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- 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 B1, 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 B1; 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 B1.
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
(B1) and a heat-stable growth-promoting factor (B2), and it was eventually appreciated that
concentrates of so-called vitamin B2 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 B2. All doubt as to the identity of vitamin B2 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.
- Physiological Functions
FMN and FAD, the physiologically active forms of riboflavin, serve a vital role in metabolism as
coenzymes for a wide variety of respiratory flavoproteins, some of which contain metals (e.g.,
xanthine oxidase).
Symptoms of Deficiency
The features of spontaneous or experimentally produced riboflavin deficiency have been reviewed
by McCormick (1989). Sore throat and angular stomatitis generally appear first. Later, glossitis,
cheilosis (red, denuded lips), seborrheic dermatitis of the face, and dermatitis over the trunk and
extremities occur, followed by anemia and neuropathy. In some subjects, corneal vascularization
and cataract formation are prominent.
The anemia that develops in riboflavin deficiency is normochromic and normocytic and is
associated with reticulocytopenia; leukocytes and platelets are generally normal. Administration of
riboflavin to deficient patients causes reticulocytosis, and the concentration of hemoglobin returns
to normal. Anemia in patients with riboflavin deficiency may be related, at least in part, to
disturbances in folic acid metabolism.
The problem in the clinical recognition of riboflavin deficiency is that certain features, such as
glossitis and dermatitis, are common manifestations of other diseases, including deficiencies of
other vitamins. Recognition of riboflavin deficiency also is difficult because it rarely occurs in
isolation. In nutritional surveys of children in an urban area and of randomly selected hospitalized
patients, deficiency of riboflavin was observed frequently, but almost invariably in conjunction with
other vitamin deficiencies. Riboflavin deficiency has been observed likewise in association with
deficiencies of other vitamins in a large proportion of urban alcoholics of low economic status.
Biochemical evidence of riboflavin deficiency has been observed in newborn infants treated with
ultraviolet light for hyperbilirubinemia. Breast-fed infants are most susceptible to this problem
because of the relatively low riboflavin content in breast milk. Assessment of riboflavin status is
made by correlating dietary history with clinical and laboratory findings. Biochemical tests include
evaluation of urinary excretion of the vitamin (excretion of less than 50 g of riboflavin daily is
indicative of deficiency). Although concentrations of flavins in blood are not of diagnostic value, an
enzyme activation assay that utilizes glutathione reductase from erythrocytes correlates well with
riboflavin status (Prentice and Bates, 1981).
Human Requirements
The Recommended Dietary Allowance (RDA) of riboflavin is 1.3 mg/day for men and 1.1 mg/day
for women (see Table XIII–2). Turnover of riboflavin appears to be related to energy expenditure,
and periods of increased physical activity are associated with a modest increase in requirement.
Food Sources
Riboflavin is abundant in milk, cheese, organ meats, eggs, green leafy vegetables, and whole-grain
and enriched cereals and breads.
Absorption, Fate, and Excretion
Riboflavin is absorbed readily from the upper gastrointestinal tract by a specific transport
- mechanism involving phosphorylation of the vitamin to FMN [Reaction (63–1); Jusko and Levy,
1975]. Here and in other tissues, riboflavin is converted to FMN by flavokinase, a reaction that is
sensitive to thyroid-hormone status and inhibited by chlorpromazine and by tricyclic
antidepressants; the antimalarial quinacrine also interferes with the utilization of riboflavin.
Riboflavin is distributed to all tissues, but concentrations are uniformly low, and little is stored.
When riboflavin is ingested in amounts that approximate the minimal daily requirement, only about
9% appears in the urine. As the intake of riboflavin is increased above the minimal requirement, a
larger proportion is excreted unchanged. Boric acid, a common household chemical, forms a
complex with riboflavin and promotes its urinary excretion. Boric acid poisoning, therefore, may
induce riboflavin deficiency.
Riboflavin is present in the feces. This probably represents 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 States as a discrete deficiency but may
accompany other nutritional disorders. Specific therapy with riboflavin, 5 to 10 mg daily, should
thus be given in the context of treating multiple nutritional deficiencies. A recent randomized,
controlled trial of high-dose riboflavin (400 mg/day) in patients suffering migraine headaches
showed significant reductions in attack frequency and illness days (Schoenen et al., 1998).
Nicotinic Acid
History
Pellagra (from the Italian pelleagra, "rough skin") has been known for centuries in countries where
maize is eaten in quantity, notably Italy and in North America. In 1914, Funk postulated that the
disease was due to dietary deficiency. Over the next few years, Goldberger and his colleagues
demonstrated conclusively that pellagra could be prevented by increasing the dietary intake of fresh
meat, eggs, and milk. Goldberger subsequently produced an excellent animal model of human
pellagra, "black tongue," by feeding deficient diets to dogs. Although initially thought to be a
deficiency of essential amino acids, pellagra soon was found to be prevented by a distinct heat-
resistant factor in "water-soluble B" vitamin preparations.
In 1935, Warburg and associates obtained nicotinic acid amide (nicotinamide) from a coenzyme
isolated from the red blood cells of the horse; this stimulated interest in the nutritional value of
nicotinic acid. Since liver extracts were known to be highly effective in curing human pellagra and
canine black tongue, Elvehjem and associates prepared highly active concentrates of liver; in 1937,
they identified nicotinamide as the substance that was effective in the treatment of black tongue.
Proof was established by the demonstration that synthetic nicotinic acid derivatives also were
effective in alleviating the symptoms of black tongue and in curing human pellagra. Goldberger and
Tanner previously had shown that tryptophan could cure human pellagra; this effect later was
determined to be due to the conversion of tryptophan to nicotinic acid. Goldsmith (1958) produced
pellagra experimentally in human beings by feeding a diet deficient in nicotinic acid and
tryptophan.
- Nicotinic acid also is known as niacin, a term introduced to avoid confusion between the vitamin
and the alkaloid nicotine. Pellagra now is quite uncommon in the United States, probably as a direct
result of supplementation of flour with nicotinic acid since 1939.
Chemistry
Nicotinic acid functions in the body after conversion to either nicotinamide adenine dinucleotide
(NAD) or nicotinamide adenine dinucleotide phosphate (NADP). It is to be noted that nicotinic acid
occurs in these two nucleotides in the form of its amide, nicotinamide. The structures of nicotinic
acid, nicotinamide, NAD, and NADP are shown below, where R= H in NAD and R= PO3H2 in
NADP. Synthetic analogs with antivitamin activity include pyridine-3-sulfonic acid and 3-acetyl
pyridine.
Pharmacological Actions
Nicotinic acid and nicotinamide are identical in their function as vitamins. However, they differ
markedly as pharmacological agents, reflecting the fact that nicotinic acid is not directly converted
to nicotinamide, which arises only from metabolism of NAD. The pharmacological effects and
toxicity of nicotinic acid in man include flushing, pruritus, gastrointestinal distress, hepatotoxicity,
and activation of peptic ulcer disease. Large doses of nicotinic acid (2 to 6 g per day) are sometimes
- used in the treatment of hyperlipoproteinemia (see Chapter 36: Drug Therapy for
Hypercholesterolemia and Dyslipidemia). The important toxic effects of nicotinic acid are generally
seen only with these doses.
Physiological Functions
NAD and NADP, the physiologically active forms of nicotinic acid, serve a vital role in metabolism
as coenzymes for a wide variety of proteins that catalyze oxidation-reduction reactions essential for
tissue respiration. The coenzymes, bound to appropriate dehydrogenases, function as oxidants by
accepting electrons and hydrogen from substrates and thus becoming reduced. The reduced pyridine
nucleotides, in turn, are reoxidized by flavoproteins. NAD also participates as a substrate in the
transfer of ADP-ribosyl moieties to proteins.
The metabolic pathway for conversion of nicotinic acid to NAD has been elucidated for a variety of
tissues, including human erythrocytes. [See Reactions (63–3), (63–4), and (63–5) below, where
PRPP is 5-phosphoribosyl-1-pyrophosphate. NADP is synthesized from NAD according to
Reaction (63–6).] The biosynthesis of NAD from tryptophan is more complicated. Tryptophan is
converted to quinolinic acid by a series of enzymatic reactions; quinolinic acid is converted to
nicotinic acid ribonucleotide, which enters the pathway at Reaction (63–4).
Nicotinic acid + PRPP Nicotinic Acid Ribonucleotide + PP (63–3)
Nicotinic Acid ribonucleotide + ATP Desamido-NAD + PP (63–4)
Desamido-NAD + Glutamine + ATP NAD + Glutamate + ADP + P (63–5)
NAD + ATP NADP + ADP (63–6)
Symptoms of Deficiency
A deficiency of nicotinic acid leads to the clinical condition known as pellagra. Pellagra is
characterized by signs and symptoms referable especially to the skin, gastrointestinal tract, and
central nervous system, a triad frequently referred to as dermatitis, diarrhea, and dementia, or the
"three D's." Pellagra now occurs most often in the setting of chronic alcoholism, protein-calorie
malnutrition, and deficiencies of multiple vitamins. An erythematous eruption resembling sunburn
first appears on the back of the hands. Other areas exposed to light (forehead, neck, and feet) are
later involved, and eventually the lesions may be more widespread. The cutaneous manifestations
are characteristically symmetrical and may darken, desquamate, and scar.
The chief symptoms referable to the digestive tract are stomatitis, enteritis, and diarrhea. The
tongue becomes very red and swollen and may ulcerate. Salivary secretion is excessive, and the
salivary glands may be enlarged. Nausea and vomiting are common. Steatorrhea may be present,
even in the absence of diarrhea. When present, diarrhea is recurrent and stools may be watery and
occasionally bloody.
Symptoms referable to the central nervous system are headache, dizziness, insomnia, depression,
and impairment of memory. In severe cases, delusions, hallucinations, and dementia may appear.
Motor and sensory disturbances of the peripheral nerves also occur. Common laboratory findings
include macrocytic anemia, hypoalbuminemia, and hyperuricemia.
- Biochemical assessment of deficiency is attempted by the measurement of urinary excretion of
methylated metabolites of nicotinic acid (e.g., N-methylnicotinamide). These tests do not provide
unequivocal evidence of deficiency. The measurement of nicotinamide in blood and urine has not
been shown to be useful in evaluating niacin status. In most cases, the diagnosis rests on a
correlation of clinical findings with the response to supplemental nicotinamide.
Human Requirements
As indicated above, the dietary requirement for this vitamin can be satisfied not only by nicotinic
acid but also by nicotinamide and the amino acid tryptophan. Therefore, the nicotinic acid
requirement is influenced by the quantity and the quality of dietary protein. Administration of
tryptophan to normal human subjects, as well as to patients with pellagra, and analysis of urinary
metabolites indicate that an average of 60 mg of dietary tryptophan is equivalent to 1 mg of
nicotinic acid. This conversion rate is reduced in women taking oral contraceptives. The minimal
requirement of nicotinic acid (including that formed from tryptophan) to prevent pellagra averages
4.4 mg/1000 kcal. The RDA of niacin is 14 and 16 mg/day for women and men, respectively (see
Table XIII–2).
The relationship between the nicotinic acid requirement and the intake of tryptophan has helped to
explain the historical association between the incidence of pellagra and the presence of large
amounts of corn in the diet. Corn protein is low in tryptophan, and the nicotinic acid in corn and
other cereals is largely unavailable. When cornmeal provides the major portion of dietary protein,
pellagra will develop at levels of intake of nicotinic acid that would be adequate if the dietary
protein contained more tryptophan. Intake of animal protein is high among Americans; tryptophan
thus helps significantly to meet the daily requirement for niacin.
Food Sources
Nicotinic acid is obtained from liver, meat, fish, poultry, whole-grain and enriched breads and
cereals, nuts, and legumes. Tryptophan as a precursor is provided by animal protein, in particular.
Absorption, Fate, and Excretion
Both nicotinic acid and nicotinamide are absorbed readily from all portions of the intestinal tract,
and the vitamin is distributed to all tissues. When 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 Uses
Nicotinic acid, nicotinamide, and their derivatives are used for prophylaxis and treatment of
pellagra. In the acute exacerbations of the disease, therapy must be intensive. The recommended
oral dose is 50 mg, given up to ten times daily. If oral medication is impossible, intravenous
injection of 25 mg is given two or more times daily. Pellagra may occur in the course of two
metabolic disorders. In Hartnup's disease, intestinal and renal transport of tryptophan is defective.
In some patients with carcinoid tumors, large amounts of tryptophan are utilized by the tumor for
the synthesis of 5-hydroxytryptophan and 5-hydroxytryptamine (serotonin).
- The response to nicotinic acid or its derivatives is dramatic. Within 24 hours, the fiery redness and
swelling of the tongue disappear and sialorrhea diminishes. Associated oral infections heal rapidly.
Other infections of mucous membranes also disappear. Nausea, vomiting, and diarrhea may stop
within 24 hours, and at the same time the patient is relieved of epigastric distress, abdominal pain,
and distention. Appetite also improves. Mental symptoms are quickly relieved, sometimes
overnight. Confused patients become mentally clear, and those who are delirious become calm,
adjusted to their environment, and remember with insight the events of their psychotic state. So
specific are nicotinic acid and its derivatives in this regard that they can be used as diagnostic
agents in patients with frank psychoses but with questionable additional evidence of pellagra. Large
doses of niacin are recommended, especially when the psychosis is associated with encephalopathy.
The dermal lesions blanch and heal, but this occurs more slowly. The vitamin has less effect on
cutaneous lesions that are moist, ulcerated, or pigmented. The porphyrinuria associated with
pellagra also disappears.
Pellagra may be complicated by thiamine deficiency with associated peripheral neuritis. This
complication does not respond to nicotinic acid or its congeners and must be treated with thiamine.
Many pellagrins also benefit from additional therapy with riboflavin and pyridoxine.
In gram doses, nicotinic acid lowers circulating concentrations of low-density-lipoprotein
cholesterol and triglycerides, plasma fibrinogen, and lipoprotein(a). Nicotinic acid therefore is used
in the management of hyperlipoproteinemias (see Chapter 36: Drug Therapy for
Hypercholesterolemia and Dyslipidemia).
Nicotinamide has shown promise in the primary prevention of type I diabetes mellitus in high-risk
individuals (Elliott et al., 1996; Lampeter et al., 1998). Large population-based intervention trials
currently are in progress.
Pyridoxine
History
In 1926, dermatitis was produced in rats by feeding a diet deficient in vitamin B2. However, in 1936
György distinguished from vitamin B2 the water-soluble factor whose deficiency was responsible
for the dermatitis and named it vitamin B6. The structure of the vitamin was elucidated in 1939.
Several related natural compounds (pyridoxine, pyridoxal, pyridoxamine) have been shown to
possess the same biological properties, and therefore all should be called vitamin B6. However, the
Council on Pharmacy and Chemistry has assigned the name pyridoxine to the vitamin.
Chemistry
The structures of the three forms of vitamin B6—that is, pyridoxine, pyridoxal, and 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 to pyridoxine have been synthesized and are capable of blocking the action of the
vitamin and producing signs and symptoms of deficiency. The most active is 4-deoxypyridoxine, for
which the antivitamin activity has been attributed to the formation in vivo of 4-deoxypyridoxine-5-
phosphate, a competitive inhibitor of several pyridoxal phosphate–dependent enzymes.
Isonicotinic acid hydrazide (isoniazid; see Chapter 48: Antimicrobial Agents: Drugs Used in the
Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease, and Leprosy), as well as
other carbonyl compounds, combines with pyridoxal or pyridoxal phosphate to form hydrazones; as
a result, it is a potent inhibitor of pyridoxal kinase. Enzymatic reactions in which pyridoxal
phosphate participates as a coenzyme also are inhibited, but only by much greater concentrations
than those required to inhibit the formation of pyridoxal phosphate. Isoniazid thus appears to exert
its antivitamin B6 effect primarily by inhibiting the formation of the coenzyme form of the vitamin.
Pharmacological Actions
Pyridoxine has low acute toxicity and elicits no outstanding pharmacodynamic actions after either
oral or intravenous administration. However, neurotoxicity may develop after prolonged ingestion
of as little as 200 mg of pyridoxine per day (Schaumberg et al., 1983; Parry and Bredesen, 1985).
Physiological Functions
As a coenzyme, pyridoxal phosphate is involved in several metabolic transformations of amino
acids—including decarboxylation, transamination, and racemization—as well as in 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 of tryptophan to 5-hydroxytryptamine. In vitamin B6–deficient human
beings and in animals, a number of metabolites of tryptophan are excreted in abnormally large
quantities. The measurement of these urinary metabolites, particularly xanthurenic acid, following
loading with tryptophan is used as a test of vitamin B6 status. The conversion of methionine to
- cysteine also is dependent on the vitamin.
Interactions with Drugs
Biochemical interactions occur between pyridoxal phosphate and certain drugs and toxins. The
relationship with isoniazid has been discussed above. Prolonged use of penicillamine can cause
deficiency of vitamin B6. The drugs cycloserine and hydralazine are also antagonists of the vitamin,
and administration of vitamin B6 reduces the neurological side effects associated with the use of
these compounds. Vitamin B6 enhances the peripheral decarboxylation of levodopa and reduces its
effectiveness for the treatment of Parkinson's disease (see Chapter 22: Treatment of Central
Nervous System Degenerative Disorders).
Symptoms of Deficiency
Skin
Seborrhealike skin lesions about the eyes, nose, and mouth accompanied by glossitis and stomatitis
can be produced within a few weeks by feeding a diet poor in vitamin B complex plus daily doses
of the vitamin antagonist 4-deoxypyridoxine. The lesions clear rapidly after the administration of
pyridoxine but do not respond to other members of the B complex.
Nervous System
Convulsive seizures may occur when human beings are maintained on a diet deficient in
pyridoxine, and these seizures can be prevented by the vitamin. The induction of convulsive
seizures by pyridoxine deficiency may be the result of a lowered concentration of gamma-
aminobutyric acid; glutamate decarboxylase, a pyridoxal phosphate–requiring enzyme, synthesizes
this inhibitory central nervous system (CNS) neurotransmitter (see Chapter 12: Neurotransmission
and the Central Nervous System). In addition, pyridoxine deficiency leads to decreased
concentrations of the neurotransmitters norepinephrine and 5-hydroxytryptamine. A peripheral
neuritis associated with carpal synovial swelling and tenderness (carpal tunnel syndrome) has been
attributed in some cases to deficiency of pyridoxine, although earlier claims that high doses of
pyridoxine reverse carpal tunnel syndrome have not been confirmed (Smith et al., 1984).
Erythropoiesis
Although dietary deficiency of pyridoxine in human beings may cause anemia rarely, the usual
pyridoxine-responsive anemia apparently is not due to inadequate supplies of this vitamin as judged
by normal standards. This type of anemia is described in Chapter 54: Hematopoietic Agents:
Growth Factors, Minerals, and Vitamins.
Human Requirements
The requirement for pyridoxine increases with the amount of protein in the diet. The average adult
minimal requirement for pyridoxine is about 1.6 mg per day in individuals ingesting 100 g of
protein per day (Hansen et al., 1997). The current RDA for pyridoxine has been set at 1.3 mg for
young adult men and women, with modest increases for individuals above 50 years of age (see
Table XIII–2).
- Food Sources
Pyridoxine is supplied by meat, liver, whole-grain breads and cereals, soybeans, and vegetables.
Substantial losses occur during cooking, and pyridoxine is sensitive to both ultraviolet light and
oxidation.
Absorption, Fate, and Excretion
Pyridoxine, pyridoxal, and pyridoxamine are readily absorbed from the gastrointestinal tract
following hydrolysis of their phosphorylated derivatives. Pyridoxal phosphate accounts for at least
60% of circulating vitamin B6. Pyridoxal is thought to be the primary form that crosses cell
membranes. The principal excretory product when any of the three forms of the vitamin is fed to
human beings is 4-pyridoxic acid, formed by the action of hepatic aldehyde oxidase on free
pyridoxal (see Leklem, 1988).
Therapeutic Uses
Although there is no doubt that pyridoxine is essential in human nutrition, the clinical syndrome of
simple pyridoxine deficiency is rare. Nevertheless, it may be presumed that an individual with a
deficiency of other members of the B complex may also have a deficiency of pyridoxine. Therefore,
pyridoxine should be a component of therapy for individuals suffering from a deficiency of other
members of the B complex. On the basis that pyridoxine is essential in human nutrition, it is
incorporated into many multivitamin preparations for prophylactic use.
As indicated above, vitamin B6 influences the metabolism of certain drugs and vice versa. With
considerable justification, vitamin B6 is given prophylactically to patients receiving isoniazid to
prevent the development of peripheral neuritis. In addition, pyridoxine is an antidote for the seizures
and acidosis in patients who have ingested an overdose of isoniazid.
The concentration of pyridoxal phosphate is reduced in the blood of women who are pregnant or
who are taking oral contraceptives, although the recommended intakes of vitamin B6 appear to be
sufficient to meet the requirements of such individuals.
Pyridoxine-responsive anemia is a well-documented but uncommon condition. The use of the
vitamin in this disease is discussed in Chapter 54: Hematopoietic Agents: Growth Factors,
Minerals, and Vitamins. A group of genetically determined clinical states of "pyridoxine
dependency," manifested by a requirement for large amounts of the vitamin, include pyridoxine-
responsive anemias in patients without apparent pyridoxine deficiency, a seizure disorder in infants
that responds to the administration of pyridoxine, and those abnormalities characterized by
xanthurenic aciduria, primary cystathioninuria, or homocystinuria (see Fowler, 1985).
Pantothenic Acid
History
Pantothenic acid was first identified by Williams and associates in 1933 as a substance essential for
the growth of yeast. Its name, derived from Greek words signifying "from everywhere," is
indicative of the wide distribution of the vitamin in nature. The role of pantothenic acid in animal
nutrition was first defined in chicks, in which a deficiency disease characterized by skin lesions was
known to be cured by fractions prepared from liver extract. Although first thought to be a form of
- "chick pellagra," it was not cured by nicotinic acid. In 1939, Woolley and coworkers and also Jukes
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 and linkage to cysteamine; this derivative is 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.
Pharmacological Actions
Pantothenic acid has no outstanding pharmacological actions when it is administered to
experimental animals or normal human beings, even in large doses.
Physiological Functions
Coenzyme A serves as a cofactor for a variety of enzyme-catalyzed reactions involving transfer of
acetyl (two-carbon) groups; the precursor fragments of various lengths are bound to the sulfhydryl
group of coenzyme A. Such reactions are important in the oxidative metabolism of carbohydrates,
gluconeogenesis, degradation of fatty acids, and the synthesis of sterols, steroid hormones, and
porphyrins. As a component of acyl carrier protein, pantothenate participates in fatty acid synthesis.
Coenzyme A also participates in the posttranslational modification of proteins, including N-terminal
acetylation, acetylation of internal amino acids, and fatty acid acylation. Such modifications can
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