Section XIII - The Vitamins docx

Section XIII. The Vitamins Overview The diet is the source of some 40 nutrients for human beings. These classically are divided into energy-yielding dietary components (carbohydrates, fats, and proteins), sources of essential and nonessential amino acids (proteins), essential unsaturated fatty acids (fats), minerals (including trace minerals), and vitamins (water-soluble and fat-soluble organic compounds) (see Shils et al. , 1999). Vitamins, despite their diverse chemical composition, can be defined as organic substances that must be provided in small quantities from the environment because either they cannot be synthesized de novo in human beings or their rate of synthesis is inadequate for the maintenance of health [e.g., the production of nicotinic acid (niacin) from tryptophan]. In most cases, the environmental source is the diet, but an obvious exception to this general rule is the endogenous synthesis of vitamin D under the influence of ultraviolet light. This definition differentiates vitamins from essential trace minerals, which are inorganic nutrients needed in small quantities. It also excludes the essential amino acids, which are organic substances needed preformed in the diet in much larger quantities. The term vitamin is restricted here to include only organic substances required for the nutrition of mammals; substances required only by microorganisms and cells in culture should be defined as growth factors, to prevent scientifically unsound claims for their therapeutic benefit as vitamins for human beings. When the vitamin occurs in more than one chemical form (e.g., pyridoxine, pyridoxal, pyridoxamine) or as a precursor (e.g., carotene for vitamin A), these analogs sometimes are referred to as vitamers. Although the individual vitamins differ widely in structure and function, some general statements do apply. Water-soluble vitamins are stored to only a limited extent, and frequent consumption is necessary to maintain saturation of tissues. Fat-soluble vitamins can be stored to massive degrees, and this property confers upon them a potential for serious toxicity that greatly exceeds that of the water-soluble group. As consumed, many vitamins are not biologically active and require processing in vivo. In the case of several water-soluble vitamins, activation includes phosphorylation (thiamine, riboflavin, nicotinic acid, pyridoxine) and also may require coupling to purine or pyridine nucleotides (riboflavin, nicotinic acid). In their major known actions, water- soluble vitamins participate as cofactors for specific enzymes, whereas at least two fat-soluble vitamins, A and D, behave more like hormones and interact with specific intracellular receptors in their target tissues. Vitamin Requirements Dietary Reference Intakes In many countries throughout the world, scientific committees periodically assess the evidence about the requirements of the population for individual nutrients. In the United States, the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences, with active involvement of Health Canada are taking a new approach to the Recommended Dietary Allowances (RDAs) that have been published since 1941. The development of Dietary Reference Intakes (DRIs) expands and replaces the RDA. DRIs are a family of reference values that are quantitative estimates of nutrient intakes designed to be used for planning and assessing diets for healthy people. They include RDAs as goals for intake of individuals, but also present three new types of reference values. These include Adequate Intake (AI), the Tolerable Upper Intake Level (UL), and the Estimated Average Requirement (EAR) (Yates et al. , 1998 ). The Food and Nutrition Board has embarked on a multiyear project to expand the framework for quantitative recommendations regarding nutrient intake, which includes evaluating both nutrients and other food components for impact on health. The review goes beyond criteria needed to prevent classical deficiencies and includes review of data related to risk of chronic diseases. Current recommendations for males and females of different ages are summarized in Tables XIII–1, XIII–2, and XIII–3. Table XIII–1 contains RDAs for those nutrients yet to be reviewed by the DRI committee. Table XIII–2 contains the newly revised recommended intakes. Age groupings have been changed from the earlier RDA publications. Finally, Table XIII–3 contains the ULs for the newly revised intakes. The RDA for a given nutrient, which is an individual intake goal, represents the intake at which the risk of inadequacy is very small, about 2% to 3% of the population. Those with intakes below the recommended allowance will not necessarily develop a deficiency; however, their long-term risk of deficiency rises in proportion to the degree to which the recommended allowance is not met. Intakes at the level of RDAs or AIs would not necessarily be expected to replete an undernourished individual, nor would it be adequate for disease states which lead to increased requirements. Because the DRIs are based on data from the U.S. and Canada, they may not apply globally where food and indigenous practices may result in different bioavailability of nutrients. The tolerable upper intake level (ULs) is the highest level of daily intake that is likely to pose no risk of adverse health effects to most individuals. ULs are useful because of increased interest in and availability of fortified foods and continued use of dietary supplements. As the standing committee on the scientific evaluation of DRIs of the Food and Nutrition Board completes the review of each set of nutrients, reports are issued. For up-to-date information about these reports visit the Food and Nutrition Board home page at http://www.nas.edu/iom/fnb. Federal Regulations on Vitamins and Minerals The United States Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act, regulates the labeling of vitamin and mineral products sold as foods or drugs. The Nutrition Labeling and Education Act of 1990 (NLEA), with the final rules published in the Federal Register in early 1993, has led to nutrition labeling on virtually all packaged food, new nomenclature for declaring nutrient contents using the term Daily Values (DVs), and a series of disease-specific health claims. The FDA has only limited authority to control the nutrient content of supplements, except those intended for use by children under 12 years of age and by pregnant or lactating women. However, because of uniform labeling procedures, the purchaser can determine what proportion of the recommended daily allowance for each nutrient is provided by a given amount of the food. The use of vitamins and other nutrients to treat disease comes under FDA review, either as foods for special dietary use, including food supplements, or as "over-the-counter" or prescription drugs, depending on the purposes for which the product is intended and the claims made for it. Nutrient products designed specifically for special application in medical treatment, such as parenteral solutions for hyperalimentation and so-called medical foods (e.g., defined formula diets), are evaluated for safety and efficacy, as are "over-the-counter" drugs containing vitamins and minerals. Dietary supplements are used by more than 50% of the U.S. population (Report of the Commission on Dietary Supplement Labels , 1997 ). The most commonly used supplements are vitamins and minerals. Forty-seven percent of the U.S. population takes a vitamin and/or mineral supplement (USDA's 1994–1996 Continuing Survey of Food Intakes by Individuals , 1999 ). The intense interest in supplements by consumers and those who market them has put pressure on Congress to keep this area free of regulation. The history of supplement regulation shows efforts by the FDA to regulate the potency and combinations of marketed nutrients and Congress taking action to prevent regulation. The Dietary Supplement Health and Education Act (DSHEA) resulted in substantial deregulation of supplement marketing and the assertions that can be made about their benefits (Bass and Young, 1996). DSHEA broadens the definition of dietary supplements, which includes vitamins and minerals, and maintains their regulation as foods. Thus, a supplement must be safe under the conditions recommended on the label or under ordinary conditions of use. The responsibility for safety is placed on the manufacturer. This changes the FDA regulating procedure for supplements from one of preclearance to policing (see Chapter 3: Principles of Therapeutics). Range of Intakes of Vitamins and Minerals Many millions of individuals living in the United States regularly ingest quantities of vitamins vastly in excess of the RDA. One reason some people take vitamin supplements is the erroneous belief that such preparations provide extra energy and make one "feel better." This evidence of widespread nutritional self-medication should be kept in mind when taking a medication history from a patient. The use of vitamin supplements is medically advisable in a variety of circumstances where vitamin deficiencies are likely to occur. Such situations may arise from inadequate intake, malabsorption, increased tissue needs, or inborn errors of metabolism (see Position of the American Dietetic Association, 1996). In practice, these causes may overlap, as in the case of the alcoholic, who may have both inadequate food intake and impaired absorption. The patient who requires long-term total parenteral nutrition is absolutely dependent on supplemental vitamins added to the infusates. Unfortunately, a serious undersupply of parenteral multivitamin preparations in the United States has made it difficult to meet clinical demand. While gross vitamin deficiencies due to inadequate intakes are encountered in underdeveloped areas of the world, few florid cases are seen in the United States. Ongoing surveillance of dietary intake is conducted periodically by the United States government. Mean intakes consistently exceed RDA for several major vitamins (vitamin A, thiamine, riboflavin, niacin, and ascorbic acid). Individuals living below the poverty level, particularly the elderly and ethnic minorities, may have a substantially greater risk of inadequate intake of some vitamins, especially vitamins A and C. Certain individuals are exposed to deficient intakes of vitamins as a result of eccentric diets, such as food faddism, and the avoidance of food because of anorexia. Intakes of vitamins less than those recommended also can occur in subjects on reducing diets and among elderly people who eat little food for economic or social reasons. The consumption of excessive amounts of alcohol also can lead to inadequate intakes of vitamins and other nutrients. Malabsorption of vitamins also is seen in various conditions. Examples include hepatobiliary and pancreatic diseases, prolonged diarrheal illness, hyperthyroidism, pernicious anemia, sprue, and intestinal bypass operations. Moreover, since a substantial proportion of vitamin K and biotin is synthesized by the bacteria of the gastrointestinal tract, treatment with antimicrobial agents that alter the intestinal bacterial flora inevitably leads to decreased availability of these vitamins. Increased tissue requirements for vitamins may cause a nutritional deficiency to develop despite the ingestion of a diet that previously had been adequate. For example, requirements for some vitamins may be altered by the use of certain antivitamin drugs, such as the interference with the utilization of folic acid by trimethoprim (see Roe, 1981). Diseases associated with an increased metabolic rate, such as hyperthyroidism and conditions accompanied by fever or tissue wasting, also increase the body's requirements for vitamins. Finally, an increasing number of cases are recorded in which genetic abnormalities lead to an increased need for a vitamin. This often is due to an abnormality in the structure of an enzyme for which the vitamin provides a cofactor, leading to a decreased affinity of the abnormal enzyme protein for the cofactor (Scriver, 1973). The impact of disease on requirements for nutrients may vary according to its phase and intensity. The need for therapy with vitamins may change throughout the course of the illness; eventually, cure should be associated with cessation of this therapy. Chapter 63. Water-Soluble Vitamins: The Vitamin B Complex and Ascorbic Acid Overview This chapter provides a summary of physiological and therapeutic roles of members of the vitamin B complex and of vitamin C. The vitamin B complex comprises a large number of compounds that differ extensively in chemical structure and biological action. They were grouped in a single class because they originally were isolated from the same sources, notably liver and yeast. There are traditionally eleven members of the vitamin B complex—namely, thiamine, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, folic acid, cyanocobalamin, choline, inositol, and paraaminobenzoic acid. Paraaminobenzoic acid is not considered in this chapter, as it is not a true vitamin for any mammalian species but is a growth factor for certain bacteria, where it is a precursor for folic acid synthesis. Although not a traditional member of the group, carnitine also is considered in this chapter because of its biosynthetic relationship to choline and the recent recognition of deficiency states. Folic acid and cyanocobalamin are considered in Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins because of their special function in hematopoiesis. Vitamin C is especially concentrated in citrus fruits and thus is obtained mostly from sources differing from those of members of the vitamin B complex. The Vitamin B Complex Thiamine History Thiamine, or vitamin B 1 , was the first member of the vitamin B complex to be identified. Lack of thiamine produces a form of polyneuritis known as beriberi; this disease became widespread in East Asia in the nineteenth century due to the introduction of steam-powered rice mills, which produced polished rice lacking the vitamin-rich husk. A dietary cause for the disease was first indicated in 1880, when Admiral Takaki greatly reduced the incidence of beriberi in the Japanese Navy by adding fish, meat, barley, and vegetables to the sailors' diet of polished rice. In 1897, Eijkman, a Dutch physician working in Java where beriberi also was common, showed that fowl fed polished rice develop a polyneuritis similar to beriberi and that it could be cured by adding the rice polishings (husks) or an aqueous extract of the polishings back into the diet. He also demonstrated that rice polishings could cure beriberi in human beings. In 1911, Funk isolated a highly concentrated form of the active factor and recognized that it belonged to a new class of food factors, which he called vitamines, later shortened to vitamins. The active factor subsequently was named vitamin B 1 ; in 1926 it was isolated in crystalline form by Jansen and Donath, and in 1936 its structure was determined by Williams. The Council on Pharmacy and Chemistry adopted the name thiamine to designate crystalline vitamin B 1 . Chemistry Thiamine contains a pyrimidine and a thiazole nucleus linked by a methylene bridge. Thiamine functions in the body in the form of the coenzyme thiamine pyrophosphate (TPP). The structures of thiamine and thiamine pyrophosphate are as follows: The conversion of thiamine to its coenzyme form is carried out by the enzyme thiamine diphosphokinase, with adenosine triphosphate (ATP) as the pyrophosphate (PP) donor. Antimetabolites to thiamine that inhibit this enzyme have been synthesized. The most important of these are neopyrithiamine(pyrithiamine) and oxythiamine. Pharmacological Actions Thiamine is practically devoid of pharmacodynamic actions when given in usual therapeutic doses; even large doses produce no discernible effects. Isolated clinical reports of toxic reactions to the long-term parenteral administration of thiamine probably represent rare instances of hypersensitivity. Physiological Functions The vitamins of the B complex function in intermediary metabolism in many essential reactions; some of these functions are summarized in Figure 63–1. Thiamine pyrophosphate, the physiologically active form of thiamine, functions in carbohydrate metabolism as a coenzyme in the decarboxylation of -keto acids such as pyruvate and -ketoglutarate and in the utilization of pentose in the hexose monophosphate shunt; the latter function involves the thiamine pyrophosphate–dependent enzyme transketolase. Several metabolic changes of clinical importance can be related directly to the biochemical action of thiamine. In thiamine deficiency, the oxidation of -keto acids is impaired, and an increase in the concentration of pyruvate in the blood has been used as one of the diagnostic signs of the deficiency state. A more specific diagnostic test for thiamine deficiency is based upon measurement of transketolase activity in erythrocytes (Brin, 1968). The requirement for thiamine is related to metabolic rate and is greatest when carbohydrate is the source of energy. This fact is of practical significance for patients who are maintained by parenteral nutrition and who thereby receive a substantial portion of their calories in the form of dextrose. Such patients should be given a generous allowance of the vitamin. Figure 63–1. Some Major Metabolic Pathways Involving Coenzymes Formed from Water-Soluble VItamins. (Abbreviations are defined in the text throughout this chapter.) Symptoms of Deficiency Severe thiamine deficiency leads to the condition known as beriberi. In Asia, this is due to consumption of diets of polished rice, which are deficient in the vitamin. In Europe and North America, thiamine deficiency is seen most commonly in alcoholics, although patients with chronic renal failure on dialysis and patients receiving total parenteral nutrition also may be at risk. A severe form of acute thiamine deficiency also can occur in infants. The major symptoms of thiamine deficiency are related to the nervous system (dry beriberi) and to the cardiovascular system (wet beriberi). Many of the neurological signs and symptoms are characteristic of peripheral neuritis, with sensory disturbances in the extremities, including localized areas of hyperesthesia or anesthesia. Muscle strength is lost gradually and may result in wrist-drop or complete paralysis of a limb. Personality disturbances, depression, lack of initiative, and poor memory also may result from lack of the vitamin, as may syndromes as extreme as Wernicke's encephalopathy and Korsakoff's psychosis (see below). Cardiovascular symptoms can be prominent and include dyspnea on exertion, palpitation, tachycardia, and other cardiac abnormalities characterized by an abnormal electrocardiogram (ECG) (chiefly low R-wave voltage, T-wave inversion, and prolongation of the Q-T interval) and cardiac failure of the high-output type. Such failure has been termed wet beriberi; there is extensive edema, largely as a result of hypoproteinemia from an inadequate intake of protein or concomitant liver disease together with failing ventricular function. Absorption, Fate, and Excretion Absorption of the usual dietary amounts of thiamine from the gastrointestinal tract occurs by carrier-mediated active transport (Said et al. , 1999 ); at higher concentrations, passive diffusion also is significant (Rindi and Ventura, 1972). Absorption usually is limited to a maximal daily amount of 8 to 15 mg, but this amount can be exceeded by oral administration in divided doses with food. Cellular thiamine uptake is mediated by a specific plasma membrane transporter, which recently has been cloned (Diaz et al. , 1999 ; Dutta et al. , 1999 ). In adults, approximately 1 mg of thiamine per day is completely degraded by the tissues, and this is roughly the minimal daily requirement. When intake is at this low level, little or no thiamine is excreted in the urine. When intake exceeds the minimal requirement, tissue stores are first saturated. Thereafter, the excess appears quantitatively in the urine as intact thiamine or as pyrimidine, which arises from degradation of the thiamine molecule. As the intake of thiamine is increased further, more of the excess is excreted unchanged. Therapeutic Uses The only established therapeutic use of thiamine is in the treatment or the prophylaxis of thiamine deficiency. To correct the disorder as rapidly as possible, intravenous doses as large as 100 mg per liter of parenteral fluid commonly are used. Once thiamine deficiency has been corrected, there is no need for parenteral injection or the administration of amounts in excess of daily requirements except in instances when gastrointestinal disturbances preclude the ingestion or absorption of adequate amounts of vitamin. The syndromes of thiamine deficiency seen clinically can range from beriberi through Wernicke's encephalopathy and Korsakoff's syndrome to alcoholic polyneuropathy. Because normal metabolism of carbohydrate results in consumption of thiamine, it has been observed repeatedly that administration of glucose may precipitate acute symptoms of thiamine deficiency in marginally nourished subjects. This also has been noted during the correction of endogenous hyperglycemia. Thus, in any individual whose thiamine status may be suspect, the vitamin should be given before or along with dextrose-containing fluids; all alcoholic patients seen in an emergency room should routinely receive 50 to 100 mg of thiamine. The clinical findings depend on the amount of deprivation. Encephalopathy and Korsakoff's syndrome result from severe deprivation, whereas beriberi heart disease occurs in less-deficient subjects; polyneuritis is observed in milder deprivation. The following discussion describes briefly the varieties of thiamine deficiency and their treatment. Alcoholic Neuritis Alcoholism is the most common cause of thiamine deficiency in the United States. Alcoholic neuritis is caused by an inadequate intake of thiamine. Two factors contribute to such inadequate intake in the chronic alcoholic: (1) Appetite usually is poor, so food consumption drops; and (2) a large portion of the caloric intake is in the form of alcohol. The symptoms of neurological involvement in alcoholics are those of a polyneuritis with motor and sensory defects. Wernicke's syndrome is an additional serious consequence of alcoholism and thiamine deficiency. Certain characteristic signs of this disease, notably ophthalmoplegia, nystagmus, and ataxia, respond rapidly to the administration of thiamine but to no other vitamin. Wernicke's syndrome may be accompanied by an acute global confusional state that also may respond to thiamine. Left untreated, Wernicke's encephalopathy frequently leads to a chronic disorder in which learning and memory are impaired out of proportion to other cognitive functions in the otherwise alert and responsive patient. This disorder (Korsakoff's psychosis) is characterized by confabulation, and it is less likely to be reversible once established (Victor et al. , 1971 ). Although the thiamine stores of some patients with Wernicke's encephalopathy are similar to those in patients without neurological findings, it has been found that patients with Wernicke's encephalopathy have an abnormality in the thiamine-dependent enzyme transketolase (see Haas, 1988). In such instances, marginal concentrations of thiamine might produce serious neurological damage. The prevalence of Wernicke's encephalopathy in Australia decreased following the introduction of thiamine-enriched flour (Harper et al. , 1998 ). Chronic alcoholics with polyneuritis and motor or sensory defects should receive up to 40 mg of oral thiamine daily. The Wernicke-Korsakoff syndrome represents an acute emergency that should be treated with daily doses of at least 100 mg of the vitamin, intravenously. Infantile Beriberi Thiamine deficiency also occurs as an acute disease in infancy and may run a rapid and fulminating course. Although rare in modern societies, infantile beriberi has been a common cause of infant death throughout this century in regions where rice consumption is high. It still is of significance in Third World countries and is related to the low content of thiamine in breast milk of thiamine- deficient women. The onset consists of loss of appetite, vomiting, and greenish stools, followed by paroxysmal attacks of muscular rigidity. Aphonia due to loss of laryngeal nerve function is a diagnostic feature. Signs of cardiac involvement are prominent, and death may occur within 12 to 24 hours unless vigorous treatment is instituted. Infants with mild forms of this condition respond to oral therapy with 10 mg of thiamine daily. If acute collapse occurs, doses of 25 mg intravenously can be given cautiously, but the prognosis remains poor. Subacute Necrotizing Encephalomyelopathy This is a fatal inherited disease of children. Neuropathological features resemble those of the Wernicke-Korsakoff syndrome, and clinical features include difficulties with feeding and swallowing, vomiting, hypotonia, external ophthalmoplegia, peripheral neuropathy, and seizures. Although the syndrome may have multiple causes, the distribution of lesions and the elevated plasma concentrations of pyruvate and lactate suggest a pathogenetic relationship to thiamine; however, this remains unproven (see Haas, 1988). Some cases appear to be caused by a circulating inhibitor of the enzyme that synthesizes thiamine triphosphate from thiamine pyrophosphate in the nervous system. Metabolic abnormalities also have been found in tissue samples from affected infants, including defects in pyruvate dehydrogenase and cytochrome c-oxidase (Medina et al. , 1990). Other inborn errors of metabolism that are sensitive to the administration of thiamine also have been described (see Scriver, 1973). Cardiovascular Disease Cardiovascular disease of nutritional origin is observed in chronic alcoholics, pregnant women, persons with gastrointestinal disorders, and those whose diet is deficient for other reasons. When the diagnosis of cardiovascular disease due to thiamine deficiency has been made correctly, the response to the administration of thiamine is striking. One of the pathognomonic features of the syndrome is an increased blood flow due to arteriolar dilation. Within a few hours after the administration of thiamine, the cardiac output is reduced and the utilization of oxygen begins to return to normal. If edema is present and due to myocardial insufficiency, diuresis results after proper therapy. However, individuals suffering from a chronic deficiency may require protracted treatment. The usual dose of thiamine is 10 to 30 mg three times daily, given parenterally. The dosage can be reduced and the patient maintained on oral medication or by dietary management after signs of the deficiency state have been reversed. It is emphasized that administration of glucose may precipitate heart failure in individuals with marginal thiamine status. All patients potentially in this category should receive thiamine prophylactically; 100 mg is commonly given intramuscularly or added to the first few liters of intravenous fluid. Gastrointestinal Disorders In experimental and clinical beriberi, certain symptoms are referable to the gastrointestinal tract. On this basis, thiamine has been used uncritically as a therapeutic agent for such unrelated conditions as ulcerative colitis, gastrointestinal hypotonia, and chronic diarrhea. Unless the disease being treated is the direct result of a deficiency of thiamine, the vitamin is not efficacious. Neuritis of Pregnancy Pregnancy increases the thiamine requirement slightly. The neuritis of pregnancy takes the form of multiple peripheral nerve involvement, and the signs and symptoms in well-developed cases resemble those described in patients with beriberi. The problem may occur because of poor intake of thiamine or in patients with hyperemesis gravidarum. Proof that the neuritis is due to thiamine deficiency is gained in those cases in which dramatic clinical improvement follows thiamine therapy. The dose employed is from 5 to 10 mg daily, given parenterally if vomiting is severe. Megaloblastic Anemia Thiamine-responsive megaloblastic anemia (TRMA) with diabetes mellitus and deafness is an autosomal recessive disease that responds to large doses of thiamine. This disorder was shown to be caused by mutations in the plasma membrane–associated thiamine transporter (Diaz et al. , 1999 ; Fleming et al. , 1999 ). Defective thiamine transport in cultured fibroblasts from TRMA patients is associated with decreased cell survival, apparently by enhanced apoptosis (Stagg et al. , 1999 ). Riboflavin History At various times from 1879 onward, series of yellow-pigmented compounds have been isolated from a variety of sources and designated as flavins, prefixed to indicate the source (e.g., lacto-, ovo-, and hepato-). Subsequently it has been demonstrated that these various flavins are identical in chemical composition. In the meantime, water-soluble vitamin B had been separated into a heat-labile antiberiberi factor (B 1 ) and a heat-stable growth-promoting factor (B 2 ), and it was eventually appreciated that concentrates of so-called vitamin B 2 had a yellow color. In 1932, Warburg and Christian described a yellow respiratory enzyme in yeast, and in 1933 the yellow pigment portion of the enzyme was identified as vitamin B 2 . All doubt as to the identity of vitamin B 2 and the naturally occurring flavins was removed when lactoflavin was synthesized and the synthetic product was shown to possess full biological activity. The vitamin was designated as riboflavin because of the presence of ribose in its structure. Chemistry Riboflavin carries out its functions in the body in the form of one or the other of two coenzymes, riboflavin phosphate, commonly called flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD). Their structures are shown above. Riboflavin is converted to FMN and FAD by two enzyme-catalyzed reactions, shown as Reactions (63–1) and (63–2): Riboflavin + ATP FMN + ADP (63–1) FMN + ATP FAD + PP (63–2) Pharmacological Actions No overt pharmacological effects follow the oral or parenteral administration of riboflavin. [...]... mammals was established in the laboratories of Fritz and Bremer in the late 1950s Chemistry Carnitine ( -hydroxy- -trimethylammonium buty-rate) has the following structural formula: Only L-carnitine is synthesized in tissues and possesses biological activity The pathway of carnitine biosynthesis has been reviewed by Rebouche (1991) Pharmacological Actions The administration of L-carnitine to normal individuals... enzymatic steps in the metabolism of sulfur-containing and hydroxy-amino acids In the case of transamination, enzyme-bound pyridoxal phosphate is aminated to pyridoxamine phosphate by the donor amino acid, and the bound pyridoxamine phosphate is then deaminated to pyridoxal phosphate by the acceptor -keto acid Vitamin B6 also is involved in the metabolism of tryptophan A notable reaction is the conversion... Pantothenic acid is absorbed readily from the gastrointestinal tract It is present in all tissues, in concentrations ranging from 2 to 45 g/g Pantothenic acid apparently is not degraded in the human body, since the intake and the excretion of the vitamin are approximately equal About 70% of the absorbed pantothenic acid is excreted in the urine Therapeutic Uses No clearly defined uses for pantothenic... therapeutic doses of nicotinic acid or its amide are administered, only small amounts of the unchanged vitamin appear in the urine When extremely high doses of these vitamins are given, the unchanged vitamin represents the major urinary component The principal route of metabolism of nicotinic acid and nicotinamide is by the formation of N-methylnicotinamide, which, in turn, is metabolized further Therapeutic... incorporated into either coenzyme A or acyl carrier protein, the functional forms of the vitamin The chemical structures of pantothenic acid and coenzyme A are as follows: Many analogs of pantothenic acid have been studied in an attempt to find an antimetabolite Although active antagonists have been synthesized (e.g., -methyl pantothenate) and are of value as research tools, they are not therapeutic agents... pyridoxamine— are shown below The compounds differ in the nature of the substituent on the carbon atom in position 4 of the pyridine nucleus: a primary alcohol (pyridoxine), the corresponding aldehyde (pyridoxal), an aminoethyl group (pyridoxamine) Each of these compounds can be utilized readily by mammals after conversion in the liver to pyridoxal 5'-phosphate, the active form of the vitamin Antimetabolites... called biotin It was then demonstrated that biotin and the factor that protected against egg-white toxicity were the same (György, 1940) In 1942, duVigneaud established the structural formula of biotin, and the vitamin was synthesized shortly thereafter In the meantime, the nature of the antagonist to biotin in egg white received extensive study The compound is a protein, first isolated by Eakin and... facilitates transport of fat from the liver Methyl Donor Choline can donate methyl groups necessary for the synthesis of other compounds The first step in transfer is the formation of betaine, which is the immediate donor of the methyl group Thus, choline can transfer a methyl group to homocysteine to form methionine The roles of cyanocobalamin and folic acid in the metabolism of one-carbon compounds are discussed... vitamin synthesized by intestinal microorganisms, since, on low intakes of riboflavin, the amount excreted in the feces exceeds that ingested There is no evidence that riboflavin synthesized by the bacteria in the colon can be absorbed Therapeutic Uses The only established therapeutic application of riboflavin is to treat or prevent disease caused by deficiency Ariboflavinosis seldom occurs in the United... demonstrated that the chick antidermatitis factor was pantothenic acid Elucidation of the biochemical function for the vitamin began in 1947 when Lipmann and coworkers showed that the acetylation of sulfanilamide required a cofactor that contained pantothenic acid Chemistry Pantothenate consists of pantoic acid complexed to -alanine This is transformed in the body to 4'phosphopantetheine by phosphorylation . Section XIII. The Vitamins Overview The diet is the source of some 40 nutrients for human beings. These classically are divided into energy-yielding dietary components. quantities from the environment because either they cannot be synthesized de novo in human beings or their rate of synthesis is inadequate for the maintenance of health [e.g., the production. intensity. The need for therapy with vitamins may change throughout the course of the illness; eventually, cure should be associated with cessation of this therapy. Chapter 63. Water-Soluble Vitamins: