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Vitamin B complex
By Venom
You would not be able to even type ABC into your browser without
ATP. In fact, within a few seconds death would wrought its ugly
head had this source of energy ceased to be produced. Think
logically for a moment; if this complex molecule is of such
importance, then its optimization must be of prime significance if
one is to train at full capacity--enter the B-Complex. It is integral to
almost every step of cellular respiration (energy production). Can
you afford a deficiency in this area? The answer is a clear no. I
must warn you, however, the body’s ability to form energy is
indeed complex beyond the readers wildest imaginations. It will
therefore be no easy task to understand all the mechanisms
capable of enhancing it. Today, however, you will take one giant
Leap forward--that is a guarantee.
Vitamins
Vitamins can be defined as essential organic compounds required
in minuscule amounts (referred to as micronutrients). Vitamins
mainly function as catalysts for reactions within the body. They
contain no useful energy, but as catalysts, they serve as essential
links and regulators in metabolic reactions that release energy
from food. Vitamins also control the processes of tissue synthesis
and aid in protecting the integrity of the cells' plasma membrane;
they also assist growth, maintenance of health, metabolism and
much more. To refresh your memory, a catalyst is a substance
that allows a chemical reaction to occur using less energy and
less time than it would take under normal conditions. If these
catalysts are missing, as in a vitamin deficiency, normal bodily
functions can break down hindering athletic performance, and
rendering a person susceptible to disease [7].
Vitamin classification
Vitamins are classified as either fat-soluble or water-soluble. The
fat-soluble vitamins (vitamins that can mix with fat, but usually not
with water) are vitamins A, D, E, and K; the water-soluble vitamins
(can be dissolved/mixed in water) are vitamin C and the B-
complex vitamins (based on their common source distribution
and common functional relationships)[38]. Today we will narrow in
on the later group.
Vitamin B complex
B-complex consists of eight different vitamins, which
include thiamine (B1), riboflavin (B2), niacin (B3),
pantothenic acid (B5), piroxidine (B6), folic acid (B9),
cyanocobalamin (B12), and biotin. All of the above are
water soluble, and play a key role in several bodily
functions, such as protein, fat, carbohydrate, and
mitochondrial energy metabolism; maintenance of the
liver, skin, hair, mouth, and eyes; plus so much more,
which will be covered thoroughly within the following
paragraphs. As mentioned above, vitamin b complex can
be further broken down in to 3 general categories; that is,
energy releasing, hematopoietic, or other. And some fit in
both categories. Here is a list [7,12]:
Energy releasing- Thiamine (B1), Riboflavin (B2), Niacin
(B3), Pantothenic acid (B5), Piroxidine (B6), and Biotin.
Hematopoietic- Folic acid (B9), Cyanocobalamin (B12),
Pantothenic acid (B5), and Piroxidine (B6).
Other- Thiamine (B1), Niacin (B3), Piroxidine (B6), Folic
acid (B9), and Cyanocobalamin (B12).
All of these factors will be understood, after this article.
Before we begin, here is an outline of what will be covered
on each of these 8 powerhouses.
· Description- the chemical makeup and structure of
each vitamin
· Digestion- how these micronutrients are digested in
the human body.
· Function- A complete dissection of the process by
which they benefit the body
· Deficiency- the problems caused by a deficit in any
of the B-complexes
· Recommendation- within I will list food sources that
contain them, recommended doses, toxicity levels,
and much more.
For full comprehension of this article, I would highly
recommend you read last month’s issue of hyperplasia, as
many of the terms and physiological occurrences are
discussed therein.
Thiamine (B1)
The first aspect of the B-complex we will cover is Vitamin B1. The
first to publish a correct formula and synthesis for this vitamin was
Dr. Robert R. Williams in 1936. Synonyms for it are thiamine,
thiamin and aneurin. Chemically, Thiamine consists of a
pyrimidine ring and a thiazole moiety (or one of two parts) linked
by a methylene (CH2) bridge. As stated above, it is water-soluble
[63,44].
Digestion
Thiamin can travel by both active (through plasma membrane,
requires metabolic energy to “power” the exchange of materials)
and passive (through plasma membrane, requires no energy)
transport, depending on the amount of the vitamin presented in
the intestine for absorption. At low physiological concentrations,
thiamin absorption is active and sodium-dependent (type of active
transport). Absorption occurs primarily in the upper jejunum but
can occur in the duodenum and ileum (portions of the small
intestine). When intakes of thiamin are high, absorption is
predominantly passive [101, 88, 83].
Next, we will show how Vitamin b1 functions in the body, and its
many beneficial traits.
Function
Vitamin b1 is absolutely essential to several bodily functions. We
will break them down into 2 categories consisting of:
• Energy metabolism
• Nervous system
Energy metabolism
The Krebs cycle (also called the citric acid cycle and the
tricarboxylic acid cycle) is extremely important in
extracting energy from fuel molecules. Consequently, the
process is thiamin dependent. TDP functions as a
coenzyme (binds with certain protein molecules to form
active enzymes) necessary for the oxidative
decarboxylation of both pyruvate and a-ketoglutarate.
These reactions are instrumental in generating energy
(ATP). Inhibition of these decarboxylation reactions
prevents synthesis of ATP, and of acetyl CoA needed for
the synthesis of, for example, fatty acids, cholesterol, and
other important compounds, and results in the
accumulation of pyruvate, lactate, and a-ketoglutarate in
the blood [35,26,25].
Failure to oxidize the molecules listed above (and several
others), results in the accumulation of both the branched-
chain amino acids and their a-keto acids in blood and
other body fluids. This is characteristic of maple syrup
urine disease (MSUD). MSUD results from a genetic (in-
born error of metabolism) absence or insufficient activity of
the branched-chain a-keto acid dehydrogenase enzyme
complex. People with MSUD must avoid meat, poultry,
fish, and dairy products to limit intakes. But in short,
thiamin is vital for energy conversions, and if lacking in
your diet and supplementation, can induce serious health
problems, and inefficiencies in the iron jungle.
Concerning this topic, Sanz Paris A et. al states, “In
thiamine deficiency, the Krebs cycle slows large quantities
of pyruvate are diverted to lactate production and
anaerobic metabolism begins [99].” Timm DE et. al states,
“Thiamine is essential for central metabolic processes,
including the formation of acetyl CoA from glucose and the
Krebs cycle. Deficiencies in human thiamin metabolism
result in beriberi and Wernicke encephalopathy[26].”
Thiamin assists many other bodily functions, such as
synthesis of pentose, NADPH, and additional molecules.
All of which are essential for fatty acid synthesis, cell
replication and much more. Here is an additional quote
form La Selva M et. al [100], “Thiamine restores cell
replication, decreases the glycolytic flux and prevents
fluorescent AGE formation in endothelial cells cultured in
high glucose”
Nervous system
It is apparent from several neurological disorder studies
concerning thiamine deficiency, and taking into account
where thiamine is found (in both the nerves and brain),
that this vitamin plays a vital role in nerve function. Ke ZJ
et al. states [19], “results indicate that TD [thiamine
deficiency] induces alterations in neurons, endothelial
cells, and microglia contemporaneously. This model
provides a unique paradigm for elucidating the molecular
mechanisms involved in neuronal commitment to neuronal
death cascades and contributory microglial activity.”
What the exact role is has yet to be determined. But there
are many viable theories currently being investigated. One
theory is that thiamine triphosphate helps regulate nerve
impulses, via the Na+ and K+ gradient. And other
important channels, helping to regulate functions through
many reactions. Also, it is thought to act as a coenzyme in
the production of neurotransmitters (chemical messengers
between nerve fibers). Either way, results have
consistently revealed that being deficient in this vitamin is
highly detrimental to the function of your nervous system,
making this a vital supplement [55,46,17,16,].
Deficiency
Deficiency of aneurin can cause serious ailments. One of the first
symptoms of thiamin deficiency is a loss of appetite (anorexia)
and thus weight. As deficiency worsens, cardiovascular system
involvement (such as hypertrophy and altered heart rate) and
neurological symptoms appear.
Recommendations
Because of thiamin’s importance in energy metabolism, needed
intake varies according to energy (caloric) intake. The RDA for
adults is 0.5 mg/ 1000 kcal; however, an intake of no less than 1
mg/day is advised. The 1998 Dietary Reference Intakes RDA for
individual intake for thiamin for adult men aged 19 years and older
is 1.2 mg/day and for adult women aged 19 years and older 1.1
mg daily. Thiamin in-takes with pregnancy and lactation (secreting
milk) are increased to 1.4 and 1.5 mg/day, respectively [113,47].
Digestion
Riboflavin is primarily absorbed in the proximal small intestine by
a sodium dependent carrier. Within cells, b2 is converted to its
coenzyme forms, regulated by hormones, such as the thyroid
hormone. These coenzymes, than bind to apoenzymes (an
enzyme, which needs a co-enzyme to be activated) forming what
is called a flavoprotein (discussed below) [62,61,60,59].
Function
FMN and FAD (flavoproteins) are the principle forms of riboflavin.
They are coenzymes, and used in several actions, particularly in
the oxidation (reactant that accepts electrons from another
reactant) of agents, vital for many process to occur. Here is a list
of the many uses of vitamin b 2 [111,79,59,29]:
Deficiency
There is no exact understood mechanism for disease related to
b2 deficiency; however, clinical symptoms of deficiency after
almost four months of inadequate intake have shown
inflammation of the tongue, loss of function on the outside of the
lips and at the sides of the mouth, sore throat, a red or
bloody/puffy mouth, inflammation of skin, eyes become light
sensitive, and nerve dysfunction, to name a few.
Recommendation
The 1989 RDA for riboflavin is given in milligrams per 1,000 kcal.
The recommended allowance for people of all ages is 0.6 mg/
l,000 kcal with a minimum intake of 1.2 mg for persons whose
caloric intake may be more than 2,000 kcal. Through the years,
the recommended allowances for riboflavin have been calculated
in relation to:
• Protein requirement,
• Energy intake
• Metabolic body size.
Niacin (B3)
Niacin, also known as nicotinic acid nicotinamide, and vitamin b 3,
is a water-soluble vitamin, and apart of the b-complex.
Digestion
Function
Deficiency
Recommendation
The 1989 RDA for adults is 6.6 mg of niacin per 1,000 cals
consumed. The DRI RDA recommends at least 16 mg per day.
For pregnancy and lactation, the DRI RDA recommends 18 mg a
day. Up to 35 mg a day has been suggested. For high cholesterol,
up to 3 g of nicotinic acid per day has been applied. The
mechanism of action for lowered cholesterol is not clearly
understood; it is proposed that nicotinic acid decreases the levels
of camp in the adipocytes, thereby decreasing lipase activity.
Decreased lipase activity results in a decreased mobilization of
fatty acids from the adipocytes and, therefore, a decreased
substrate for synthesis of very low-density lipoproteins (VLDLs) in
the liver. Decreased production of VLDLs lowers
triacylglycerollevels, because VLDLs contain relatively high
amounts of triacylglycerols. Furthermore, with decreased VLDLs
there is less synthesis of LDL (bad cholesterol) and thus lower
serum cholesterol levels. An increase in the HDL (good
cholesterol) appears to be due to a decrease in their breakdown
within the liver [113,107,70].
Digestion
Function
Deficiency
Recommendation
Pyridoxine (B6)
The b-complex Pyridoxine, is a water-soluble vitamin. It was
discovered in 1934 by P. Gyorgy. Its composition is complex;
made of several vitamers (one of two or more similar compounds
capable of fulfilling a specific vitamin function in the body) its 3
major forms are pyridoxine (PN), pyridoxal (PL), and
pyridoxamine (PM). These vitamers are comparable in function,
and quite often interchangeable within a given reaction [63].
Digestion
Function
Deficiency
Recommendation
Digestion
To be absorbed, B9 must be broken down to monoglutamate. This
occurs in the small intestine by the enzyme conjugase. This
process is zinc dependent--a deficiency in zinc will inhibit this
process. Absorption primarily occurs in the jejunum of the small
intestine, and is sodium dependent. In the blood, folate is
primarily found as monoglutamate. Throughout the body, B9 is
reduced to several forms such as THF, N5/N10 Methyl THF, among
others. The liver stores the majority of folic acid [108,91,52,18,9,].
Function
Histidine
Histidine (an amino acid) can be broken down to uronic acid; this
can further be reduced to formiminoglutamate (FIGLU). This with
the help of THF can further be broken down to glutamic acid.
When deficient in Pteroylglutamate, FIGLU accumulates, instead
of being converted, and used as glutamate (as stated early, this is
vital for nervous function).
Methionine
THF is required for breakdown of homocysteine to methionine.
Tying the article together, folate, vitamin B 12 (discussed next),
and B6, all show to play a role in this process. Research shows
that high homocysteine concentrations promotes heart disease.
An experiment revealed supplementing with these 3 vitamins
reduced homocysteine concentrations by 50%!
Other
Deficiency
Recommendation
Cyanocobalamin (B12)
Vitamin B12, also called cobalamin, and cyanocobalamin, is an
active coenzyme, vital for many reactions, discussed shortly.
Digestion
Function
Deficiency
Recommendation
The DRI RDA recommends 2.4 ug of vitamin B12 per day for
adults age 19 and up. With an increase of .2 and .4ug for
pregnancy and lactation accordingly.
Biotin
Biotin is also known as vitamin H and coenzyme R. It was isolated
in 1936 when researchers showed consumption of raw eggs
caused a deficiency. Uncooked egg whites contain a protein
called avidin, which strongly binds to biotin in the intestinal tract
and inhibits absorption. Thankfully, cooking eggs effectively
destroys this protein. It is water soluble, and considered to be
apart of the B-complex. It is made of two rings, an ureido ring,
connected to a thiophene ring, with an additional valeric acid side
chain [63].
Digestion
Function
This enzyme is vital for the catabolism of the amino acid leucine
(the most abundant amino acid found in proteins). B-
methylcrotonyl CoA carboxylase is formed during leucine
catabolism. This is a biotin dependent reaction, and further
changed to B-methylglutaconyl CoA carboxylase, which is broken
down to form acetoacetate and acetyl CoA.
Pyruvate carboxylase
Deficiency
Lack of this vitamin may induce hair loss, rashes around the
openings of the eyes, nose, mouth ect., central nervous system
abnormalities such as depression, lethargy, hallucinations, and
paresthesias (tingling, numbness, ect.). dermatitis, muscle pain,
loss of appetite, slight anemia, an inflamed tongue, and
weakness. Excess alcohol intake, bowel diseases, ingestion of
raw eggs, and certain drugs, will induce greater biotin needs
[114,109,66]. Furthermore, Bender DA. States [10], “Biotin
deficiency leads to impaired glucose tolerance”
Recommendation
Final Recommendations
Conclusion
20 Wisdom crieth without; she uttereth her voice in the streets:
21 She crieth in the chief place of concourse, in the openings of
the gates: in the city she uttereth her words, saying, 22 How long,
ye simple ones, will ye love simplicity? and the scorners delight in
their scorning, and fools hate knowledge? 23 Turn you at my
reproof: behold, I will pour out my spirit unto you, I will make
known my words unto you. Proverbs 1:20-23 [48]
These are exciting times my friends. The Lord Jesus has blessed
Abcbodybuilding with an abundance of innovation. My final
suggestion to our fellow hyperplasia viewers is to take advantage
of this opportunity. Knowledge is literally knocking at your door--all
you have to do is open up.
Venom
Venom@abcbodybuilding.com
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24.Carpal tunnel syndrome and vitamin B6. Kasdan ML, Janes
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Table of contents
Prologue Introduction Conclusion References
Teachers’ Topics
Biochemistry of the Water Soluble Vitamins: A Lecture for First Year
Pharmacy Students
Michael G. Bartlett, PhD1
1
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy,
University of Georgia, Athens, GA 30602-2352
PROLOGUE
This manuscript describes the lecture on vitamins contained in the core course
entitled, “The Biochemical Basis of Drugs and Diseases” (Pharmacy 3050). In the
first year, our curriculum is designed to focus on systems and diseases. As such, this
course acts in concert with both the Anatomy & Physiology course and the
Pathophysiology course to present an integrated view of human diseases and
systems. The second year of our curriculum is focused on learning about drugs
classes and the mechanism of action. The third year of the curriculum is focused on
simulated patients, while the forth year of the curriculum the students are presented
with real patients.
The lecture on vitamins is the last topic of a course focused primarily on
metabolism. Because many vitamins play major roles in metabolic cycles, this
lecture allows for a brief review of much of the material covered throughout the
course. Therefore, vitamin examples are primarily chosen to reinforce major
metabolic cycles and also their role in human disease. There is more clinical
information that is relevant to vitamins than what is presented in this lecture.
However, since first year students in our curriculum have almost no knowledge of
therapeutics, the focus of the lecture is on diseases and not clinical practice.
INTRODUCTION
Vitamins are a multibillion dollar industry.1 They are readily available to the public
and are the focus of the most frequently asked questions to pharmacists.2
Surprisingly, most pharmacy students receive little training on the many roles of
vitamins in nutrition.2 Therefore, this lecture attempts to not only reinforce
fundamental biochemical and metabolic pathways in the human body, but also to
provide pharmacy students with practical information.
The diet is a vast source of important nutrients. These nutrients include several
important classes of biomolecules such as: (1) energy yielding components
(carbohydrates, lipids, and proteins), (2) essential and nonessential amino acids, (3)
essential fatty acids, (4) minerals, and (5) vitamins. Vitamins are organic substances
that must be provided by the diet either because they cannot be biosynthesized or
the amount that is provided through biosynthesis is inadequate for maintaining
normal health. Vitamins are broadly divided into 2 classes based upon their
hydrophobicity. The more hydrophilic vitamins are termed the water-soluble
vitamins and are composed of the B-complex vitamins and vitamin C. The more
hydrophobic vitamins, referred to as the fat-soluble vitamins, are composed of
Vitamins A, D, E, and K. This article focuses primarily on the water-soluble
vitamins due to their greater role in the major metabolic cycles, which are the
primary focus of this course.
The normal North American diet is sufficient to prevent significant vitamin
deficiencies and the related diseases associated with these deficiencies. However,
there is increasing concern that slight vitamin deficiencies in a number of water-
soluble vitamins (B1, B6, B12, folate and vitamin C) are risk factors for diseases
such as depression, cancer, cardiovascular disease, and neural tube defects. The
prevalence of this slight vitamin deficiency is likely related to diet, since most of
these vitamins are supplied by fruit and vegetable intake. A recent survey has shown
that only 25% of the population meets their daily intake of 5 servings.3 Food
preparation is another source of vitamin loss. For example, heating food for more
than 2 hours causes more than a 10% loss of most water-soluble vitamins.
Refrigeration, freezing, and reheating have all been shown to lead to further loss of
vitamins. Exposure to light causes significant loss of riboflavin from foods and the
combination of heating and light can almost completely remove this vitamin from
food.4
Thiamin (Vitamin B 1 )
Thiamin functions in the body as thiamin pyrophosphate (TPP) an important
enzyme co-factor.5 Thiamin reacts with adenosine triphosphate (ATP) to form
thiamin pyrophosphate through a reaction mediated by the enzyme thiamin
diphosphokinase. Following its production, TPP is incorporated into 2 important
enzymes: pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Pyruvate
dehydrogenase is part of a multi-enzyme complex that acts to convert pyruvate
generated in glycolysis into acetyl-CoA for entry into the tricarboxylic acid (TCA)
cycle. Thiamin pyrophosphate is also used as a co-factor for the enzyme α-
ketoglutarate dehydrogenase, which is a key point of regulation in the TCA cycle.
α-Ketoglutarate dehydrogenase is involved in the conversion of α-ketoglutarate to
succinyl CoA. In the case of both enzymes, TPP assists in decarboxylation of a
small ketoacid.
In addition to its uses in metabolism, thiamin may enhance circulation and blood
formation. It is required for maintenance of the nervous system and is used in the
biosynthesis of the neurotransmitters acetylcholine and γ-hydroxybutyrate (GABA).
Thiamin also is used in the production of hydrochloric acid in the stomach and,
therefore, has a role in digestion.
Thiamin is provided in the diet through most grains. A deficiency of thiamin is
called beriberi and it is most often observed in Southeast Asia.6 The main staple of
diet in this part of the world is rice, which does not provide dietary thiamin to as
great an extent as other grains. The symptoms of beriberi include limb pain, muscle
weakness, and low cardiac output. All symptoms are related to the diminished
capacity of the major energy producing pathways that are dependent on TPP as a
co-factor.
Mild deficiencies of thiamin are sometimes observed in the elderly and in low-
income groups on restricted diets. The earliest symptoms of thiamin deficiency are
loss of appetite, constipation, and nausea. Other symptoms such as mental
depression, peripheral neuropathy, irritability, and fatigue are related to the role of
thiamin in maintaining a healthy nervous system.
The most common form of thiamin deficiency in the United States is alcoholic
neuritis. Because alcoholics normally have a poor appetite, overall food
consumption is low. In addition, alcoholics are predisposed to developing
nutritional deficiencies since alcohol is their primary calorie source. Under the
broad umbrella of alcoholic neuritis come two disorders, Wernicke’s Syndrome and
Korsakoff’s Psychosis.7 The symptoms of Wernicke’s Syndrome (ophthalmoplegia,
nystagmus, and ataxia) respond quickly to administration of thiamin, whereas the
more severe memory and learning disorders associated with Korsakoff’s Psychosis
are refractory to thiamin treatment.
Riboflavin (Vitamin B 2 )
Riboflavin functions in the body as an enzyme cofactor in many oxidation/reduction
reactions and has a central role in energy production and cellular respiration.
Riboflavin reacts with ATP to form flavin mononucleotide (FMN). Flavin
mononucleotide then reacts with a second molecule of ATP to form a molecule of
flavin adenine dinucleotide (FAD). Within cellular metabolism, enzymes such as
succinyl dehydrogenase (TCA cycle), AcylCoA Dehydrogenase (β-Oxidation), and
Glycerol-3-phosphate Dehydrogenase (Glycerol Phosphate Shuttle) use FAD as a
cofactor. The enzyme NADH-CoEnzyme Q oxidoreductase (Complex I, Electron
Transport Chain) uses FMN as a co-factor. As enzyme co-factors, FAD and FMN
are able to function as electron acceptors. The addition of 2 electrons to FAD results
in the formation of a molecule of FADH2, while the addition of 2 electrons to FMN
causes the formation of a molecule of FMNH2.
Riboflavin + ATP → FMN + 2e- ↔ FMNH2
FMN + ATP → FAD + 2e- ↔ FADH2
The reduced forms of these enzyme co-factors can donate these electrons to return
to their previous fully oxidized forms. It is this ability to act as a conduit for
electron transfer reactions that makes FAD and FMN such important enzyme
cofactors.
Riboflavin is available from a wide variety of dietary sources such as milk, cheese,
meat, eggs, and cereal products. Symptoms associated with riboflavin deficiency
include sore throat, dermatitis, anemia, neuropathy, and cataract formation.
Riboflavin deficiency is not normally observed in the United States; however,
deficiency may be observed as part of a general case of malnutrition or in cases of
chronic alcoholism.8 The conversion of riboflavin to FMN is required for absorption
and transport into many tissues. The conversion has been shown to be inhibited by
hypothyroidism and the structurally similar medications chlorpromazine,
adriamycin, quinacrine, tetracycline, and tricyclic antidepressants.9-12
Niacin (Vitamin B 3 )
The vitamin niacin (nicotinic acid) and its structural analog nicotinamide have
identical function due to their facile interconversion in the body. Niacin is converted
through a series of reactions to its active form nicotinamide adenine dinucleotide
(NAD+). NAD+ can be converted to a reduced form NADH by gaining 2 electrons
through a process similar to FAD reduction. NADH is produced in large quantities
by the TCA cycle and β-Oxidation and to a lesser extent by glycolysis. Reduced
NADH is returned to its oxidized form under normal cellular conditions by the
electron transport chain. This newly reformed NAD+ can then return to other
metabolic pathways to harvest more electrons. In the body the ratio of
NAD+/NADH is approximately 1000 demonstrating the primary role of NAD+ in
supporting cellular oxidation. NADH also can react with ATP to form NADPH. As
opposed to the unphosphorylated form, the ratio of NADP+/NADPH is only 0.01.
This ratio points to the role of NADPH in supporting reductive processes in the
body.
Niacin → NAD+ + 2e- ↔ NADH
NADH + ATP ↔ NADPH + ADP
Niacin can be found in foods such as meats, breads, and beans. Mild niacin
deficiencies have similar symptoms to those observed with riboflavin, which is not
surprising due to the similar roles both of these vitamins play in biochemical
reactions. Niacin deficiencies are occasionally observed in alcoholics, cases of
general malnutrition, and in the elderly on restricted diets. A severe deficiency of
niacin is known as pellagra, which is derived from the Italian phrase meaning rough
skin. Pellagra is marked by dermatitis and also is notable for causing a blackening
of the tongue. Early cases of pellagra were first observed in Europe shortly after the
introduction of corn from the voyages of Christopher Columbus. In these cases,
poor farmers who were raising corn as animal feed were particularly susceptible.
Because niacin in corn is not bioavailable unless treated with a strong base such as
lye, the farmers developed niacin deficiencies. Europeans did not know this
processing method until revealed to them by Native-Americans during the early
colonial period of North America. However, the connection between pellagra and
niacin was not known until the early 20th century. Pellagra was a significant health
issue in the United States over the period from 1900-1940 resulting in over 100,000
deaths. Today most diets are supplemented with niacin through enriched flour,
which receives its name because of the added niacin.13
Niacin can be administered in doses of 2g to 4g to causes a decrease in circulating
levels of cholesterol and LDL. While the cholesterol lowering effects of niacin are
desirable there are potential side effects from such large doses of this vitamin. The
most immediate reaction observed from large doses of niacin is vasodilation
resulting in flushing. Over time there may be a reduction in fatty acid mobilization
causing a depletion of glycogen and lipid stores in muscle tissue. Long-term
exposure may also elevate blood glucose and uric acid levels, suggesting increased
risk for patients who are on the borderline for diseases such as diabetes and gout.
Prolonged use of high doses of niacin can lead to elevated levels of the serum
enzymes alanine aminotransferase and aspartate aminotransferase, which may
suggest liver damage.
Pyridoxine (Vitamin B 6 )
Pyridoxine is the precursor to the active enzyme co-factor pyridoxal phosphate
(PLP). Pyridoxal phosphate is a critical co-factor for enzymes involved in reactions
involving many amino acids. The N-terminus of the amino acid forms a covalent
bond to PLP, allowing a wide variety of displacement reactions to occur at the alpha
carbon. These include decarboxylations, transaminations, and transfers of side
chains. Pyridoxine, therefore, plays a central role in the production of many
neurotransmitters, such as serotonin, norepinephrine, and histamine. Pyridoxine also
is important in the production of heme.
The PLP co-factor in several enzymes is a therapeutic target due to the ability to
form irreversible covalent bonds with agents containing a hydrazine moiety, such as
carbidopa, isoniazid, and hydralazine.14 The combination of L-Dopa and carbidopa
is a widely used therapy that has a biochemical mechanism involving vitamin B6.
The conversion of L-Dopa to dopamine is catalyzed by the PLP-dependent enzyme
L-aromatic amino acid decarboxylase (LAAAD).
L-DOPA → Dopamine
The enzyme LAAAD is present in both the gut and in the brain. This presents a
problem because L-dopa is readily transported across the blood brain barrier while
dopamine is not. Therefore, orally administered L-dopa is rendered ineffective in
the gut by LAAAD. Co-administration of carbidopa resolves this dilemma by
inactivating LAAAD in the gut. Like dopamine, carbidopa cannot cross the blood
brain barrier leaving LAAAD in the brain free to carry out the production of
dopamine at the site of action. In addition to hydrazine containing drugs,
penicillamine, used in the treatment of Wilson’s disease, cystinuria, and rheumatoid
arthritis reacts with and inactivates pyridoxal phosphate.15 Patients treated with
penicillamine occasionally develop convulsions, which can be prevented by
supplementation with vitamin B6.
Pyridoxine is found in foods such as meats, breads, eggs, soybeans, and many
vegetables. A deficiency in pyridoxine can cause facial lesions, depression,
peripheral neuropathy, and glossitis. The neurological complications can be directly
linked to the effects on neurotransmitter production. Mild pyridoxine deficiencies
are sometimes observed in young women taking oral contraceptives. Deficiencies
have also been observed in patients with gasteroenteritis or Crohn’s Disease,
presumably due to poor absorption. Mild deficiencies are of concern due to a
correlation with an increased incidence of breast cancer and to the risk of coronary
heart disease.16,17 Neurotoxicity has been noted with doses of vitamin B6 in excess
of 500 mg/day.18
Cobalamin (Vitamin B 12 )
Cobalamin is vital for cell growth and replication. Its major site of action is at the
interface between the folic acid cycle and the active methyl cycle, where cobalamin
is a co-factor for the enzyme homocysteine methyltransferase. This enzyme
catalyzes the transfer of a methyl group from tetrahydrofolate to homocysteine,
forming the amino acid methionine. These 2 cycles impact many other pathways
due to the large number of methylation reactions in the body, especially nucleic acid
biosynthesis and neurotransmitter biosynthesis.
Cobalamin is found in meats and dairy products. Deficiencies are not common
because the liver can store a 6-year supply of cobalamin. In addition, cobalamin is
highly conserved by enterohepatic recirculation. Strict vegetarians (vegans) may
take up to 20 to 30 years to develop a deficiency, whereas inadequate absorption
from the ileum due to ileitis or loss of a glycoprotein that complexes with
cobalamin prior to absorption may take from 2 to 10 years to become symptomatic.
The anesthetic nitrous oxide inactivates cobalamin and can cause patients with
marginal serum levels to develop deficiencies within a week.19 While rare,
deficiencies in vitamin B12 are severe and manifest in erythrocytes and nervous
tissue. In erythrocytes, nucleic acid biosynthesis is slowed. This results in stem cells
that are committed to development into erythrocytes possessing twice their normal
protein content but lacking the necessary nuclear material for proper cell division.
The resulting anemia, termed megaloblastic anemia, can be quite severe. Cobalamin
deficiency can also cause permanent damage to the nervous system. The results are
swelling of neurons and demylination of nerve cells, followed by cell death. These
progressive manifestations cause a wide range of neurological symptoms including
unsteadiness, decreased reflexes, paresthesias of the extremities, and ultimately
confusion, memory loss, hallucinations, and psychosis. The neurological symptoms
of cobalamin deficiency may be mistaken for multiple sclerosis. In the elderly and
in alcoholics, cobalamin deficiency should be considered as a possible cause of
dementia even in the absence of anemia. The neurological symptoms associated
with cobalamin deficiency are not directly related to irregularities in the formation
of erythrocytes.20
Pantothenic Acid
Pantothenic acid is one of the many B-complex vitamins. Once in the body,
pantothenic acid combines with ADP and cysteamine to form coenzyme A
(HSCoA). Coenzyme A is involved in a number of cellular pathways, most notably
in transferring an acetyl unit from the pyruvate dehydrogenase complex or from β-
oxidation to oxaloacetate in the TCA cycle. Coenzyme A is also involved in the
biosynthesis of cholesterol, steroid hormones, fatty acids, and porphyrins.
Pantothenic acid derives its name from the Greek word meaning “from
everywhere”, which reflects its ubiquitous nature in foods. Deficiencies in
pantothenic acid are difficult to achieve but result in neuromuscular degeneration.26
Biotin
Biotin is an important co-factor for enzymes involved in carboxylation reactions.
Biotin aids in these reactions by binding carbon dioxide. An important example of a
biotin-containing enzyme is pyruvate carboxylase. This enzyme catalyzes the
conversion of pyruvate to oxaloacetate as a preliminary step in gluconeogenesis.
Biotin is found in foods such as liver, egg yolks, milk, fish and nuts. Deficiencies in
biotin result in dermatitis, glossitis, muscle pain and anorexia. Deficiency in biotin
has been observed in patients ingesting raw eggs over a long period of time. Egg
white contains avidin, a protein that binds biotin, strongly preventing its absorption
from the intestine.27 Biotin deficiency was observed in early attempts at parenteral
nutrition before proper vitamin supplementation became standard practice.28
Choline
Choline has many important biochemical roles in the body. It is incorporated into
the formation of lecithin, an important structural phospholipid found most
abundantly in mitochondrial membranes. It is also incorporated into platelet-
activating factor, an important signaling agent in the clotting cascade. Choline also
affects lipid mobilization from the liver. However, its most important role is as a
precursor for the neurotransmitter acetylcholine where it plays a critical role in
motor coordination.
Choline is found in eggs, peanuts, and liver. Deficiency in choline has not been
reported in humans. It is believed that daily needs for choline can be met through
biosynthesis and diet.
Carnitine
Carnitine has an important role in the metabolism of fatty acids. Carnitine accepts
and donates fatty acids to co-enzyme A. This is an equilibrium process facilitated by
cytosolic and mitochondrial enzymes known as carnitine acyl transferases. The
attachment of fatty acids to carnitine is critical for their transport from the cytosol to
the mitochondria, where they are later metabolized through β-oxidation.
Carnitine is found abundantly in meats and dairy products. Carnitine deficiency is
not normally observed in adults unless it is caused by an inherited genetic disorder
related to its transport or biosynthesis. Carnitine deficiency causes the storage of
lipids in muscle tissue resulting in functional abnormalities in both cardiac and
skeletal muscles. However, carnitine deficiencies are not uncommon in preterm or
low birth weight infants. These infants generally respond to supplements of
carnitine as well as changing to a low-fat, high-carbohydrate diet.29
CONCLUSIONS
Questions concerning the use of vitamins are common. Vitamins have important
roles in many of the major metabolic pathways in the human body. In addition, drug
interactions with vitamin and diseases involving vitamin deficiencies are important
topics for pharmacy curricula. An understanding of the functional roles of vitamins
can contribute to improved understanding of general biochemistry and help
pharmacy students become better prepared for their roles as health care educators.
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Corresponding Author:
Address: Department of Pharmaceutical and Biomedical Sciences, College of
Pharmacy, University of Georgia, Athens, GA 30602-2352
Tel: (706) 542-5390
Fax: (706) 542-5358
E-mail: bartlett@rx.uga.edu
Bartlett M. Biochemistry of the Water Soluble Vitamins: A Lecture for First Year
Pharmacy Students. Am J Pharm Educ. 2003; 67(2):article 64.
53vit.htm