophysiology course to present an integrated view of human diseases and systems. The second year of our curriculum is focused on learning about drugs classes and the mechanism of action. The third year of the curriculum is focused on simulated patients, while the forth year of the curriculum the students are presented with real patients. The lecture on vitamins is the last topic of a course focused primarily on metabolism. Because many vitamins play major roles in metabolic cycles, this
lecture allows for a brief review of much of the material covered throughout the course. Therefore, vitamin examples are primarily chosen to reinforce major metabolic cycles and also their role in human disease. There is more clinical information that is relevant to vitamins than what is presented in this lecture. However, since first year students in our curriculum have almost no knowledge of therapeutics, the focus of the lecture is on diseases and not clinical practice.
Vitamins are a multibillion dollar industry.1 They are readily available to the public and are the focus of the most frequently asked questions to pharmacists.2 Surprisingly, most pharmacy students receive little training on the many roles of vitamins in nutrition.2 Therefore, this lecture attempts to not only reinforce fundamental biochemical and metabolic pathways in the human body, but also to provide pharmacy students with practical information. The diet is a vast source of important nutrients. These nutrients include several important classes of biomolecules such as: (1) energy yielding components (carbohydrates, lipids, and proteins), (2) essential and nonessential amino acids, (3) essential fatty acids, (4) minerals, and (5) vitamins. Vitamins are organic substances that must be provided by the diet either because they cannot be biosynthesized or the amount that is provided through biosynthesis is inadequate for maintaining normal health. Vitamins are broadly divided into 2 classes based upon their hydrophobicity. The more hydrophilic vitamins are termed the water-soluble vitamins and are composed of the B-complex vitamins and vitamin C. The more hydrophobic vitamins, referred to as the fat-soluble vitamins, are composed of Vitamins A, D, E, and K. This article focuses primarily on the water-soluble vitamins due to their greater role in the major metabolic cycles, which are the primary focus of this course. The normal North American diet is sufficient to prevent significant vitamin deficiencies and the related diseases associated with these deficiencies. However, there is increasing concern that slight vitamin deficiencies in a number of watersoluble vitamins (B1, B6, B12, folate and vitamin C) are risk factors for diseases such as depression, cancer, cardiovascular disease, and neural tube defects. The prevalence of this slight vitamin deficiency is likely related to diet, since most of these vitamins are supplied by fruit and vegetable intake. A recent survey has shown that only 25% of the population meets their daily intake of 5 servings.3 Food preparation is another source of vitamin loss. For example, heating food for more than 2 hours causes more than a 10% loss of most water-soluble vitamins. Refrigeration, freezing, and reheating have all been shown to lead to further loss of vitamins. Exposure to light causes significant loss of riboflavin from foods and the combination of heating and light can almost completely remove this vitamin from food.4
Thiamin (Vitamin B 1 ) Thiamin functions in the body as thiamin pyrophosphate (TPP) an important enzyme co-factor.5 Thiamin reacts with adenosine triphosphate (ATP) to form thiamin pyrophosphate through a reaction mediated by the enzyme thiamin diphosphokinase. Following its production, TPP is incorporated into 2 important enzymes: pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Pyruvate dehydrogenase is part of a multi-enzyme complex that acts to convert pyruvate generated in glycolysis into acetyl-CoA for entry into the tricarboxylic acid (TCA) cycle. Thiamin pyrophosphate is also used as a co-factor for the enzyme αketoglutarate dehydrogenase, which is a key point of regulation in the TCA cycle. α-Ketoglutarate dehydrogenase is involved in the conversion of α-ketoglutarate to succinyl CoA. In the case of both enzymes, TPP assists in decarboxylation of a small ketoacid. In addition to its uses in metabolism, thiamin may enhance circulation and blood formation. It is required for maintenance of the nervous system and is used in the biosynthesis of the neurotransmitters acetylcholine and γ-hydroxybutyrate (GABA). Thiamin also is used in the production of hydrochloric acid in the stomach and, therefore, has a role in digestion. Thiamin is provided in the diet through most grains. A deficiency of thiamin is called beriberi and it is most often observed in Southeast Asia.6 The main staple of diet in this part of the world is rice, which does not provide dietary thiamin to as great an extent as other grains. The symptoms of beriberi include limb pain, muscle weakness, and low cardiac output. All symptoms are related to the diminished capacity of the major energy producing pathways that are dependent on TPP as a co-factor. Mild deficiencies of thiamin are sometimes observed in the elderly and in lowincome groups on restricted diets. The earliest symptoms of thiamin deficiency are loss of appetite, constipation, and nausea. Other symptoms such as mental depression, peripheral neuropathy, irritability, and fatigue are related to the role of thiamin in maintaining a healthy nervous system. The most common form of thiamin deficiency in the United States is alcoholic neuritis. Because alcoholics normally have a poor appetite, overall food consumption is low. In addition, alcoholics are predisposed to developing nutritional deficiencies since alcohol is their primary calorie source. Under the broad umbrella of alcoholic neuritis come two disorders, Wernicke’s Syndrome and Korsakoff’s Psychosis.7 The symptoms of Wernicke’s Syndrome (ophthalmoplegia, nystagmus, and ataxia) respond quickly to administration of thiamin, whereas the more severe memory and learning disorders associated with Korsakoff’s Psychosis are refractory to thiamin treatment.
Riboflavin (Vitamin B 2 ) Riboflavin functions in the body as an enzyme cofactor in many oxidation/reduction reactions and has a central role in energy production and cellular respiration. Riboflavin reacts with ATP to form flavin mononucleotide (FMN). Flavin mononucleotide then reacts with a second molecule of ATP to form a molecule of flavin adenine dinucleotide (FAD). Within cellular metabolism, enzymes such as succinyl dehydrogenase (TCA cycle), AcylCoA Dehydrogenase (β-Oxidation), and Glycerol-3-phosphate Dehydrogenase (Glycerol Phosphate Shuttle) use FAD as a cofactor. The enzyme NADH-CoEnzyme Q oxidoreductase (Complex I, Electron Transport Chain) uses FMN as a co-factor. As enzyme co-factors, FAD and FMN are able to function as electron acceptors. The addition of 2 electrons to FAD results in the formation of a molecule of FADH2, while the addition of 2 electrons to FMN causes the formation of a molecule of FMNH2. Riboflavin + ATP → FMN + 2e- ↔ FMNH2 FMN + ATP → FAD + 2e- ↔ FADH2 The reduced forms of these enzyme co-factors can donate these electrons to return to their previous fully oxidized forms. It is this ability to act as a conduit for electron transfer reactions that makes FAD and FMN such important enzyme cofactors. Riboflavin is available from a wide variety of dietary sources such as milk, cheese, meat, eggs, and cereal products. Symptoms associated with riboflavin deficiency include sore throat, dermatitis, anemia, neuropathy, and cataract formation. Riboflavin deficiency is not normally observed in the United States; however, deficiency may be observed as part of a general case of malnutrition or in cases of chronic alcoholism.8 The conversion of riboflavin to FMN is required for absorption and transport into many tissues. The conversion has been shown to be inhibited by hypothyroidism and the structurally similar medications chlorpromazine, adriamycin, quinacrine, tetracycline, and tricyclic antidepressants.9-12
Niacin (Vitamin B 3 ) The vitamin niacin (nicotinic acid) and its structural analog nicotinamide have identical function due to their facile interconversion in the body. Niacin is converted through a series of reactions to its active form nicotinamide adenine dinucleotide (NAD+). NAD+ can be converted to a reduced form NADH by gaining 2 electrons through a process similar to FAD reduction. NADH is produced in large quantities by the TCA cycle and β-Oxidation and to a lesser extent by glycolysis. Reduced NADH is returned to its oxidized form under normal cellular conditions by the electron transport chain. This newly reformed NAD+ can then return to other metabolic pathways to harvest more electrons. In the body the ratio of NAD+/NADH is approximately 1000 demonstrating the primary role of NAD+ in supporting cellular oxidation. NADH also can react with ATP to form NADPH. As
opposed to the unphosphorylated form, the ratio of NADP+/NADPH is only 0.01. This ratio points to the role of NADPH in supporting reductive processes in the body. Niacin → NAD+ + 2e- ↔ NADH NADH + ATP ↔ NADPH + ADP Niacin can be found in foods such as meats, breads, and beans. Mild niacin deficiencies have similar symptoms to those observed with riboflavin, which is not surprising due to the similar roles both of these vitamins play in biochemical reactions. Niacin deficiencies are occasionally observed in alcoholics, cases of general malnutrition, and in the elderly on restricted diets. A severe deficiency of niacin is known as pellagra, which is derived from the Italian phrase meaning rough skin. Pellagra is marked by dermatitis and also is notable for causing a blackening of the tongue. Early cases of pellagra were first observed in Europe shortly after the introduction of corn from the voyages of Christopher Columbus. In these cases, poor farmers who were raising corn as animal feed were particularly susceptible. Because niacin in corn is not bioavailable unless treated with a strong base such as lye, the farmers developed niacin deficiencies. Europeans did not know this processing method until revealed to them by Native-Americans during the early colonial period of North America. However, the connection between pellagra and niacin was not known until the early 20th century. Pellagra was a significant health issue in the United States over the period from 1900-1940 resulting in over 100,000 deaths. Today most diets are supplemented with niacin through enriched flour, which receives its name because of the added niacin.13 Niacin can be administered in doses of 2g to 4g to causes a decrease in circulating levels of cholesterol and LDL. While the cholesterol lowering effects of niacin are desirable there are potential side effects from such large doses of this vitamin. The most immediate reaction observed from large doses of niacin is vasodilation resulting in flushing. Over time there may be a reduction in fatty acid mobilization causing a depletion of glycogen and lipid stores in muscle tissue. Long-term exposure may also elevate blood glucose and uric acid levels, suggesting increased risk for patients who are on the borderline for diseases such as diabetes and gout. Prolonged use of high doses of niacin can lead to elevated levels of the serum enzymes alanine aminotransferase and aspartate aminotransferase, which may suggest liver damage.
Pyridoxine (Vitamin B 6 ) Pyridoxine is the precursor to the active enzyme co-factor pyridoxal phosphate (PLP). Pyridoxal phosphate is a critical co-factor for enzymes involved in reactions involving many amino acids. The N-terminus of the amino acid forms a covalent bond to PLP, allowing a wide variety of displacement reactions to occur at the alpha carbon. These include decarboxylations, transaminations, and transfers of side
chains. Pyridoxine, therefore, plays a central role in the production of many neurotransmitters, such as serotonin, norepinephrine, and histamine. Pyridoxine also is important in the production of heme. The PLP co-factor in several enzymes is a therapeutic target due to the ability to form irreversible covalent bonds with agents containing a hydrazine moiety, such as carbidopa, isoniazid, and hydralazine.14 The combination of L-Dopa and carbidopa is a widely used therapy that has a biochemical mechanism involving vitamin B6. The conversion of L-Dopa to dopamine is catalyzed by the PLP-dependent enzyme L-aromatic amino acid decarboxylase (LAAAD). L-DOPA → Dopamine The enzyme LAAAD is present in both the gut and in the brain. This presents a problem because L-dopa is readily transported across the blood brain barrier while dopamine is not. Therefore, orally administered L-dopa is rendered ineffective in the gut by LAAAD. Co-administration of carbidopa resolves this dilemma by inactivating LAAAD in the gut. Like dopamine, carbidopa cannot cross the blood brain barrier leaving LAAAD in the brain free to carry out the production of dopamine at the site of action. In addition to hydrazine containing drugs, penicillamine, used in the treatment of Wilson’s disease, cystinuria, and rheumatoid arthritis reacts with and inactivates pyridoxal phosphate.15 Patients treated with penicillamine occasionally develop convulsions, which can be prevented by supplementation with vitamin B6. Pyridoxine is found in foods such as meats, breads, eggs, soybeans, and many vegetables. A deficiency in pyridoxine can cause facial lesions, depression, peripheral neuropathy, and glossitis. The neurological complications can be directly linked to the effects on neurotransmitter production. Mild pyridoxine deficiencies are sometimes observed in young women taking oral contraceptives. Deficiencies have also been observed in patients with gasteroenteritis or Crohn’s Disease, presumably due to poor absorption. Mild deficiencies are of concern due to a correlation with an increased incidence of breast cancer and to the risk of coronary heart disease.16,17 Neurotoxicity has been noted with doses of vitamin B6 in excess of 500 mg/day.18
Cobalamin (Vitamin B 12 ) Cobalamin is vital for cell growth and replication. Its major site of action is at the interface between the folic acid cycle and the active methyl cycle, where cobalamin is a co-factor for the enzyme homocysteine methyltransferase. This enzyme catalyzes the transfer of a methyl group from tetrahydrofolate to homocysteine, forming the amino acid methionine. These 2 cycles impact many other pathways due to the large number of methylation reactions in the body, especially nucleic acid biosynthesis and neurotransmitter biosynthesis. Cobalamin is found in meats and dairy products. Deficiencies are not common
because the liver can store a 6-year supply of cobalamin. In addition, cobalamin is highly conserved by enterohepatic recirculation. Strict vegetarians (vegans) may take up to 20 to 30 years to develop a deficiency, whereas inadequate absorption from the ileum due to ileitis or loss of a glycoprotein that complexes with cobalamin prior to absorption may take from 2 to 10 years to become symptomatic. The anesthetic nitrous oxide inactivates cobalamin and can cause patients with marginal serum levels to develop deficiencies within a week.19 While rare, deficiencies in vitamin B12 are severe and manifest in erythrocytes and nervous tissue. In erythrocytes, nucleic acid biosynthesis is slowed. This results in stem cells that are committed to development into erythrocytes possessing twice their normal protein content but lacking the necessary nuclear material for proper cell division. The resulting anemia, termed megaloblastic anemia, can be quite severe. Cobalamin deficiency can also cause permanent damage to the nervous system. The results are swelling of neurons and demylination of nerve cells, followed by cell death. These progressive manifestations cause a wide range of neurological symptoms including unsteadiness, decreased reflexes, paresthesias of the extremities, and ultimately confusion, memory loss, hallucinations, and psychosis. The neurological symptoms of cobalamin deficiency may be mistaken for multiple sclerosis. In the elderly and in alcoholics, cobalamin deficiency should be considered as a possible cause of dementia even in the absence of anemia. The neurological symptoms associated with cobalamin deficiency are not directly related to irregularities in the formation of erythrocytes.20
Folic Acid (Pteroylglutamic Acid) Folic acid is derived from the addition of a pteroyl group to the amino acid glutamate. Folic acid can be reduced to form tetrahydrofolate, which is an important acceptor of one-carbon units. Folic acid plays an important role in the conversion of homocysteine to methionine by providing the methyl to the vitamin B12 dependent methyl transferase. Therefore, folic acid levels have a strong influence on the endogenous concentration of homocysteine. Elevated levels of homocysteine are associated with increased risk of coronary heart disease. Supplementation with folic acid has been shown to correct plasma homocysteine levels and decrease the morbidity and mortality from atherosclerotic disease.21 Folic acid plays an important role in the biochemistry of amino acids; it is critical for the interconversion of the amino acids serine and glycine and in histidine metabolism. Folic acid also is necessary for the biosynthesis of the nucleic acids thymidine, adenine, guanine, and inosine. Because of its role in amino acid and nucleic acid biosynthesis, folic acid supplementation during pregnancy has been shown to prevent most birth defects involving the brain and spinal cord, known as neural tube defects.22 Folic acid is found in organ meats such as liver, green leafy vegetables, yeast, and some fruits. Deficiencies in folic acid are most often observed with poor intake or
alcoholism but are sometimes seen in pregnancy where there is an increased need for folic acid. The recommended daily allowance for pregnant women is at least twice that for nonpregnant women.23 Folic acid deficiencies can also be observed from reduced absorption due to diseases in the intestine. Additionally anticonvulsants, such as phenytoin, phenobarbital, and primidone appear to not only to inhibit folic acid absorption, but also to increase catabolism.24 There is also concern that supplementation with folic acid may impact the effectiveness of these anticonvulsants. The most common effect of folic acid deficiency is megaloblastic anemia. The appearance of this type of anemia is identical to that observed with vitamin B12 deficiency due to the common pathway shared by the folic acid and the active methyl cycles. One major difference between folic acid deficiency and vitamin B12 deficiency is the absence of the neurological symptoms from lowered serum folic acid levels.25
Pantothenic Acid Pantothenic acid is one of the many B-complex vitamins. Once in the body, pantothenic acid combines with ADP and cysteamine to form coenzyme A (HSCoA). Coenzyme A is involved in a number of cellular pathways, most notably in transferring an acetyl unit from the pyruvate dehydrogenase complex or from βoxidation to oxaloacetate in the TCA cycle. Coenzyme A is also involved in the biosynthesis of cholesterol, steroid hormones, fatty acids, and porphyrins. Pantothenic acid derives its name from the Greek word meaning “from everywhere”, which reflects its ubiquitous nature in foods. Deficiencies in pantothenic acid are difficult to achieve but result in neuromuscular degeneration.26
Biotin Biotin is an important co-factor for enzymes involved in carboxylation reactions. Biotin aids in these reactions by binding carbon dioxide. An important example of a biotin-containing enzyme is pyruvate carboxylase. This enzyme catalyzes the conversion of pyruvate to oxaloacetate as a preliminary step in gluconeogenesis. Biotin is found in foods such as liver, egg yolks, milk, fish and nuts. Deficiencies in biotin result in dermatitis, glossitis, muscle pain and anorexia. Deficiency in biotin has been observed in patients ingesting raw eggs over a long period of time. Egg white contains avidin, a protein that binds biotin, strongly preventing its absorption from the intestine.27 Biotin deficiency was observed in early attempts at parenteral nutrition before proper vitamin supplementation became standard practice.28
Choline Choline has many important biochemical roles in the body. It is incorporated into the formation of lecithin, an important structural phospholipid found most abundantly in mitochondrial membranes. It is also incorporated into plateletactivating factor, an important signaling agent in the clotting cascade. Choline also affects lipid mobilization from the liver. However, its most important role is as a precursor for the neurotransmitter acetylcholine where it plays a critical role in motor coordination. Choline is found in eggs, peanuts, and liver. Deficiency in choline has not been reported in humans. It is believed that daily needs for choline can be met through biosynthesis and diet.
Carnitine Carnitine has an important role in the metabolism of fatty acids. Carnitine accepts and donates fatty acids to co-enzyme A. This is an equilibrium process facilitated by cytosolic and mitochondrial enzymes known as carnitine acyl transferases. The attachment of fatty acids to carnitine is critical for their transport from the cytosol to the mitochondria, where they are later metabolized through β-oxidation. Carnitine is found abundantly in meats and dairy products. Carnitine deficiency is not normally observed in adults unless it is caused by an inherited genetic disorder related to its transport or biosynthesis. Carnitine deficiency causes the storage of lipids in muscle tissue resulting in functional abnormalities in both cardiac and skeletal muscles. However, carnitine deficiencies are not uncommon in preterm or low birth weight infants. These infants generally respond to supplements of carnitine as well as changing to a low-fat, high-carbohydrate diet.29
Ascorbic Acid (Vitamin C) Ascorbic acid acts as an enzyme co-factor for 2 major biochemical processes. It is important for many hydroxylation reactions, especially those involved in the posttranslational hydroxylation of the amino acid proline in the formation of the structural protein collagen. In the gut, vitamin C is involved in the reduction of iron (III) to iron (II), allowing iron to be absorbed into the bloodstream. Humans are one of the few organisms that are incapable of biosynthesizing ascorbic acid. As such they are highly dependent on obtaining it from their diet. Vitamin C is found in citrus fruits, tomatoes, strawberries, and potatoes. During the Age of Exploration, British sailors were given the nickname “limeys” due to the barrels of limes that were used on long voyages to supply vitamin C to the crew. The sailors were trying to avoid a deficiency in ascorbic acid known as scurvy.30 The symptoms of scurvy are related to inhibited synthesis of collagen. These effects include failure
of wounds to heal, defects in tooth formation, and capillary leakage. Anemia caused from failure to adequately absorb iron is also common.31 Several factors have been shown to lower serum vitamin C levels including smoking, oral contraceptives, and the use of aspirin.32-34 Patients exposed to any of these conditions long-term should consider taking a vitamin C supplement. However, the use of high doses of vitamin C, a theory popularized by Nobel Laureate Linus Pauling, has not been shown to provide any medical benefit.35 The use of high doses of vitamin C has been shown to cause nausea, diarrhea, and lead to the formation of oxalate kidney stones.18, 35
Student Perception of Lecture Student opinions were obtained using minute papers. Minute papers are given to a group of 25-30 students following each lecture in this course.36 From the results of the minute papers in Table 1, the student’s perception of the lecture is apparent. The students believe that the most significant material in the lecture was the discussion on the major biochemical functions of the vitamins. This is consistent with the intent of the instructor. The students also felt that understanding vitamin deficiencies and the sources of the various vitamins was important. The students were asked what they found interesting about the lecture and not surprisingly they selected various stories as their favorite points. They especially liked the link between biotin, avidin, and eggs, the nautical history of scurvy resulting in the nickname “Limeys” being given to British sailors, and understanding the role of appetite suppression in alcoholism and general vitamin deficiencies. Over the years, students have commented that they enjoy having interesting health related facts to aid them in retaining and understanding the utility of biochemical information. Vitamins provide an enormous number of examples that can be used. Finally, the students were asked to recommend areas that could have increased focus in the future. In general these comments fall into 2 catagories. The students are either confused and would like more information to more fully understand the topic, or they are genuinely interested and would like to know more. In this case, 71% of the student responded that they did not see anything else to add. There were a few suggestions for adding additional information on folic acid deficiency, alcoholism, and drug-vitamin interactions. This text incorporates many of these suggestions with the inclusion of the link between folic acid and neural tube defects, discussions of alcoholism throughout the lecture rather than being highly focused around thiamin, and drug interactions involving the vitamins pyridoxine, folic acid, and riboflavin.
Questions concerning the use of vitamins are common. Vitamins have important roles in many of the major metabolic pathways in the human body. In addition, drug
interactions with vitamin and diseases involving vitamin deficiencies are important topics for pharmacy curricula. An understanding of the functional roles of vitamins can contribute to improved understanding of general biochemistry and help pharmacy students become better prepared for their roles as health care educators.
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Corresponding Author: Address: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602-2352 Tel: (706) 542-5390 Fax: (706) 542-5358 E-mail: email@example.com Bartlett M. Biochemistry of the Water Soluble Vitamins: A Lecture for First Year Pharmacy Students. Am J Pharm Educ. 2003; 67(2):article 64.
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