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Contents

1 Introduction, 361
1.1 What Is a Vitamin?, 361
1.1.1Vitamins Are Naturally Occurring, 361
1.1.2 Vitamins Are Essential Because They
Are Not Produced by Human
Biochemical Pathways, 361
1.1.3 Organic, 361
1.1.4 Normal Constituent of the Diet, 362
1.1.5 Vitamins Are Required in Minute
Amounts, 362
1.1.6 Vitamins Are Required to Maintain
Normal Biochemical Functions of the
Tissues, 362
1.2 Causes of Vitamin Deficiencies, 362
2 Dietary Reference Intakes, 362
2.1 Determination of a Vitamin Dose, 362
2.2 Methods to Determine a Valid Dose
of a Vitamin, 362
2.2.1 Extrapolate from Animal Studies, 362
2.2.2 Metabolic Balance Studies in Humans,
363
2.2.3 Compare Nutrient Intake in Areas
with and without the Deficiency
Disease, 363
2.2.4 Saturation of Biochemical Function, 363
2.2.5 Serum Levels, 363
2.3 Dietary Reference Intakes 363
2.3.1 Introduction, 363
2.3.2 How Do the Differ 363
2.3.3 Uses of Dietary Reference Intakes, 363
2.3.3.1 Estimated Average
Requirement (EAR), 363
2.3.3.2 Recommended Dietary
Allowance 363
2.3.3.3 Adequate Intake 368
2.3.3.4 Tolerable Upper Intake Level
368
3 Vitamins, 368
3.1 Retinol A) Family 368
3.1.1 Chemistry, 368
Vitamins

3.1.2 Uptake and Metabolism (Fig. 369 3.6.1 Chemistry (Fig. 392
3.1.3 Biochemical Functions and Deficiency, 3.6.2 Riboflavin Uptake and Chemistry (Fig.
370 392
3.1.4 Dosage Forms, 370 3.6.3 Metabolic Role, 392
3.1.5 Hypervitamininosis A, 370 3.6.4 Riboflavin Deficiency, 392
3.1.6 Hypercarotenosis, 371 3.6.5 Hypervitaminosis Riboflavin, 392
3.1.7 Dietary Reference Intakes (as Retinoic 3.6.6 Dietary Reference Intakes, 392
Acid Equivalents), 371 3.7 Niacin (Nicotinic
3.1.8 Pharmacologically Active 372 392
3.1.8.1 and Retinoid-like 3.7.1 Chemistry, Uptake
Drugs Used in the Treatment of and Metabolism, 394
Acne (Fig. 8.7) 372 3.7.2 Niacin Deficiency, 394
3.1.8.2 Drug Based on th e 3.7.3 Hypervitaminosis Niacin, 395
Structure Used to Treat 3.7.4 Dietary Reference Intakes, 397
Psoriasis (Fig. 373 3.8 Vitamin B, Family, 397
3.1.8.3 Retinoids Used in the 3.8.1 Uptake and Metabolism, 397
Treatment of Malignancies (Fig. 3.8.2 Pyridoxal Phosphate Biochemistry
374 397
3.2 Vitamin D Family 374 3.8.3 Vitamin B, Deficiency, 398
3.2.1 Chemistry, 374 3.8.4 Vitamin-Drug Interactions 399
3.2.2 Vitamin Uptake and Metabolism, 375 3.8.5 Hypervitaminosis Pyridoxine, 400
3.2.3 Biochemical Function, 376 3.8.6 Dietary Reference Intakes, 400
3.2.3.1 Calcium Regulation, 376 3.9 Pantothenic Acid
3.2.3.2 Vitamin D Analogs Used in 3.9.1 Chemistry, Uptake, and Metabolic
Chronic Renal Failure, 377 Role, 401
3.2.3.3 Cell Division, 377 3.9.2 Hypervitaminosis Pantothenic Acid, 401
3.2.4 Dosage Forms, 379 3.9.3 Dietary Reference Intakes, 401
3.2.5 Hypervitaminosis D, 379 3.10 Biotin
3.2.6 Dietary Reference Intakes, 379 3.10.1 Uptake, 402
3.2.7 Drug Interactions, 379 3.10.2 Chemistry, 402
3.3 Vitamin E Family (Tocopherols 3.10.3 Metabolic Role, 402
and Tocotrienols) 380 3.10.4 Biotin Deficiency, 405
3.3.1 Chemistry, 381
3.3.2 Uptake and Metabolism, 381
3.10.5 Hypervitaminosis Biotin, 405
3.10.6 Dietary Reference Intakes, 405
.
3.3.3 Biochemical Function, 383 3.11 Folic Acid 405
3.3.4 Deficiencies, 383 3.11.1 Chemistry, 405
3.3.5 Hypervitaminosis E, 384 3.11.2 Uptake, 405
3.3.6 Dosage Forms, 384 3.11.3 Metabolic Roles, 406
3.3.7 Dietary Reference Intakes (based on 3.11.4 Folic Acid Deficiency, 407
d-a-Tocopherol), 384 3.11.5 Hypervitaminosis Folic Acid, 411
3.4 Vitamin K Family 3.11.6 Dietary Reference Intakes, 411
3.4.1 Chemistry, 385 3.12 Vitamin B,,
3.4.2 Vitamin K Uptake and Metabolism, 386 3.12.1 Chemistry, 413
3.4.3 Vitamin K Biochemistry and Defi- 3.12.2 Uptake, 413
ciency, 386 3.12.3 Biochemical Role, 413
3.4.4 Causes of Vitamin K Deficiency, 387 3.12.4 Cobalmin Deficiency, 415
3.4.5 Hypervitaminosis K, 387 3.12.5 Hypervitaminosis B,,, 415
3.4.6 Dietary Reference Intakes, 387 3.12.6 Dietary Reference Intakes, 415
3.5 Thiamine (Vitamin 387 3.13 Ascorbic Acid (Vitamin
3.5.1 Chemistry, 388 3.13.1 Chemistry, 415
3.5.2 Uptake and Metabolism, 388 3.13.2 Uptake, 417
3.5.3 Thiamine Deficiencies, 389 3.13.3 Metabolic Roles, 417
3.5.4 Hypervitaminosis Thiamine, 389 3.13.4 Ascorbic Acid Deficiency, 417
3.5.5 Dietary Reference Intakes, 389 3.13.5 Hypervitaminosis C, 417
3.6 Riboflavin (Vitamin 392 3.13.6 Dietary Reference Intakes, 418
1 INTRODUCTION as long as the natural and synthetic products
are identical. This includes stereochemistry.
Vitamins are enjoying renewed popularity L-Ascorbicacid is twice as activeas the racemic
with the lay public that, in some ways, mimics acid. A similar statement can be
the attention seen in the early part of the made for D-pantothenic acid and S-biotin rela-
twentieth century when they were first being tive to their racemic mixtures. The situation
discovered. Paralleling the interest by the for a-tocopherol (vitamin with three asym-
increased focus on the biochem- metric centers is more complex and is dis-
at the molecular level. cussed in more detail later in this chapter.
Some vitamins can be considered prototypes
for pharmacological agents used to treat dis- 1.1.2 Vitamins Are Essential Because They
eases that do not appear directly related to the Are Not Producedby Human Biochemical Path-
patient's vitamin status. Although all animals ways. With two exceptions, this requirement
require vitamins, the discussion in this chap- is obvious. If a compound is required for a bio-
ter focuses on humans and human chemical process and our pathways cannot
produce it, it must be obtained from exoge-
Vitamins are complex biochemically and nous sources. The evolutionary history of the
functionally and may be classified many ways. human species is such that we sought out
This chapter acknowledges the traditional sol- sources in our environment that contained
ubility model but focuses on Un- these essential substances, and those sub-
fortunately,the loose regulation of nutritional stances containing vitamins became our food.
products in the United States has led to mis- One of the substances commonly treated as
leading promotion of these items to the lay a vitamin is niacin, which is synthesized from
at individualsare confused as to the essential amino acid tryptophan. The ratio
at can be called a vitamin. General criteria is approximately 60 mg of tryptophan being
a substance truly is a vitamin required to produce 1 mg of niacin This
presented. Another problem is to decide has led to niacin requirements being ex-
nt actually has a vitamin pressed as niacin equivalents based on
in the next section, this can be the amount of tryptophan in the diet. It must
complex question. Finally, deciding how be kept in mind that tryptophan is essential
vitamin should be con- and is the precursor to the neurotransmitter
ed has moved from the familiar serotonin in addition to being part of protein
ended Dietary Allowance to four structure. Therefore, niacin can be thought of
rent ways to evaluate vitamin requirements as tryptophan sparing.
dconsumption. These are called the Dietary The other exception is vitamin or chole-
ference Intakes calciferol. Assuming adequate sunlight, chole-
calciferol is the photochemical product from
What i s a Vitamin? ultraviolet irradiation of 7-dehydrocholesterol
found in our skin. A significant proportion of
In general a vitamin must be a naturally the world's population produces all of the
olecule that is a normal cholecalciferol it needs from this photochemi-
iet. It should be essential and cal reaction. It is true that a
inute amounts. Finally, it is reaction is not a biochemical pathway, but ex-
ain normal cellular biochem- posure to adequate sunlight does fulfill the re-
and tissue integrity. Let us examine quirement for cholecalciferol. As noted in the
in more detail. discussion for this particular substance, the
compounds commonly referred to as vitamins
1.1.1 Vitamins Are Naturally Occurring. and are not normal constituents of most
his criterion frequently is misinterpreted. human diets.
though the vitamin is a natural product,
ere is no difference in efficacy between 1.1.3 Organic. Trace elements are not
sting the or a synthetic product properly called vitamins. Therefore, iron, zinc,
Vitamins

magnesium, manganese, chromium, sele- including economics, genetics, diseased intes-


nium, and the other trace elements that are tinal tract, alcoholism, a variety of medical
obviously obtained from food sources are es- conditions, lifestyle, and vitamin-drug inter-
sential, but they are not vitamins. actions. Table 8.1 contains a classification
scheme for possible causes of vitamin deficien-
1.1.4 Normal Constituent of the Diet. With cies.
the exception of cholecalciferol,all of the other
compounds that we treat as vitamins are nor-
mal constituents of our diets, with most found 2 DIETARY REFERENCE INTAKES
in more than one food group. The situation
with cholecalciferol is such that, except for the 2.1 Determination of a Vitamin Dose
small part of the world's population that ob-
tains its protein from marine species, neither This is not easy. Ideally, a dose-response curve
cholecalciferol nor ergocalciferolfrom irradia- could be constructed that would provide de-
tion of the plant sterol ergosterol, is a normal fined endpoints such as an ED,, or ED,, and
component of foods. doses that would cause serious toxicities, the
The problem is defining a biological or
1.1.5 Vitamins Are Required in Minute pharmacological endpoint. Not all vitamin de-
Amounts. This is arbitrary, but ranges from ficiencies have defined syndromes. Little is
2.0 for cyanocobalamin to 90 mg known of the pharmacokinetics of individual
for ascorbic acid. Other essential nutrients in- vitamins. In contrast with most drugs, the
cluding the essential amino acids and fatty ac- body stores vitamins, sometimes several
ids generally are required in larger amounts. months' supply. This should not be surprising
For example, the National Research Council's when one examines human history. Until
recommended daily intake of amino acids fairly recent times, humans regularly experi-
ranges from a low of 245 mg for tryptophan to enced food plenty and food deprivation (famine)
980 mg for phenylalanine and (com- as crops failed and animals moved away from
bined) and (2). Note that the value for settlements. Causes ranged from weather to
tryptophan provides only about 4 mg of niacin, war. To survive, the evolutionary development
assuming all 245 mg of tryptophan is con- of humans includes ways to store and reuse vi-
verted to niacin. tamins. Assuming a good diet, humans have a
6- to 9-month supply of vitamin A. Humans ef-
ficiently recycle cobalamin (vitamin B,,) by
1.1.6 Vitamins Are Required to Maintain
enterohepatic circulation. The intestinal flora
Normal Biochemical Functions of the Tissues.
produce a precursor to vitamin K.
Most vitamins function either as a
chemical messenger (cholecalciferol), struc-
tural component in some metabolic process 2.2 Methods to Determine a Valid Dose
(pantothenic acid), or a coenzyme of a Vitamin
one, thiamine, riboflavin, niacin, pyridoxine, Each of the methods outlined in the following
biotin, folic acid, cyanocobalamin). At least sections has significant problems in determin-
one vitamin has more than one biochemical ing a dose-response curve for a vitamin. Table
role. Vitamin A as an aldehyde (retinal) is a 8.2 lists methods that are being used to deter-
structural component of the visual pigment mine vitamin requirements or are under de-
rhodopsin and, in its acid form (retinoic acid), velopment as possible procedures.
is a regulator of cell differentiation. The pre-
cise biochemical functions of ascorbicacid and
a-tocopherol still are not well defined. 2.2.1 Extrapolate from Animal Studies.
This method is dependent on the species. The
vitamin requirements differ among the com-
1.2 Causes of Vitamin Deficiencies
mon laboratory animals. The classic example
There are a variety of reasons why a person is ascorbic acid, which is not a vitamin in most
might be experiencing a vitamin deficiency animals. Humans do not exhibit specific
2 Dietary Reference Intakes

symptoms for a-tocopherol, biotin, and takes for Canada. These are being replaced by
pantothenic acid, whereas many animals do. the Dietary Reference Intakes, a joint effort of
the United States and Canada. The DRIs are
2.2.2 Metabolic Balance Studies in Humans. published by the Food and Nutrition Board of
This usually involves a specified number of the National Academy of Sciences National
days on a defined diet in which the urine and Research Council. The expert panels are made
feces are monitored. The problem is that cor- up of U.S. and Canadian scientists.
rections have to be made for the vitamins that
are stored. The pharmacokinetics of most vi- 2.3.2 How Do the Differ from RDAs?.
tamins have not been carefully determined. There is one set of reference values for both
Canada and the United States and clear docu-
2.2.3 Compare Nutrient Intake in Areas mentation on how reference values are se-
with and without the Deficiency Disease. lected. A goal is the promotion of nutrient
First, not all vitamin deficiencies lead to a de- function and biologic-physical well-being. Ev-
fined deficiency state. Second, rarely does one idence concerning the prevention of disease
an area deficient in only one nutrient. and developmental disorders is examined in
Most common deficiencies are attributed to in- addition to the traditional "how much nutri-
adequate diet, which means several nutrient ent is needed to prevent a deficiency symp-
deficiencies will result. tom." Data supporting food components that,
up to this time, have not been considered es-
2.2.4 Saturation of Biochemical Func- sential nutrients will be examined. Finally,
tion. A reliable biochemical indicator is re- there are recommendations for future re-
quired. For niacin, which or search.
ntaining enzyme should be selected? Which
ansaminase will be the indicator for 2.3.3 Uses of Dietary Reference Intakes.
e? Which function of vitamin A should be The DRIs consist of four components. Each
lected for retinol, vision in the rods or cell type of reference value is calculated from daily
rentiation? As noted from Table 8.2, intakes averaged over time (usually one or
of the assays for vitamin status have more weeks). The surveys include, but are not
gnificant limitations to estimate reliable limited to, (1)random selection of healthy in-
dividuals and asking them to either report
what they have eaten or to maintain food dia-
2.2.5 Serum Levels. This probably is the ries, (2) monitoring overall food production
ost reliable, but it does require very and consumption, and (3) correlating a de-
ve assay methods for those vitamins re- fined population's health status with the
ired in microgram amounts. It also group's food intake. Sometimes the results
knowledge as to how the vitamin is from the surveys are correlated with the type
ansported: free or bound to a plasma protein of assays listed in Table 8.2. The four Dietary
on a specific transport protein. Examples of Reference Intakes are:
e latter are transport proteins for vitamin A Estimated Average Requirement
d vitamin D,. The tocopherols will be found (EAR). The EAR is the intake that meets the
in the lipoproteins LDL, etc.). estimated nutrient need of 50%of the individ-
uals in that group infants, children, adult
3 Dietary Reference Intakes (3, 4)
males, adult females, pregnant women, nurs-
ing women, the elderly, etc.). It is used to eval-
e adult DRI values for each vitamin are uate the adequacy of nutrient intakes of pop-
und in the section for that vitamin. ulation groups and for planning intakes for
group. It can be used in diet planning. The
2.3.1 The last official set of EAR is based on a median rather than a mean.
rence values were the 1989 Recommended 2.3.3.2 Recommended Dietary Allowance
Allowances for the United (RDA). The RDA is the intake that meets the
and 1990 Recommended Nutrient nutrient need of almost all (97-98%)
Vitamins

als in that group. The RDA are the values ing of the structural chemistry of the vita-
found on most vitamin products. They vary mins. There was fat-soluble A and
depending on whether the product is intended ble B. Thiamine was the first vitamin
for infants, children, or adults. The can whose structure was elucidated. It is an
function as a guide to achieve adequate nutri- leading to the term vital amine and finally vi-
ent intake. By themselves, they are not gener- tamin (without the e ) . The letter designations,
ally recommended for diet planning for spe- for the most part, are being relegated to his-
cific groups of individuals. Diet planning must tory. Many of the vitamins are groups of struc-
take into account extensive physical activity, tures and, therefore, using a single letter can
type of body build including lean vs. adipose be misleading. Also, the structures occurring
tissue, general lifestyle, and so forth. If the naturally in food and commercial prepara-
sampling and endpoints are well defined, the tions may actually be provitamins that have to
RDA can be calculated from the EAR. be converted to the biochemically active form.
Unless specified differently, the information
in the following summaries is found in the Di-
etary ReferenceIntakes, published by the Insti-
where is the standard deviation above tute of Medicine
the EAR.
2.3.3.3 Adequate Intake The is the 3.1 (Vitamin A) Family (9)
average observed or experimentally derived
intake by a defined population or subgroup Early work on this vitamin was confusing be-
that appears to sustain a defined nutritional cause similar outcomes were seen with inges-
state, such as normal circulating nutrient val- tion of "yellow" vegetables and colorless fish
ues, growth, or other functional indicators of liver oils. It finally was shown that carotene
health. It is derived from mean intakes of (the yellow pigment) extracts from vegetables
groups (rather than individuals). The AI be- were converted to colorless retinal. Because
comes most useful when a reliable EAR is not the retinoids are discussed in considerably
available. Many times the AI probably exceeds more detail elsewhere, this chapter presents
the EAR and possibly the RDA. only a cursory overview of their biochemical
2.3.3.4 Tolerable Upper Intake Level functions. .
The UL is the maximum intake by an individ-
ual that is unlikely to pose risks of adverse 3.1.1 Chemistry. The commercial form of
health effects in almost all (97-98%)individu- vitamin A is all-trans retinol, usually
als. It includes intake of a nutrient from all lated as the acetate or palmitate ester. The
sources (food, fortified food, water, and active forms are the two oxidation products
dements). Water can include fluoride and (Fig. 8.1, (1) retinal, which is a structural
minerals depending on the source of water. component of the visual pigment rhodopsin,
"Tolerable" is used to "avoid implying any and (2) retinoic acid, which is required for cell
possible beneficial effect." It is the amount of differentiation. There are specific nuclear re-
vitamin that can be "tolerated" without the ceptors for retinoic acid. Although the vitamin
person's exhibiting or experiencing adverse is marketed in the all-trans form, retinal and
reactions. The UL should not be considered retinoic acid are present, in in cis forms.
the upper dose for those who self-dose with There are also commercial forms related to the
megadoses of vitamins. retinoic acid structure that have cis
stereochemistry.
Carotenes are promoted commercially for
3 VITAMINS their antioxidant activity rather than as a
source of the retinol group. Nevertheless, the
The order of vitamins in this chapter follows carotenes are the source of the vitamin in yel-
the classical classification-based solubility:fat low vegetables. There are many carotenes, of
soluble and water soluble. This classification which three are shown in Fig. 8.2. Only
originated before there was any understand- otene is symmetrical (note the dashed line)
of As the stores in the liver reach
capacity, there is less conversion of
being oxidized to retinal. This is one of the
reasons that nutritional supple-
ments enter the body intact. Further, the
(commercial form) availability of is significantly lower
I
than that of

3.1.2 Uptake and Metabolism (Fig. 8.3).


Both esters, whether from animal
tissues or a vitamin supplement, and
otene must be incorporated into mixed
celles along with other lipid material. The
esters are hydrolyzed by intestinal
Retinal (vision) Both and are
then absorbed into the mucosa cell, where
is oxidatively cleaved to retinal
and then reduced to The in-
dependent of the source, follows the same
steps seen with 2-monoglyceride from
glyceride digestion. The is
fied, usually with acid, and attached
to the along with the other di-
etary lipids. The first enter the
Retinoic acid (celldifferentiation) lymph and then move to the circulatory
tem. The are removed from the
Retinol chemistry.
and deposited in the adipose
and theoretically will produce two equivalents and skeletal muscle cells, leaving
.
the enzyme-catalyzed oxidative
liver where the vitamin is stored
Transportation from the liver tis-
A activity derived from sues where required is done on specific
isone of capacity in the intestinal nol-binding proteins. Humans consuming a
cell to cleave the carotenes. Further, balanced diet store several months of
appears to be regulation of the cleavage esters in their livers.

Carotene chemistry.
Vitamins

oxidation cell
mucosa cell retinal \ reductase
reesterify
cell palmitate
A

Retinol esters
(food or vitamin supplements) esterases

4
retinal retinoic acid chylomicron
transported on Retinal remnent
Binding Protein (RBP)

Figure 8.3. Uptake and metabolism of retinol esters and

3.1.3 Biochemical Functions and Deficiency. nerve. In the dark, re-forms fol-
Two retinoic acid and retinal, ap- lowed by oxidation to 11-cis-retinal and the
pear to have most of the biochemical functions cycle repeats.
attributed to vitamin A. Retinoic acid is re- A deficiency causes night blindness, which
quired for cell differentiation and is the ligand is considered an early symptom of de-
for two families of nuclear receptors, ficiency. Night blindness refers to decreased
and These receptors are part of a ability to see in very dim light because there is
family of superreceptors that include the ste- an inadequate amount of retinal in the eye to
roid hormones and Vitamin A "stock" the rods with functional
deficiency can lead to a variety of symptoms sin. There is some evidence that as lev-
depending on the age of the deficient person. els in the liver decrease, the equilibrium fa-
The most serious is vors the movement of from the eye
which results in desiccation, ulceration, and back to the liver.
of the cornea and conjunctiva.
It is one of the leading causes of blindness in 3.1.4 Dosage Forms. Retinol is unstable. It
infants and children. easily dehydrates (Fig. forming a stable
Retinoic acid is for the development ion. Therefore, the two most com-
of goblet mucous cells. A deficiency results in mon forms for both oral and ad-
basal cell proliferation increased ministration are the acetate or palmitate es-
zation of the epithelial Mucus is one ters. With the extensive conjugation is
of the essential physical barriers (part of innate light sensitive and subject to oxidation. There-
that prevents pathogens from enter- fore, the vitamin formulator must protect the
ing the body. Therefore, a deficiency in- product from light and air.
creases the risk of infection.
The aldehyde form, retinal, is an essential Hypervitamininosis A. In high doses,
component of the visual pigment found in the can be toxic. Acute poisoning is rare
rods of the eye. A very brief outline of the and dependent on the dosage form. Nausea
dopsin cycle is shown in Fig. 8.4. Retinol is and vomiting are the most common symp-
transported from the liver to the eye, where it toms. Most rapidly absorbed are the "clear"
is converted to 11-cis-retinal. In the rod, the emulsions (usually formulated with a Tween
aldehyde forms an enamine (Schiff's base) or other surfactant). Next in order are the
with a lysine on opsin forming (Fig. emulsions, usually produced from
8.5). In the presence of light, trans-retinal fish liver oils. The most slowly absorbed are
forms with cleavage of the enamine, a the dry tablet formulations or an oil solution
nerve impulse to the brain along the optic in a capsule. Chronic is
Rhodopsin
(visual pigment)

/
impulse
Changes in the conformation Sight
to the brain
(Dark) of the Rhodopsin complex

+ Opsin trans-Retinal + Opsin

(transported to the eye


from the liver on a
binding protein)

Liver stores of
esters
Figure 8.4. Outline of the rhodopsin cycle.

re common and is more commonly seen seem to be no other The skin col-
n people consume fish liver oil oration slowly disappears when carotene in-
es. The are nondescript and take stops. commercial form of carotene is
de fatigue, malaise, lethargy, abdominal indicated for the photosensitivity seen in
comfort, pain, severe and erythropoietic Carotene capsules
g headache, insomnia, restlessness, dry are also sold with the claim that a person can
d scaly skin, loss of body hair, brittle nails, have a tanned appearance without the need of
tipation, and irregular menses, radiation. Patients who drink large
ight make users conclude that they are of carrot juice sometimes show signs
A deficient. Depending on the health of
person's liver, there is risk of developing
hosis. There is a daily Tolerable Upper 3.1.7 Dietary Reference Intakes (as
e Level (UL) of 3000 for this vitamin. Acid Equivalents).
e UL to ratio is narrow relative
that of most vitamins. This is somewhat
mparable to (1-12 months) 400-500
EAR
3.1.6 Hypercarotenosis. This occurs from Children years) 210-275
sive doses of carotene that exceed the Boys (9-18 years) 445-630
ty of the mucosa cells to cleave the Girls (9-18 years) 420485
to retinal derivatives. The excesscarotene Men (19-70+ years) 625
omes deposited in the body tissues. Except Women (19-70-t years) 500
the yellow or bronze-orange skin, there Lactating 885-900
Vitamins

RDA
Children (1-8 years) 300-400
Boys (9-18 years) 600-900
Girls (9-18 years) 600-700
Men 900
Women 700
Pregnant 750-770
Lactating 1200-1300

Opsin
3000 for all adults including
pregnant women. There is some concern of
effects based on the experience
of the retinoids used in therapy.

3.1.8 Pharmacologically Active Retinoids.


Because retinol deficiency results in
zation of epithelial tissue, at one time retinol
was recommended for conditions includ-
ing acne. There is no clinical evidence that
is effectivefor conditions. Now that it
is realized that the active form is acid,
the focus has been on developing pharmaco-
logically active compounds based on this
structure. These are divided into treatment of
three groups: acne, the autoimmune
disease psoriasis, and (3) malignancies.
Rhodopsin and Retinoid-like Drugs
Used in the Treatment of Acne (Fig. 8.7)
Figure 8.5. Rhodopsin. The first product introduced was tretinoin,
which is a topical all-trans acid. Its
effectiveness may not be related to any direct
activity, but attributed by its produc-
ing a complex response related to increasing

= acetate or

Figure 8.6. Commercial retinol esters.


the turnover of epithelial cells. The
result is decreased cohesiveness of follicular
epithelial cells.
Tretinoin is also used as an antiwrinkle
cream. There is disagreement on the mecha-
nism and there may be more than one. Some
Tretinoin
Retinoic acid improvement may be attributable to the irri-
tation the causes. There is an increase in
epidermal cell turnover, shedding older cells
and thickening the skin. Also the drug may
combine with epidermal retinoic acid recep-
tors, thereby decreasing keratin production.
Keratin can contribute to skin wrinkling
Isotretinoin, 13-cis-retinoic acid, is very ef-
fective at treating severe forms of acne. It also
lsotretinoin
13-cis-Retinoicacid is very teratogenic. There are elaborate proce-
dures involving the prescribing physician and
dispensing pharmacist before a female patient
can receive the drug. There is also some con-
cern that the sperm of men using the drug
'OH
might be affected.
Although used topically, the nonretinoid,
adapalene, does bind to the retinoic acid nu-
clear receptor and does affect cell differentia-
tion, keratinization, and inflammatory re-
sponses.
Drug Based on the Struc-
ture Used to Treat Psoriasis (Fig. 8.8). Etrinate
is the ethyl ester of acitretin and is active after
(Dierin hydrolysis to the acidic drug. The "terminal"
half-life after 6 months of etrinate therapy is
8.7, and retinoid-like used 120 days. In contrast, the "terminal" half-life
the treatment of acne. of acitretin is only 33-96 h. Both drugs are

Etretinate (TegisonTM); = CH;


Acitretin =H

8.8. based on the


Tazarotene Gel structure used to treat psoriasis.
Vitamins

D, thyroid, and proliferator acti-


vator receptors, which probably explains its
numerous adverse reactions. The drug is indi-
cated for cutaneous T-cell lymphoma and is
available as capsules and a topical gel.

3.2 Vitamin D Family 5)


9-cis-Retinoic Acid Rickets was first reported in the mid-seven-
century. It could be lethal, but bone
deformation was more common. In the United
States, rickets continued to be a problem into
the 1930s until vitamin D-fortified milk be-
came common. Older adults show bowlegs
characteristic of childhood rickets. There were
many attempts at giving calcium phos-
phorous supplements. Finally, it was realized
0 that rickets was not found in sunny climates,
(Targretin and populations whose main source of protein
was fish did not have rickets. In 1924, Profes-
8.9. Retinoids used in the treatment of sor Henry Steenbock, University of Wiscon-
malignancies. sin, demonstrated that irradiation of foods,in-
cluding milk, produced food that was
teratogenic and require elaborate warnings antirachitic (16,
before being prescribed and dispensed. The When there is adequate sunlight, no di-
third drug, tazarotene gel, is administered etary source of the vitamin is required. In-
topically and is indicated for both acne and deed, an argument can be made that the cal-
psoriasis. Although there appears to be mini- ciferols are not normal components of the diet.
mal absorption if used over a limited skin area, In the United States. it is added to milk. other
there is some absorption, with retention by dairy products, and dairy substitutes. Fish is
the body for up to 3 months. It also can cause about the only natural food source.
fetal damage and cannot be used by pregnant ciferol is produced in the body from endog-
women or women who may become pregnant. enously 7-dehydrocholecalciferol
Retinoids Used in the Treatment of (Fig. 8.10). Consistent with a hormone model,
Malignancies (Fig. 8.9). Retinoic acid has been excess amounts of can result in
evaluated as a possible treatment for malig- excess calcium uptake from the intestinal
nancies. This is based on the fact that it is tract, leading to calcification of soft tissues.
required for proper cell differentiation and
products based on the structure are 3.2.1 Chemistry. There are two forms
teratogenic. All-trans retinoic acid is used in D, and both are considered biologically
combination with other chemotherapeutic equivalent. of the major plant ste-
agents for the treatment of acute promyelo- rol, ergosterol, produces ergocalciferol, also
leukemia (14). It does not the malig- known as vitamin (Fig.8.11).Because they
nant cell, but seems to facilitate the cell's are photochemical reactions and in contrast to
differentiation into a nonproliferating myelo- enzyme-catalyzed biochemical reactions, the
Alitretinoin, 9-cis-retinoic acid, is indi- formation of cholecalciferol is not clean. Expo-
cated for Kaposi's sarcoma and is adminis- sure of human to sunlight of nm
tered topically. It binds to all six acid converts 7-dehydrocholesterol to
receptors. D,. The to (vita-
Bexarotene is most selective for the three min is heat catalyzed. Continuous expo-
receptors. It also binds several other sure to ultraviolet radiation from the sun re-
nuclear receptors including the vitamin sults in the reversible formation of lumisterol
(Vitamin

Figure 8.10. Photochemical formation of cholecalciferol (vitamin

tachysterol (18, 19). Once the B-ring of shown in Fig. 8.10 toward the desired
two steroids has been cleaved, the prod- calciferol. Dependency on the binding protein
should no longer be referred to as ste- for transport from the also provides a
rproduction of the
roidal vitamins. mone and possible hypercalcemia.
When taken orally, it follows the same route

mucosa cells. It is then


the chylomicron
ogenously produced
the 7-dehydrocholesterol in the skin. In cholecalciferol from sunlight, it is hydroxylated
D vitamins, when administered in to 25- OH-cholecalciferol.
ements, could be considered The 25-hydroxylated product is then
therapy. When photochemically synthe- ported to the where it is hydroxylated a
-1
specific binding protein formed in the skin forming the active
ter is transported
e it attaches to a
the mucosa cell
Vitamins

poietic cells, and (20). Like the retinoic


acid receptors, the vitamin D receptor is a nu-
clear receptor to the steroid hor-
mone superfamily of nuclear receptors, which
includes receptors for estrogen,
coids, hormones, and retinoic acid.
There are at least 50 genes that respond to
Ergosterol hydroxylated calciferols regulating calcium
release and uptake and cell division.

I
Calcium Regulation. There are at
least three hormones that regulate calcium
metabolism, parathyroid
and Bone is the principal calcium
reservoir and is a dynamic tissue, with cal-
cium being released and deposited. New
calcium comes from our diet, and excessserum
calcium is excreted through the In
response to low serum calcium levels, PTH
stimulates the hydroxylation of
leading to formation of calcium transport pro-
tein and activation of osteoclast cells required
to release calcium from bone. PTH also inhib-
its calcium excretion by the In con-
trast, calcitonin (produced in the thyroid
Ergocalciferol (Vitamin gland) acts when serum calcium levels are
high. It promotes the deposition of calcium
Figure 8.11. Formation of ergocalciferol from into bone by osteoblast cells and excretion of
ergosterol. calcium by the
Rickets in infants and children and
and possibly osteoporosis,in adults is
to synthesize a calcium transport protein. The caused by a deficiency of D vitamins. Today
final product can be considered a most deficiencies are caused by a lack of sun-
kidney hormone that regulates calcium in- light or restricted diet. The lack of sunlight
take. Finally, is oxidized to inac- may be caused by living in northern latitudes.
tive calcitroic acid that is excreted through the
The latter also can be affected by the amount
The metabolite may be
of skin pigmentation (21-23). A strict vegetar-
part of the degradation process for
that is not transported to the kidney, but it ian diet cholecalciferol-fortified dairy
also can elevate serum calcium levels Pa- products or fatty fish, particularly in children,
tients with kidney failure can experience vita- may also result in rachitic lesions in the bone
min D-resistant rickets. Because they cannot (24,251.Mechanistically,rickets and
carry out the final step, are similar and are characterized by bone
is prescribed for their softening. Normal bone growth and mainte-
hormone replacement therapy. nance require that the osteoblast cells lay cal-
cium onto a cartilage matrix.
3.2.3 Biochemical Function. func- A deficiency of D vitamins results in a lack of
tion is complex and, with the exception of cal- mixed calcium salt available to the osteoblast
cium transport from the intestinal tract, is cells. In infants and children, the cartilage
poorly understood. Specific vitamin D recep- continues to grow. Cartilage, being soft, can-
tors are found in 30 different tissues not support the child's weight, leading to the
including bone, intestine, prostate, typical bowlegs seen in a rachitic child. An
3 Vitamins

(Kidney) (Kidney)

HO

(Calcitrol)
I
!
6 (Intestine) (Liver) (Liver kidney)

Variety of hydroxylated
and carboxylic acid products
(Ref 17)

HO
Calcitroic acid

8.12. Metabc o f D vitamins.

adult also will have bone deformations, partic- the lack of The result is in- .
ularly in the pelvic area, because the bones creased osteoclast activity, leading to loss
support the heavy upper torso. of calcium from the patient's bones, further
Osteoporosis is a disease. It can be resulting in hypercalcemia and either
thought of as osteoclast cells removing calcium or osteoporosis. To overcome these
quickly that osteoblast cells can lay complications,two synthetic ergocalciferolan-
down. The result is porous, brittle bones alogs (Fig. 8.13) are indicated for secondary
that break easily. At one time some- hyperparathyroidism associated with chronic
times was to decrease the release of renal failure. Note that both compounds con-
osteoclast cells. In tain the hydroxy group at position 1, the posi-
and npact exercise, tion at which the kidney carries out its
is droxylation to produce the
being released from product. Doxercalciferol is
the gocalciferoland, in the liver, is hydroxylated to
3.2.3.2 Vitamin Analogs Used in Chronic active (the ergocalciferolanalog of
Failure. Because is calcitriol). It is not clear why doxercalciferol is
renal leads to a more selective than calcitriol. In contrast,
none a nd .vitamin is the 19-normethyl analog of
t rickets. The solution is prescribing produced from
(generic name: and requires nofurther reactions.
I). Nevertheless, these patients can 3.2.3.3 Cell Division. The role of
hyperparathyroidism caused by the D vitamins in regulating cell division is under
oid gland attempting to compensate for active investigation. There are many reports
Vitamins

OH

Doxercalciferol (HectoralTM) Calcipotriene


analogindicated for psoriasis.

explain how vitamin D may exert its protec-


tive effect against cancer of the colon
In contrast with other vitamins that are
associated with reducing cancer risk and have
minimal adverse reactions in high doses, such
as a-tocopherol and ascorbic acid, taking
larger doses of Dvitamins can lead to clinically
significant hypercalcemia. Therefore, the
challenge is to develop compounds that not
only are selective for receptors involved with
controlling cell division but also activate
calcium transport leading to hypercalcemia.
The initial analog on the market is
Paricalcitol riene, which is indicated for psoriasis, a
malignant proliferation of cells (Fig. 8.14). Its
use is limited to topical application. When ad-
Ergocalciferol analogs indicated for
chronic renal failure.
ministered internally, hypercalcemia can re-
sult. Attempts have been made at pulse dosing
of to maximize inhibition of cell
that indicate that vitamin D a division with minimal calcemic activity (28).
role. Populations in with Most of the calciferol analogs are based on
higher to sunlight have lower inci- modifications of the side-chain.
dence of prostate, breast, and colon cancers (26). Modifications of the A-ring include 19-nor
In the intestine, the vitamin D receptor methylene and 3-nor analogs with
also functions as a receptor for lithocholic and without the moiety. The la-
acid, a bile acid produced by the action of in- hydroxy-24-ethyl cholecalciferol analog (Fig.
testinal bacteria on endogenously produced 8.15) was less calcemic in mice and inhibited
chenocholic acid. Lithocholic acid is the development of preneoplastic lesions in
toxic and may be a carcinogen. In the intes- mammary glands (29). Unsaturation at posi-
tine, vitamin D receptors, activated by vita- tion 16 (Fig. 8.16) provides modest
min D and possibly lithocholic acid, induce erative effects on prostate cancer cells with
both liver and intestine P450 3A little hypercalcemia A series of
oxidase This enzyme metabolizes propyl-cholecalciferol analogs (Figs. 8.17 and
lithocholic acid to inactive hydroxylated 8.18) showed good activity against human
forms. The process of inducing 3A might prostate, breast, and myeloid leukemia cell
ment. It is stabilized with antioxidants and
protective coatings.

3.2.5 Hypervitaminosis D. Think of a vita-


min D overdose in the same way as an over-
supply of any hormone. The role of the
hormone is exaggerated or magnified.
pervitaminosis D causes increased absorp-
tion of calcium and phosphorous follows
Ca), leading to calcification of the tissues,
vomiting, kidney damage, and so forth. It
can be the most serious of the
-(OH)-24-ethyl-cholecalciferol oses. The reports that D vitamins inhibit
proliferation of tissue and may protect
8.15. D,." against certain cancers could cause the
lic to overdose with this vitamin. The
lines The most
the 19-nor methylene analogs, independent of
whether the side-chain had ethylene or acety-
lene unsaturation. Modification of the side 3.2.6 Dietary Reference Intakes. There is
chain with a 25 keto or or NOH,
additional

tively), produced analogs as antiproliferative

were less calcemic (32). the diverse population of the United States
3.2.4 Dosage Forms. The commercial means that of color need of
vitamin from fortified relative those
or ergosterol under con- whose ancestors came from
lled conditions. The final yield is about
.
ough more stable than vitamin A, D Infants (0-12 months) 5 (200
ns are sensitive to oxygen and tend to Children (1-8years) 5 (200
inactive isomers in the Boys (9-18 years) 5 (200
ace metals, which can cause Girls (9-18 years) 5 (200
lating a Men years) 5 (200
Women (19-50 years) 5 (200
Men years) (400
Women years) 10 (400
Men years) 15 (600
Women years) 15 (600
Pregnancy 5 (200
Lactation 5 (200

Infants 25 (1000
Children (1-18 years) 50 (2000
Adults (over 19 years) 50 (2000
Pregnancy 50 (2000
Lactation 50 (2000
1 6-ene
3.2.7 Drug Interactions. Phenobarbital and
8.16. 16-ene-23-yne analogs. possibly other used in
Vitamins

lepsy induce liver hydroxylation, leading to mals not being able to produce offspring. These
subsequent formation of the inactive end same rats seemed normal in all other respects
products. As long as the epileptic child re- including physical growth. The condition could
ceives a normal amount of fortified milk, there be corrected by addition of lettuce, whole wheat,
is no problem with this interaction. and cereal grains, with the best source being
wheat germ followed by vegetable oils. Think of
3.3 Vitamin E Family (Tocopherols
the tocopherols and tocotrienols (Table 8.3) as
and Tocotrienols) (33)
nature's antioxidants. Most of the vitamin activ-
This vitamin group was discovered in rat feed- ity is found in a-tocopherol. "Tocopherol"
ing experiments, which resulted in these ani- means child-bearingalcohol.
Vitamins

mixture or the natural RRR-a-tocopherol. All


of the tocopherols found in food have the R
configuration at position 2. The synthetic
form of the vitamin is a mixture of all eight
stereo isomers (now referred to as
copherol rather than Be-
cause there is both general and stereospecific
antioxidant activity, the RDA tables state that
the activity ratio of to
a-tocopherol is 1 to 1.36 (Table 8.4) (34). All
isomers are antioxidants and probably do pro-
vide general antioxidant protection internally
or in On the other hand, evidence points
to the RRR isomer as being specific for a vari-
ety of reductase systems, possibly involving
selenium and glutathione
The "Relative Biological Activity" in Table 8.3
is based on a rat assay, as
are the conversion factors in Table 8.4.

3.3.2 Uptake and Metabolism. Like the


retinol esters, tocopherol, both esterified and
nonesterified, requires bile salts to become
part of the mixed micelles containing the di-
etary lipids. They are absorbed into the
sal cell by passive diffusion. The tocopherols
follow the dietary lipids onto the
crons. Because the latter first enter the lym-
8.18. 23-E-ene-20-cyclopropyl analogs. phatic system before the circulatory system,
the tocopherols do not go directly to the liver.
3.3.1 Chemistry. The vitamin E family Instead, the chylomicrons are distributed
of tocopherols and tocotrienols. There throughout the body, and some of the toco-
as been considerable debate as to whether pherols enter the adipose tissue with the fatty
RRR isomer is the only biologically active acids that were also being transported on the
of the vitamin. The vitamin of commerce chylomicrons. The chylomicron remnants fi-
either as a racemic synthetic nally reach the liver. The remaining tocoph-
erols leave the liver on the very low density
lipoproteins which become the low
density lipoproteins In other words, to-
copherols will be found wherever there is a sig-
nificant amount of lipid material, including the
high density lipoproteins There is no
specific organ where the tocopherolsare stored.
Consistent with antioxidant model, the RDA is
based on the polyunsaturatedfatty acid
consumption. The implication is that, if in-
creased PUF'Aintake is recommended,the
for tocopherol should be increased.
There is increasing evidence that the RRR
stereoisomer is preferentially transferred in
8.19. Keto and oxime cholecalciferol the liver onto the lipid transport proteins, but
it is not absolute. This could explain why
382 Vitamins

Table 8.3 Relative Biological Activities of Tocopherols and Tocotrienolsa

Tocopherols Relative biological

Tocotrienols Relative Biological


0.3
0.05
Inactive
Inactive
"Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids, Food and Nutrition Board, Institute of
Medicine, National Academy Press, 2000, p. 193.
fetal reabsorption assay.

Table 8.4 Factors for Converting International Units of Vitamin E to a-Tocopherol


to Meet Recommended
Molar a-Tocopherol
USP conversion factors conversion conversion
factors factors

Synthetic vitamin E and estersc


acetate 1.00 1.00 2.12 0.45
succinate 0.89 1.12 2.12 0.45
1.10 0.91 2.12 0.45
Natural vitamin E and estersd
d-a-Tocopherol Acetate 1.36 0.74 1.56 0.67
d-a-Tocopherol Succinate 1.21 0.83 1.56 0.67
d-a-Tocopherol 1.49 0.67 1.56 0.67
"Dietary Reference Intakes for Vitamin Vitamin E, Selenium and Carotenoids, Food and Nutrition Board, Institute of
Medicine, National Academy Press, 2000, p. 192.
United States Pharmacopeia has defined one IU as 1 mg of all racemic a-tocopherol acetate based on a 1940s
rat fetal resorption assay.
"Synthetic vitamin E supplements labeled as can consist of eight possible isomers RSR-, RRS-,
RSS-, SSS-,SRS-,
refers to the RRR-isomer, the only one found naturally in foods, and the other two R stereoisomers
RSR-, and
Chromanoxyl radical Chromanol radical Chromanoneda radical
Figure 8.20. Resonance-stabilized tocopherol radicals.

is more active in but hepatic tocopherol transfer preference


the other isomers are also active. for the RRR as the explanation for
the partial preference.
3.3.3 Biochemical Function. The best way
to describe tocopherol's role is that of a 3.3.4 Deficiencies. The current model for
soluble antioxidant. It protects unsaturated lip- the cause of vitamin E deficiencies points to
ids from oxygen-induced peroxide formation. malabsorption of lipids. Thus, there may be
evidence for both free-radicalone-elec- malabsorption of other lipid-soluble vitamins.
(Fig. 8.20) and two-electron Little is known regarding the
chemistry (Fig. 8.21) of the tocopherols. Part of the reason for
The glutathione system may this may be attributed to lack of a specific
be part of the system that regenerates reduced age organ for the vitamin.
a-tocopherol. At one time it was thought that Correlating human medical conditions
the preference for the stereoisomers the biochemical role of the tocopherols is
that the was part of a difficult because of the lack of correlations be-
system, possibly as a coen- tween deficiency diseases seen in animals rel-
So far that role for has not ative to what is seen in humans. Deficiency
been found. The current evidence points to the diseases seen in animals include reversible

Reduced Tocopherol (hydroquinone)

Figure 8.21. Tocopherol


Oxidized Tocopherol (quinone)
Vitamins

8.22. a-Tocopherol
age forms. = acetate, (sodium salt)

productive failure in female rats; irreversible commercially (Fig. the oil-soluble ace-
degeneration of rat testicular tissue leading to tate and water-soluble hemisuccinate. The lat-
male sterility; nutritional muscular dystro- ter is commonly found in dry dosage forms
phies in monkeys, rabbits, guinea pigs, lambs, requiring a powder. Oxidation to
calves, turkeys, and chicks; and an anemia in the quinone form is blocked by esterifying the
monkeys. Vitamin E does not treat human free phenolic hydroquinone.
muscular dystrophy nor the various causes
3.3.7 Dietary Reference Intakes (based on
preventing a couple from conceiving a child or
d-a-Tocopherol).
inability of pregnant women to go to full term.
What is seen in humans is a partially revers-
ible set of neurological problems and Infants months)
anemia in premature infants. Because of EAR
poor placental transfer, newborns have little Children (1-8 years) 5-6 mglday
of the vitamin. Human milk contains Boys (9-18 years) 9-12
cow's milk contains less. Girls (9-18years) 9-12
There are numerous studies evaluating the Men (19-50 years) 12 mglday
possible role of tocopherols in preventing Women (19-50 years) 12
and/or treating cardiovascular disease, malig- Men (51-70+ years) 12
nancies, diabetes mellitus, cataracts, immune Women (51-70+ years) 12
function, and Alzheimer's Disease. In all of Pregnancy 12 mglday
these conditions, there is evidence of Lactation 16 mglday
ical formation or general oxidation mecha- RDA
nisms as part of the disease process. The evi- Children (1-8years) 6-7
dence for taking supplements in addition to Boys (9-18 years) 11-15 mglday
proper diet is mixed (36, 37). Girls (9-19 years) 11-15 mglday
Men (19-50 years) 15 mglday
Women (19-50 years) 15
3.3.5 Hypervitaminosis E. This is a rela- 15
Men (51-70+ years)
tively safe vitamin. Toxicities have been re- Women (51-70+ years) 15 mglday
ported involving chronic administration of Pregnancy 15 mglday
300-1200 mg per day. The can be Lactation 19
very serious and include thrombophlebitis,
pulmonary embolism, hypertension, breast Infants Not established
development in men and children, severe fa- (Do not give
tigue, and nonmalignant breast tumors. Nev- supplements;
ertheless, the UL to RDA ratio is about 66 to1 use only food
for adults, making it a very safe vitamin. and formula for
sources.)
3.3.6 Dosage Forms. The tocopherols, be- Children 200 (1-3
ing antioxidants, are very sensitive to oxygen. years) up to 600
Sensitivity to light is another problem.
There are two provitamin esters that are used (9-13 years)
3 Vitamins

Phytonadione (Vitamin phylloquinone)

Removal of the side chain

Menadione

Addition of the

Figure 8.23. Formation of menoquinone form


Vitamin (n = 4; of vitamin K.

Adolescents 800 receive in significant amounts from their in-


Adults years) testinal bacterial, and there is some question
Pregnancy 800-1000 regarding this commonly held assumption.
Lactation 800-1000 Because of this source, it has been very diffi-
cult to establish a recommended daily allow-
Vitamin K Family (38) ance. An estimated safe intake was estab-
K was discovered by accident by lished for this vitamin for the first time with
scientists who, using a special fat-free diet the 1989 RDA tables. With the release of the
to whether chickens Dietary Reference Intakes, there is an ade-
cholesterol, observed that the animals quate intake, but no RDA.
a condition
by a prolonged clotting time. The 3.4.1 Chemistry. There are two series for
ion could be cured by an organic factor found this vitamin (Fig. 8.23). The vitamin series
fresh cabbage, ether extract of alfalfa, is mostly obtained from green plants, whereas
fish meal, cereals, or hog livers. It was the series is the product of bacteria. The
Vitamin K for koagulation vitamin. active is in the series. Menadione
may be the only vitamin that humans has sometimes been referred to as vitamin
Vitamins

I
Several
steps
I
OH 0
Vitamin Vitamin K Base I

I
0 0
Vitamin Vitamin K oxide

Figure 8.24. Outline of vitamin K in of glutamic acid.

The common commercial form is called 3.4.3 Vitamin K Biochemistry and Defi-
tonadione in the United States Pharmacopeia ciency. Deficiencies of this vitamin lead to se-
and phylloquinone by Chemical Abstracts. rious hemorrhaging. The vitamin is required
for formation of proteins that complex cal-
3.4.2 Vitamin K Uptake and Metabo- cium. This is done by functioning as a coen-
lism. Dietary vitamin and the pharmaceu- in the y-carboxylation of glutamic acid
tical form, phytonadione or vitamin (Fig. 8.24). Vitamin is reduced to the
must be converted to the series known as droquinone. After several steps, a complex ox-
menoquinones. The most common of these is idation occurs, resulting in the "vitamin K
menoquinone-4 or This conversion to base" that is an integral part of the
the series occurs in the liver and possibly step. In a key step, the K oxide is
the intestinal flora. It involves removing the reduced to the original vitamin It is this
chain producing the intermediate final reduction that is inhibited by the
adione. Menadione sometimes is prescribed din anticoagulants widely used by patients
when there is impaired uptake of lipids from susceptible to stroke, pulmonary embolism,
the intestine. There is little storage reserve in phlebitis, and coronary thrombosis. This in-
the liver, and a deficiency can result when di- teraction between the coumadin anticoagu-
etary intake of vitamin K is restricted or ab- lants and the regeneration of vitamin is the
sorption is impaired. reason that patients on coumadin must moni-
Dietary vitamin K and supplements are tor their vitamin K intake both from vitamin
processed similarly as the other supplements and diet. This usually is done by
ble vitamins. Bile salts are required for emul- regularly scheduled determinations of
sification and formation of mixed micelles. thrombin time.
They travel to the liver on chylomicronsalong The carboxylation reaction is required for
with vitamins A and E. production of several clotting proteins
ingprothrombin, protein C, protein S, and fac- termination of prothrombin time is ordered by
tors VII, and X. It is also required for the surgeon to determine whether menadione
of osteocalcin, an important or phytonadione is indicated.
d in the matrix of The third cause is hemorrhagic disease of
ne and required for proper deposition of the newborn. Infants are born with a sterile
um onto bone. This latter finding has led to intestinal tract. Until the flora are estab-
everal studies to determine whether patients lished, the infant will have to get along with
d coumadin anticoagulants are at the vitamin K they received from the mother.
risk for osteoporosis and fractures In the past an infant might die from hemor-
All of these studies indicate that rhaging. Most states require that each new-
born receive an injection of phytonadione.
supplementation might be beneficial
Menadione injection is not given because it
of osteoporosis. If vitamin
can cause a hemolytic anemia in the newborn.
osteoporosis, then it would
patients on anticoagulant therapy 3.4.5 Hypervitaminosis K. Although it is
be at increased risk for bone fractures. possible to overdose with this vitamin, the fact
e indication of this, but it is not that it is available only over the counter in
evertheless, some calcium small doses in multivitamin preparations has
both vitamins D and K added to resulted in little knowledge of any toxicities.
Toxicities do not appear in animals adminis-
tered large doses. It is known that excess in-
3.4.4 Causes of Vitamin K Deficiency. take of the vitamin does not promote clot for-
ly is a vitamin K deficiency caused by in- mation. There is no Tolerable Upper Intake
cient diet. It more likely is attributable to Level.
n. At one time, multivita-
supplements rarely contained vitamin K. 3.4.6 Dietary Reference Intakes.
It is now routinely found in these products.
K deficiency include Infants 2-2.5
ctive jaundice (now uncommon),loss of Children (1-8years) 30-55
for intestinal Boys and Girls (9-18 years) 60-75 ,
gic disease of the newborn. Men 120
ed by obstructive jaundice Women
kage of the bile duct, usu- Pregnancy 75-90
from cholelithiasis, preventing the release Lactation 75-90
bile into the intestinal tract for
3.5 Thiamine (Vitamin (43)

years ofconstant research, the vitamin


e prescribed because it preventative of the disease beri-beri has been iso-
s not require micelle formation, given that lated, its chemical constitution determined and
through the mucosa into the vitamin itself synthesized at a cost far lower
he liver. than that of recovering it from
American, February 1938; reprinted in 12
injections of February
of the intestinal This quote summarizes the debate between
undergo 1-2 weeks' those who believedthat beriberi wascaused by
ce the level of an infectious agent vs. those who promoted
ient did not eat proper diet. Some of the early researchers os-
cillated between the two theories. About 1912
ake of dietary there were enough definitive feeding experi-
K and vitamin from the intestinal ments in humans to conclude that beriberi's
could result in a vitamin K deficiency. origin was dietary (44).
Vitamins

Thiamine Mononitrate

Thiamine HCI
(ThiamineChloride HCI)

Thiamine
kinase
AMP

Figure 8.25. Commercial


forms of thiamine and for-
of thiamine
phosphate. Thiamine Pyrophosphate

The vitamin B complex, of which thiamine of an amine on the py-


is considered the first one discovered and char- amine and a chloride on the thiazole
acterized, generally includes the group of wa- quaternary Thiamine nitrate is cor-
vitamins found in polishings, named in that the anion is found
bean yeast, and liver. There are no on the quaternary nitrogen, and the
chemical relationships in the B complex. The dine amine is not Once the vita-
is very confusing. The common min the acidic stomach, it will exist as
name implied something about the the chloride salt.
chemical nature of the vitamin. Even the con- hydrochlorideis very watersoluble
cept of water-soluble is somewhat misleading, (1 It is also very hygroscopic, makingit
that some of the vitamins in this group difficult to use in dry is
would be soluble by most commonly used in and injectable
standards. The one thing the tions. nitrate is sufficiently sol-
B complex vitamins have in common is that uble (1 that it can be used in liquid
nearly all function either as a coenzyme or a because the are less than 2
component of a coenzyme. mg per day. Because it is it is
commonly used in dry dosage forms.
3.5.1 Chemistry. Thiamine consists of a
pyrimidinejoined to a thiazole ring by a 3.5.2 Uptake and Metabolism. A saturable
ylene bridge (Fig.8.25). The thiazole nitrogen active transport system in the jejunum pro-
is a quaternary with a positive vides efficient uptake of the vitamin into the
charge. There are two commercial salts. Thia- intestinal mucosa cell. Thiamine in the
mine is, in reality, thiamine intestinal mucosa cell a
chloride hydrochloride. It is a double salt, from the ATP to the alcohol at
of the thiazole ring, forming thiamine cal literature and were called beriberi, a Japa-
pyrophosphate (Fig. 8.25). The latter nese term. Sailors in the Japanese navy
product is the coenzyme form of the vitamin. experienced thiamine deficiencies when fed
There is some evidence that this rice in which the polishings had been removed
is the rate-limiting step and controls the to prevent mold growth. This is somewhat
absorption of the vitamin. The coenzyme is analogous to removing the germ from wheat
transported to the tissues where needed. to prolong the shelf life of flour-containing
Thiamine pyrophosphate has two impor- foods. There are two forms of beriberi, wet and
tant coenzyme roles, both of which focus dry. Wet beriberi is characterized by edema
mostly on carbohydrate metabolism (Figs. and enlarged heart. Dry beriberi is more neu-
8.26 and 8.27). The active portion of the coen- rological and can include muscle wasting.
zyme is the thiazole ring. The first step in the
Assuming a reasonably balanced diet, most
oxidative decarboxylation of a-keto acids re-
thiamine deficiencies today are caused by
quires TPP. The two most common examples
are pyruvate and a-ketoglutarate, oxidatively chronic alcoholism. Alcohol reduces the active
decarboxyatedto acetyl and succinyl transport of the vitamin (45). This form of
respectively. The same reaction is found in the thiamine deficiency is called
metabolism of the branched-chain amino ac- koff syndrome. It is common for emergency
idsvaline, isoleucine, and methionine. medical personnel to add thiamine to the in-
In all cases, TPP is a coenzyme in a travenous solution being administered to a co-
multienzyme complex, consisting of matose patient suspected of experiencingsub-
TPP, lipoic acid, coenzyme A, FAD, and NAD. stance abuse.
Note the number of vitamins required for the 3.5.4 Hypervitaminosis Thiamine. The vi-
oxidative decarboxylation of a-keto acids: thi- tamin is considered very safe. There are no
amine (TPP), pantothenic acid (coenzyme A),
Tolerable Upper Intake Levels. Possibly the
riboflavin (FAD),and niacin
rate-limiting phosphorylation step in the in-
is also the coenzyme in the
lase reaction (Fig. 8.27) found in the pentose testinal mucosa reduces the risk of toxicity.
phosphate pathway that interconverts The percentage of thiamine absorbed de-
oses, pentoses, tetroses, and trioses. This reac- creases as the dose increases.
tion removes carbons 1 and 2 of a ketose and
transfers them to an acceptor aldose. Exam- 3.5.5 Dietary Reference Intakes.
plesinclude TPP transferring carbons1and 2
of to ribose-5-P, producing Infants
eraldehyde-3-P (5 carbons minus 2 carbons) EAR
and sedoheptulose-7-P (5 carbons plus 2 car- Children (1-13 years)
bons).This reaction is reversible. A second re- Males (14-18 years) 1.0
versible reaction has TPP transferring car- Females (14-18 years) 0.9
bons 1 and 2 of xylulose-5-P to erythrose-4-P, Men (19-50+ years) 1.0
producing fructose-6-P (4 carbons plus 2 car- Women + years) 0.9
bons) and glyceraldehyde-3-P (5 carbons Pregnancy 1.2
Lactation 1.2
The dietary reference intakes for thiamine RDA
are dependent on carbohydrate consumption. Children (1-13years) 0.5-0.9
This is because (1)most pyruvate comes from Males (14-18 years) 1.2
aerobic glycolysis, (2)much of the Females (14-18 years) 1.0
a-ketoglutarate originates from carbo- Men (19-50+ years) 1.2
hydrate sources, and (3)the transketolase re- Women (19-50+ years) 1.1
action uses carbohydrates as substrates. Pregnancy 1.4
Lactation 1.5
3.5.3 Thiamine Deficiencies. Thiamine de-
ficiencies are reported in the very early None reported
Vitamins

3.6 Riboflavin (Vitamin B,) (46) conversion of folic acid and pyridoxine to their
active forms, it is surprising that riboflavin
Shortly after the discovery of thiamine from deficiency does not produce a characteristic
yeast concentrates, the presence of a second set of symptoms. One of the reasons may be
nutritional factor in such materials was sug- that it is rare to see a patient who is solely
gested. This second factor was also reported to deficient in riboflavin.
have a pellagra-preventative activity because
it alleviated a deficiency-induced dermatitis in 3.6.5 Riboflavin. The com-
rats. It was called vitamin in England and bination of regulated active transport and con-
vitamin G in the United States. version to the coenzyme forms prevents
pervitaminosis problems with this vitamin.
3.6.1 Chemistry (Fig. 8.28). Riboflavin has Toxicities from the water-soluble riboflavin
a characteristicflavin ringsystem, which gives phosphate have not been reported. There are
it unique spectroscopicand instability proper- no Tolerable Upper Intake Levels.
ties. There are two commercial forms. Ribofla-
vin itself is poorly water soluble (1 3.6.6 Dietary Reference Intakes.
and is limited to oral dry dosage forms.
Riboflavin phosphate, as the sodium salt, is
very water soluble at 100 and is widely Infants 0.3-0.4 mglday
used in dry and liquid dosage forms. EAR
Children (1-13 years) 0.4-0.8 mglday
Males (14-19 years) 1.1 mglday
3.6.2 Riboflavin Uptake and Chemistry (Fig. Females years) 0.9
8.28). Most dietary riboflavin is eaten as the Men (19-70+ years) 1.1
FAD or FMN coenzymes. Intestinal Women (19-70+ years) 0.9 mglday
phatases and phosphatases produce free ribo- Pregnancy 1.2 mglday
flavin, which is actively transported in the Lactation 1.3 mglday
proximal area of the small intestine into sys- RDA
temic circulation. Because of its poor water Children (1-13 years) 0.5-0.9 mglday
solubility, it is transported on albumin and Males (14-19 years) 1.3
immunoglobulin proteins. Conversion to the Females (14-19 years) 1.0 mglday .
coenzyme forms occurs inside the cells that Men (19-70+ years) 1.3 mglday
need these coenzymes. Women (19-70+ years) 1.1 mglday
Pregnancy 1.4
3.6.3 Metabolic Role. Riboflavin coen- Lactation 1.6
zymes are required for most oxidations of
bon-carbon bonds (Fig. 8.29). Examples in- None reported
clude the oxidation of succinyl to
fumarate in the cycle and introduction 3.7 Niacin (Nicotinic
of in of fatty ac- (Nicotinamide) (47)
ids. Riboflavin is also required for the metab-
olism of other vitamins, including the reduc- The history of niacin revolved around trying
tion of tetrahydrofolate to to find a way to prevent and cure pellegra, the
5-methyl tetrahydrofolate (Fig. and late-stage deficiency disease caused by a niacin
terconversion of pyridoxine-pyridoxal phos- deficiency. Pellagra has been a serious nutri-
phate-pyridoxamine (Fig. 8.33). Because tional disorder in the United States, mostly in
that use FAD or FMN as the the southeast. Two thousand deaths from pel-
coenzyme constitute a two-step process, some lagra were reported in 1941. This is ironic be-
flavin coenzyme systems contain more than cause nicotinic acid, later known as niacin,
one FAD or FMN. was first reported during the structure eluci-
dation of the alkaloid nicotine.
3.6.4 Riboflavin Deficiency. With ribofla- Like some of the other deficiency diseases,
vin's central role in energy metabolism and there was disagreement between those who
Vitamins

mins. Structurally, it is
acid (Fig. 8.30). Strictly speaking, it is nones-
sential because the essential amino acid tryp-
tophan is a source (Fig. 8.31) (48). The
route does not produce "free" niacin by
decarboxylation of acid. In a com-
plex reaction, quinolinic acid loses the 2-car-
FAD or FMN group and adds to
(oxidized) form mononucleotide (Figs. 8.30
and 8.31) Niacin and niacinamide, in
pharmaceutical dosage forms, undergo a sim-
ilar reaction. Most vitamin prod-
ucts contain niacinamide because niacin can
cause a distracting vasodilation that leads to
flushing in the face and scalp.
The two commercial forms of the vitamin,
niacin and niacinamide, are rapidly absorbed
from both the stomach and intestine. As the
dose increases, absorption decreases. It is not
clear whether there is a feedback mechanism
operating or the transport system becomes
or saturated. Conversion to the coenzyme forms
(semiquinone) occurs in the cells where NAD and NADP are
needed.
NAD is the primary coenzyme required for
of carbon-oxygen bonds
and is required for oxidative catabolism
colysis, cycle). NADP is the
coenzyme in biosynthetic routes (fatty acid
and cholesterol synthesis) and be part of
reactions involving both
carbon-oxygen and carbon-carbon bonds.
The active part of the coenzyme is the
dine ring (Fig. 8.32). When the substrate is
I labeled with deuterium, it has been shown
H
that NAD systems can be categorized by the
or deuterium ending up on the A or B face of the
(reduced)
ring. Examples of NAD
Figure 8.29. nases where the anion attaches to the
A face are isocitrate
lactate dehydrogenase, and
thought pellegra was caused by poor sanita- alcohol in-
tion vs. those who concluded it was a nutri- volving the B face include
tional disorder. Niacin deficiency, even today, glucose-6-phosphate
is found in economically poor areas. Even genase, glutamate and
when niacin was first isolated from foods, it aldehyde-&phosphate
was ignored because it did not cure beriberi.
3.7.2 Niacin Deficiency. Niacin deficiency,
3.7.1 Chemistry, Up- manifested as pellagra, is characterized by the
take and Metabolism. Niacin is structurally four Ds: dermatitis, diarrhea, depression, and
the simplest of the vitamins, but has some of death. The dermatitis is by a
the most complex biochemistry of the vita- pigmented rash developingon skin exposed to
3 Vitamins

Add

ZATP + 1.

+ PPI +

adenine R =H

Figure 8.30. Biosynthesis of from niacin and niacinamide.

heat. Changes to the gastrointestinal tract can meal by this process have a smaller incidenceof
lead to vomiting, constipation, or diarrhea. pellagra (53). At the same time it must be re-
Depression is one of the neurological symp- membered that is the extremeform of a
toms that also can include apathy, headache, niacin deficiency. The Dietary Reference In-
fatigue, and memory loss. takes for this vitamin use clinical chemistry
Deficiencies were common in populations says listed in Table 8.2 todetermine rather
whose main calorie source was corn (51, 52). than the first appearance of pellagra symptoms.
Zein is the main protein found in corn and it is
very low in both niacin and tryptophan. When 3.7.3 Hypervitaminosis Niacin. Niacin is
corn is ground with lime water, the small considered nontoxic, and there are no Tolera-
amounts of niacin and tryptophan become more ble Upper Intake Levels based on its use as a
bioavailable. Populations who consume corn vitamin. These refer only to niacin and niaci-
Vitamins

dioxygenase
H
Tryptophan Formylkynurenine

Kynurenine
formamidase

- Kynurenine
hydroxylase
(FAD dependent)
Kynurenine
Kynureninase

3-Hydroxyanthranilic non-
acid oxidase enzymatic

OH Amino-carboxymuconic acid
3-HydroxyanthranilicAcid semialdehyde

NAD

Figure 8.31. o f NAD f r o m tryptophan.

but not and niacin equiv- head area, caused by increased intercranial
(see next section). Large doses of niacin blood flow and hepatic complications. Niacin
and do have adverse reactions. had been used for syndrome to
These are sometimes seen with patients who treat the vasoconstriction seen with this dis-
are prescribed niacin in doses up to 2 g ease. Liver toxicities have been experiencedby
for hyperlipidemia, including both patients prescribed sustained-release niacin
lesterolemia and For products for (54, 55). The UL
the former, there is the desired decreased LDL to RDA ratio is 2, but the UL is the dose before
and increased HDL. Adverse reactions include adverse reactions are experienced. Vasodila-
from niacin, in the tion from niacin occurs close to its

0 0 0

or

I I
A face; NADH B face; NADH

8.32. Stereochemistry o f reduction.


3 Vitamins

3.7.4 Dietary Reference Intakes. Many of was realized tragically when the heat process
the DRI units are milligram niacin equiva- for an infant formula reduced the
lents These units take into account itiy of the vitamin. Children developed convul-
the fact that approximately 60 mg trypto- sive disorders. Before realizing that the prob-
phan produce 1 mg of niacin. For adult lem was caused by an induced pyridoxine
males, the RDA is between 960 mg of tryp- deficiency, it was thought a contaminant had
tophan and 16 mg of niacin, given that 960 been introduced. The vitamin is a coenzyme
mg of tryptophan is equivalent to 16 mg of for amino acid and glycogen metabolism.
niacin (56, 57).
3.8.1 Uptake and Metabolism. The vitamin
Infants (0-5 months) 2 mglday of family consists of pyridoxine, pyridoxal,
preformed pyridoxamine, pyridoxine phosphate,
niacin doxal phosphate and pyridoxamine
Infants (6-11 months) 4 mg phosphate (Fig.8.33). The commercial form is
EAR pyridoxine. Pyridoxal phosphate is the coen-
Children (1-13 years) 5-9 mg zyme form. It and pyridoxamine phosphate
Boys (14-18 years) 12 mg are from animal tissues. Pyridoxine is from
Girls (14-18 years) 11 mg plant tissues. All phosphorylated forms are
Men (19-70+ years) 12 mg hydrolyzed in the intestinal tract by
Women (19-70+ years) 11 mg tases before being absorbed passively. Conver-
Pregnancy 14 mg sion to the phosphorylated forms occurs in the
Lactation 13 mg liver. Notice that niacin and riboflavin
RDA (FMN, FAD) are required for interconversion
Children (1-13years) 6-12 mg among the vitamin family. The
Girls (14-19 years) 1.3 mg lated forms are transported to the cells where
Boys years) 16 mg needed. The major excretory product is 4-pyr-
Men (19-70+ years) 16 mg idoxic acid.
Women (19-70+ years) 14 mg
Pregnancy 18 mg 3.8.2 Pyridoxal Phosphate Biochemistry
Lactation 17 mg NEIday (58). Pyridoxal phosphate is required
UL for amino acid metabolism and reactions in-
Infants (0-12 months) Source of intake volving amino acids. PLP is covalently bound
should be to the apoenzyme through an enamine
formula and base) linkage between an
food only group of lysine and the aldehyde moiety of
Children (1-13years) 10-20 of PLP (Fig. 8.34). The most common of the
niacin PLP-catalyzed reactions are transaminations
Adolescents (14-18 30 mglday of (Fig. 8.35). One-half of transamination re-
niacin actions involve a-ketoglutarate as the accep-
Pregnancy (14-18 30 mglday of tor of the group forming glutamic acid.
niacin Alternatively, glutamic acid donates the
Pregnancy (19 years 35 mglday of amine group and an a-keto acid is the acceptor
and older) niacin forming a new amino acid. Examples include:
Lactation (14-18 30 mglday of a-amino acid + a-ketoglutarate a-keto
niacin acid + glutamic acid
Lactation (19 years and 35 mglday of a-amino acid reactant a-ketoacid product
older) niacin alanine
aspartate oxalacetate
3.8 Vitamin Family
Another PLP-catalyzedreaction is
This group was discovered in the 1930s during ylation of aminoacids (Fig. 8.35). These are part
feeding experiments on rats. Its importance of the biosynthesisof neurotransmitters,
Vitamins

4-Pyridoxic acid
(metabolite)

Oxidase

CHO I

Oxidase
Oxidase
FMN
N
4-Pyridoxic acid 4-Pyridoxic acid 4-Pyridoxic acid
(metabolite) (metabolite) (metabolite)

Phosphatase Phosphatase Phosphatase

CHO

FMN
Oxidase
Oxidase
N
4-Pyridoxic acid 4-Pyridoxic acid 4-Pyridoxic acid
(metabolite) (metabolite) (metabolite)

Figure 8.33. Interconversionsamong the vitamin family.


.

from histidine; serotonin from


tryptophan,dopamine, and
from (dopa)
0
(Fig. 8.36); and acid from
acid. Other reactions in which an amino
acid is the substrate include formation of
Enzyme acid in the of heme and
two reactions in biosynthesis from
(Fig. 8.52). Although not well un-
derstood, is for
catalyzed
phosphate.glycogenolysis producing

3.8.3 Vitamin Deficiency. There is no


N distinct deficiency syndrome, but a deficiency
P can be serious. What is observed is a
rheic dermatitis, microcytic anemia, and
convulsions. The be
enzyme. caused by decreased heme biosynthesis and
3 Vitamins

H
I I II
0
a-amino acid II a-keto acid
N
+
4
!

Pyridoxal P Aldimine
Pyridoxamine P

R-C-H
I
NH+
II
CH

Amine
Figure 8.35. Pyridoxine phosphate-catalyzed transamination and decarboxylation.

the convulsions by imbalances in neurotrans- the final reactions. The homocysteine model is
mitter again under the acid and
There is reason to conclude that sections.
deficiency contribute to arteriosclerosis.
There is a correlation between elevated 3.8.4 Vitamin-Drug Interactions (60). The
cysteine levels and incidence of two most clinically significant interactions are
disease (59). There is debate as to whether ho- phosphate with L-dopa or isoniacid.
contributes to the damage of cellson Examine Fig. 8.36 and note that dopa
the interior of blood vessel or whether boxylase requires PLP. This enzyme is found
is a marker of intensive cell and for- both centrally and peripherally. The latter in-
mation of replacement cells. Nevertheless, ad- cludes the intestinal mucosa. The precursor to
ministration of acid, and dopamine, L-dopa is indicated for the treat-
are being recommended along ment of Parkinson's disease. L-Dopa is pre-
with the two vitamins, scribed because little crosses the
and ascorbic acid for arteriosclerosis. blood-brain barrier relative to its precursor
is for two of the steps in the catabo- dopa. A patient with Parkinson's disease pre-
lism of homocysteine to succinyl (Fig.8.52). scribed L-dopa and who takes a sup-
Note Fig. 8.52 (bottom) that biotin and a co- plement with amounts of pyridoxine greater
of also are for than the RDA can experience an
Vitamins

peripheral but they do not reduce


the effectiveness of isoniazid.

3.8.5 Hypervitaminosis Pyridoxine. A cer-


tain mystique has built up around this vita-
min, resulting in individuals' overdosing
themselves commercial vitamin supple-
ments. Serious problems have
been seen in doses of 2-6 for 2-40
months Megadosing below 2 glday
seems safe, but all of this information is based
mostly on anecdotal reports. There is a Toler-
able Upper Intake Level, but the UL to RDA
ratio is a comfortable 50-60.

3.8.6 Dietary Reference Intakes.


Dihydroxyphenethylarnine (Dopamine)
(any form of vitamin
Ascorbate + Infants mglday
EAR (any form of
Dehydroascorbate + H20 Children (1-13 years) mglday
Males (14-19years) 1.1
Females (14-19years) 1.0 mglday
Men (19-50 years) 1.1
Men (51 years) 1.4
Women (19-50 years) 1.1mglday
Norepinephrine Women (51+ years) 1.3 mglday
1.6 mglday
Lactation 1.7
RDA (any form of vitamin
Children (1-13 years) 0.5-1.0 mglday
Males (14-19 years) 1.3 mglday
I Females (14-19years) 1.2 mglday
Men years) 1.3 mglday
Men years) 1.7 mglday
HO OH Women years) 1.3 mglday
Epinephrine (Epi) Women (51+ years) 1.5 mglday
Pregnancy 1.9
Figure 8.36. phosphate-catalyzed dopa Lactation 2.0 mglday
UL (as pyridoxine)
Children (1-13years) 30-60 mglday
crease in tremors. This is be- Adolescents (14-18years) 80 mglday
cause L-dopa will undergo decarboxylation in Adults years) 100 mglday
the intestinal mucosa and never reach the lo- Pregnancy (14-18years) 80 mglday
cations in the brain where it is converted to Pregnancy years) 100 mglday
the needed dopamine. Lactation (14-18 years) 80
Isoniazid is widely prescribed for tubercu- Lactation years) 100 mglday
losis. It can chemically react with pyridoxal
and phosphate, thus significantly re- 3.9 Pantothenic Acid (65)
ducing the availability of this coenzyme (Fig.
8.37) (61). Pyridoxine supplements commonly Pantothenic acid is essential and is a normal
are recommended to prevent isoniazid-caused component of our diet. There has been little
3 Vitamins

lsoniazid (INH) Pyridoxal P


Acid Hydrazide

8.37. Pyridoxal phosphate-isoniazid


interaction.

research done on this vitamin and, therefore, cosmeticsincluding creams and shampoos,
it has adequate intakes and no there is no evidence that is effective
as a vitamin topically. It apparently good
3.9.1 Chemistry, Uptake, and Metabolic emollient properties, but these have nothing to
Role. This vitamin, which can be considered a do its role.
derivative of is asymmetric (Fig. Pantothenic acid is a structural compo- .
8.38). The natural form has the configu- nent, but not the active site, of coenzyme A.
ration. The stereoisomer is inactive. The The acyl thiol esters form on the mercaptan
reduced alcohol form, pantothenol, is consid- moiety that from a cysteine (Fig.
ered as equally active as the parent acid. Many 8.39). The of coenzyme A occurs
of the multiple vitamin products use a syn- in the tissues requiring it. Because coenzyme
thetic, racemic This means that dou- A is required for nearly all transfers,
ble the amount of synthetic must be
synthesis takes place in nearly all cells.
used to equivalent active vitamin.
Dietary pantothenic acid is consumed as co-
enzyme A and the from coen- 3.9.2 Hypervitaminosis Pantothenic Acid.
zyme A's biosynthesis (Fig. 8.39). These are There have been no reports of and no
hydrolyzed to free pantothenic acid. Absorp- Tolerable Upper Intake Levels. Because its ac-
tion is by saturable, active transport. tive transport is saturable, excessive uptake is
Calcium pantothenate is commonly used in Also, this vitamin does not have the
dry dosage forms. It is moderately hygro- mystique that would prompt marketing "high
scopic, with a solubility of 1 and is potency" formulations.
unstable for autoclaving. Neither the parent
acid nor the sodium salt is com- 3.9.3 Dietary Reference Intakes. There are
monly used in dosage forms. too few studies to provide sufficient informa-
is reasonablystable tion to estimate Estimated Average Require-
and freely soluble and is used both in injectable ments (EAR)or Recommended Dietary Allow-
and oral dosage forms. Although widely used ances
Vitamins

0 OH
II I

Pantothenic acid

Sodium Pantothenate

1 2

Calcium Pantothenate

OH
I I
I
8.38. Forms of
thenic acid.

linkage to produce free biotin. Biotin is


Infants 1.7-1.8 actively transported through the
Children (1-13 years) 2 4 flora into the portal vein and to the liver where
Everyone else 5 it may be stored. It appears that adults may
Pregnancy 6 store several months of biotin. From the liver
Lactation 7 mglday it is transported to tissues where it is needed.
EAR 3.10.2 Chemistry. Biotin consists of two
None reported
5-membered rings cis-fused to each other that
RDA
can be drawn either as the keto (urea)or
None reported
form (Fig. 8.40). The enolic d-isomer is the
None reported active stereoisomer, but many times commer-
cial multivitamin products contain the syn-
3.10 Biotin (66) thetic racemic mixture. There is no activity
with the 1-stereoisomer.
Biotin (Fig. 8.40) is essential, a normal constit-
uent of the diet, and required for four 3.10.3 Metabolic Role. Biotin picks up
dependent carboxylation reactions. Eating carbon dioxide that has been activated by
raw egg white can induce a deficiency. combining with an ATP-donated phosphate,
producing the mixed anhydride of phos-
3.1 0.1 Uptake. In foods, most biotin is co- phoric and carbonic acids (Fig. 8.42). The
valently bound (Fig. 8.41) to the apoenzyme, biotin enolate receives the carbon dioxide,
where it is the coenzyme for carboxylation re- producing the keto carbon dioxide-releasing
actions. Intestinal enzymes hydrolyze the coenzyme.
H H
ATP ADP

OH \
Pantothenate
kinase

Pantothenic acid 4'-Phosphopantothenate


ATP + Cys ,
ADP + Pi
Phosphopantothenoylcysteine
synthetase

Phosphopantothenoylcysteine

2 ATP
1. Dephospho-CoApyrophosphorylase

2. Dephospho-CoA kinase
ADP +

H 0 0
H
\
I I
0

Coenzyme A

Figure 8.39. acid chemistry.

Enolic form Keto or ureido form Figure 8.40. Biotin.


404 Vitamins

cetate when there are largeamounts ofacetyl


entering the Krebs cycle.
2. Acetyl carboxylase (Fig. 8.44)
This reaction, found mostly in the
is the committed step in the synthesis
of fatty acids.
3. Propionyl carboxylase (Fig. 8.45)
Propionyl is the product from the
catabolism of valine, isoleucine,
Figure 8.41. Coenzyme form of biotin. nine, and odd-numbered fatty acids. The
carboxylation reaction, found in the mito-
chondria, produces methyl malonyl
There are four biotin-dependent The latter undergoes a cobalamin (vitamin
reactions, three of which are in the mito- BIZ)-catalyzed rearrangement, forming
chondria. They are: succinyl which is metabolized further
1. carboxylase (Fig. 8.43) in the Krebs cycle.
This reaction, which converts pyruvate to 4. carboxylase (Fig. 8.46)
is in the mitochondria and This mitochondria1 reaction permits
functions. First, it is the initial reac- the final steps in the catabolism of the
tion in gluconeogenesis to overcome the 14 branched-chain amino acid The fi-
energy barrier to form nal products, acetoacetate and acetyl
pyruvate. Second, this same reaction, either are oxidative metabolized to carbon
sometimes referred to as an anapleurotic re- dioxide and water or enter other reactions
action, ensures that there is adequate in lipid metabolism.

Bicarbonate

0 0

I
0- 0
Phosphoric-carbonicacid anhydride Enz

Figure 8.42. Biotin binding carbon dioxide.


3 Vitamins

Pyruvate ATP ADP +Pi Oxalacetate 8.43. Carboxylation of


carboxylase vate producing oxalacetate.

3.10.4 Biotin Deficiency. Relative to many 1 Acid (67)


of the vitamins, it is easy to induce a biotin
deficiency by feeding volunteers raw egg Because all vitamins are essential, it is diffi-
white. a basic protein found in egg cult to state that one vitamin is more impor-
white, forms salt linkages with acidic biotin tant than another. Nevertheless, folic acid,
and prevent its transport across the intestinal with its coenzyme role in purine biosynthesis,
barrier. Cooked egg white is not a problem. can be considered crucial for some of the cells'
Because biotin is found in the yolk, eating most fundamental biochemistry, cell division.
whole raw egg will not induce a deficiency. De- This vitamin is intimately tied to vitamin
ficiencies also were caused in patients on total (cobalamin), which has made estimating its
parenteral nutrition because biotin difficult. Also, conditions that can cause
was not included in the early formulations. a folic acid deficiency also can result in a vita-
Symptoms include dermatitis, loss of hair min deficiency.
color, and central neurological effects.
3.1 1 Chemistry. The commercial form of
3.10.5 Hypervitaminosis Biotin. None has the vitamin is folic acid (Fig. 8.47). It consists
been reported in humans and there are no Tol- of a pteridine ring attached to a
erable Upper Intake Levels. zoic acid that is attached to the a -min e of
glutamic acid. Two biosynthetic changes must
3.10.6 Dietary Reference Intakes. These
occur before it is active. First, it must be re-
have been difficult to determine. There has duced to tetrahydrofolate by dihydrofolate
been some speculation that humans might ob- ductase in a two-step reduction (Fig. 8.48).
tain part of their biotin requirements from the Notice that niacin is required for this reduc-
intestinalflora in the colon. The question that tion. Second, a polyglutamate chain must be
has not been adequately answered is whether attached to the of the parent
.
there is significant absorption of tamic acid (Fig. 8.47). The remaining linkages
duced biotin from the colon. of the polyglutamate chain are traditional
a-amino-a-carboxyl peptides.
5-6 The natural vitamin is made up of a family
Children (1-13 years) 8-20 of polyglutamates all connected to the initial
Adolescents (14-18years) glutamic acid at the previously described
Adults group. The length of this
Pregnancy chain varies with the source of the vi-
Lactation tamin, but lengths of 3, 5, and 7 amino acids
EAR are seen. The most common polyglutamate
None reported found in food is 5-methyltetrahydrofolate
RDA polyglutamate (Fig. 8.47).
None reported
3.11.2 Uptake. The dietary
None reported mates are cleaved to the monoglutamate

0 0
Biotin
8.44. Carboxylation of
ATP ADP + Pi Malonyl acetyl producing
Carboxylase
Vitamins

0
Biotin

ATP ADP + Pi Methyl Malonyl


Propionyl

8.45. o f propionyl producing methylmalonyl

min by a y-L-glutamylcarboxypeptidase, com- folate polyglutamate, produced by addition of


monly called conjugase. Folic acid is absorbed formic acid to tetrahydroformate
as the monoglutamate. Conjugase is found in mate. It is the coenzyme for two reactions in
the brush border of the intestine. Therefore, purine the synthesis of
chronic inflammatory conditions in the intes- formylglycine ribotide from glycine
tine lead to low conjugase activity, which can amide ribotide (GAR) and (2)the formation of
result in significant decreased folic acid ribotide
absorption. to formamidoimidazole carbxamide ribotide
The absorbed vitamin must be converted to (Fig. 8.50).
the coenzyme form. This requires adding back tetrahydroformate
a five- to seven-member glutamate chain and is the cyclic enamime formed from
commercial folic acid must undergo the two- formyl tetrahydroformate polyglutamate. It
step reduction to tetrahydrofolic acid. There also is formed from the catabolism of histidine
are two common abbreviations for the reduced and can be considered an intermediate be-
form, and THF. These reactionsapparently tween the 10-formyl compound and, upon re-
occur in a wide variety of tissues. The liver con- duction, tetrahydroformate
tains about a 3- to supply of the vita- polyglutamate. The latter is the coenzyme re-
min, presumably in the polyglutamate form. quired for the interconversion of serine and
glycine and the methylation of
Metabolic Roles. There are five acid forming acid (Figs. 8.49
forms of tetrahydrofolate polyglutamate, and 8.51). of the one-carbon units car-
some of which are coenzymes (Fig. 8.49). The ried on position 5 or 10 or bridge come
most highly oxidized is 10-formyl from serine.

0
II SCoA
C SCoA
I
Several steps I
CH carboxvlase .
..
C C
ATP + Pi

Acetoacetate
8.46. Role o f b i o t i n in catabolism.
Vitamins
I

p-aminobenzoate glutamate
Folic Acid (FA)

Figure 8.47. Common forms of folic acid methotrexate.

The most reduced coenzyme is 5-methyl The fifth tetrahydrofolate compound is


tetrahydrofolate polyglutamate. It is the 5-formyl THF (folinicacid, factor).
source of the methyl group added to This compound is not a coenzyme, but it can
teine regenerating methionine and tetrahy- be converted to any of the active coenzyme
drofolate ready to accept a one-carbon unit forms. It is administered after treatment with
from or serine. This last reaction is the dihydrofolate reductase inhibitor,
where folic acid and vitamin come to- trexate (Fig. as a form of rescue therapy.
gether (Figs. 8.49, 8.52, and 8.53). The impli- Because it already is in the reduced tetrahy-
cations of this reaction and how folic acid can drofolate form, it does not need dihydrofolate
mask pernicious anemia are discussed in the reductase to become an active coenzyme.
section on vitamin (cyanocobalamin).
Note that the formation of nor- 3.11.4 Folic Acid Deficiency. It is obvious
mally is not reversible. Tetrahydrofolate can that folic acid is a very important vitamin for
be regenerated only if there is adequate biosynthetic reactions, particularly those re-
methyl cobalamin coenzyme. quired for the biosynthesis of purines,

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