VITAMIN

D R . J O K O W AH Y U W I B O W O , M K E S
B AG I AN : G I Z I – I K M
F K . U N I S S U L A
DIGESTING AND ABSORBING WATER-
SOLUBLE VITAMINS

Figure 10.1
 Water-Soluble Fat-Soluble
Vitamins Vitamins
Absorbed in the Small Intestine Small Intestine
Hydrophobic or
Hydrophilic Hydrophobic
Hydrophilic
Absorbed into the Blood Lymph

Stored in the body Not Generally Yes

Can build up and

Not Generally Yes
become toxic
Need to consume
Yes No
daily
 BIOAVAILABILITY

• Varies based on
• Amount in food
• Preparation
• Efficiency of digestion and absorption of food
• Individual nutritional status
• Natural or synthetic
• Fat-soluble vitamins are generally less bioavailable than water-
soluble vitamins
• Vitamins from animal foods are generally more bioavailable
than those in plant foods
 LIPID SOLUBLE VITAMINS

• Are absorbed and transported by fat

• Excess vitamins are stored in the liver
• Body draws on stored vitamins when needed
• Large amounts can harm the body
• People who take vitamin supplements are advised
to use caution

7
Copyright © Texas Education Agency, 2012. All rights reserved.
 Vitamin А

Retinol. Antixerophthalmic
 Biological functions of
carotenes
•Antioxidants
•Anticancer properties
 Biological functions of vitamin A
•Modulator of biomembranes
-changes the permeability
-synthesis of membranes components
•Growth vitamin
-stimulates the synthesis of proteins
(especially in cartilages)
-stimulates the synthesis of purine and
pyrimidine nucleotides
•Participates in oxidation-reduction
reactions
CONTINUED.........

•Regulates the synthesis of keratin (prevents

the conversion of cylindrical epithelium into
horny
•Promotes the spermatogenesis and placenta
development
Stimulates the synthesis of antibodies and
phagocytosis (antiinfectious) Regulates the
hormonal status
-prevents the oxidation of vitamin C
-inhibits the synthesis of thyroxin
•Maintains the antioxidant potential of
different tissues
Xerophthalmia (progressive
keratinization of cornea)
Bronchitis, pneumonia (metaplasia of endothelium)
Cysts in salivary glands
Cystitis, pyelonephritis (change of endothelium in
nephrones)
 1. Maintains and strengthens the skin

2. Maintains health of specialized

tissues such as the retina of the eye

3. Maintenance of the mucosal

tissues and secretions, which in turn
are responsible for normal
functioning of the immune system;
4. Normal bone development

5. Maintenance of the reproductive system:

required for sperm production in the male and
regulate reproductive cycles in the female.
• Roles in the body
• Vitamin A in protein synthesis
and cell differentiation
 VITAMIN A AND
BETA-CAROTENE
• Roles in the body
• Vitamin A in vision
 ‘‘Outer limiting
Photoreceptor membrane’’
(rod) cell
Müller cell
Outer
segment

Inner
segment Capillary

Pigment epithelium Outer of photoreceptor (rod)

Nucleus cell Segment
Functions: Vitamin A
• Vision
• Cell differentiation, growth, reproduction
• Bone development
• Immune system
Fig. 10-7, p. 334
Functions: Vitamin A
•Vision
•Cell differentiation, growth, reproduction
•Bone development
•Immune system

Fig. 10-9, p. 335

Functions: Vitamin A
•Vision
•Cell differentiation, growth, reproduction
•Bone development
•Immune system

Function: Carotenoids
• Antioxidants for singlet oxygen;
Lycopene > vitamin E >  carotene >
cryptoxanthin > zeaxanthin,  carotene >
lutein
(also work better when used together)
• Antioxidant for lipid peroxides (works with
vitamin E)
• Lower incidence of atherosclerosis through
prevention of oxidation of LDLs
Functions: Vitamin A
•Vision
•Cell differentiation, growth, reproduction
•Bone development
•Immune system
Interaction with other nutrients:
• Vitamins E and K (inversely related; high A, low E and K)
• Zinc and iron
• Protein
Excretion: most in urine as oxoretinoic acid, small amounts in expired air, some in
feces

Fig. 10-10, p. 339

Deficiency:
• increased morbidity in children under age 5 with no evident clinical signs of
deficiency
• Signs, when present include xeropthalmia, anorexia, retarded growth,
increased susceptibility to infections, enlargement of hair follicle, and
keratinization of epithelial (mucous cells) of the skin.

Toxicity:
• Hypervitaminosis A
• Nausea, vomiting, double vision,
headache, dizziness, and
desquamation of the skin
• Teratogen
 VITAMIN D

Functions Food Sources

• Works with calcium and • Fortified dairy products
phosphorus to ensure • Egg yolks
bone growth • Higher-fat fish – herring,
• Immune system salmon and mackerel
• Fortified breakfast
cereals

24
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 VITAMIN D METABOLISM

• Skin
• UV light photo-isomerises provitamin D to D3
(cholecalciferol)
• Transported by Vit D binding proteins to liver
• Intestine
• Absorbed by enterocytes & packaged into chylomicrons
• Transported to liver by portal circulation
• Hydroxylated in liver to 25-ODH
• Further in kidneys to 1,25-OHD
• Physiologically active
 Two forms of vitamin D

•Vitamin D2 – ergocalciferol
•Vitamin D3 - cholecalciferol

cholecalciferol

ergocalciferol
 Both ergo-
calciferol and
cholecalciferol
are metabo-
lized in liver

1,25-dihydroxycholecalciferol
Vit.D acts in
concert with
parathyroid
hormone
(PTH)

PTH
stimulates
the
production of
1,25-(OH)2D
 Functions of
vitamin D
regulates the Ca and
P levels in the blood
•promotes absorption of
Ca and P in the
intestine
•promotes reabsorption
of Ca in the kidneys
•high levels of serum Ca
and P increase the rate
of bone mineralization
•promote bone
resorption (at low Ca in
blood)
 Functions of vitamin D
affects immune system

•promotes
phagocytosis

•immunomodu-
latory activity

•induces
differentiation
of immune cells
 Functions of vitamin D

•Activates reabsorption of amino

acids, especially prolin

•Activates the monosaccharides

phosphorylation (glycogen synthesis)

•Promotes ATP formation

1. Vitamin D is essential for the efficient
metabolism and utilization of calcium by
the body. Maintenance of calcium levels
within a narrow range is vital for normal
functioning of the nervous system.

2. Works with calcium for bone growth

and maintenance of bone density.

3. Adequate vitamin D levels may be

important for decreasing the risk of high
blood pressure.

4. Plays a role in insulin secretion

under conditions of increased insulin
demand.
 ASSOCIATED CLINICAL CONDITIONS

• Role in Cancer Prevention

• Low intake of vitamin D and calcium has been
associated with an increased risk of non-Hodgkin
lymphomas, colon, ovarian, breast, prostate, and other
cancers.
• The anti-cancer activity of vitamin D
• a nuclear transcription factor that regulates cell
growth, differentiation, & apoptosis, central to the
development of cancer
• Vitamin D is not currently recommended for reducing
cancer risk
 ASSOCIATED CLINICAL CONDITIONS

• Role in Cardiovascular Diseases

• Vitamin D deficiency activates the renin-angiotensin-
aldosterone system and can predispose to
hypertension and left ventricular hypertrophy.
• Additionally, vitamin D deficiency causes an increase
in parathyroid hormone, which increases insulin
resistance secondary to down regulation of insulin
receptors and is associated with diabetes,
hypertension, inflammation, and increased
cardiovascular risk.
 ASSOCIATED CLINICAL CONDITIONS

• Role in Reproductive Health

• Vitamin D deficiency early in pregnancy is associated
with a five-fold increased risk of preeclampsia.
• Role in All Cause Mortality
• Researchers concluded that having low levels of
vitamin D (<17.8 ng/mL) was independently
associated with an increase in all-cause mortality in
the general population.
 SIGNIFICANCE OF FINDINGS

• Increase our understanding of the innate immune system

in humans
• Increase our understanding of how the VDR and
CYP27B1 genes are involved in innate immunity
• May lead to new treatments or medications for human
diseases
 BACKGROUND

• Exposure to sunlight was historically known to

cure tuberculosis
• Sunlight stimulates the synthesis of vitamin D
• Vitamin D stimulates the production of
cathelicidin anti-microbial peptide (CAMP) to
help fight infections
Background continued
Vitamin D Signaling Pathway
Pathogen invades cell

Toll-like receptor signaling activated

Increased expression of VDR and CYP27B1 genes

Activated vitamin D binds to VDR

Vitamin D and VDR go to the nucleus and binds

to the vitamin D response element (VDRE)

Production of CAMP increases to fight

microbes
 BACKGROUND CONTINUED
TLR = Toll-like receptor
allows immune system
to
recognize microbes by
looking at molecular
patterns

CYP27B1: a gene
that encodes an
enzyme to convert
inactive vitamin D to
active vitamin D

VDR = Vitamin D Receptor

Active vitamin D binds to VDR

Active vitamin D

Adams & Hewison (2008). Nature Clinical Practice

Endocrinology & Metabolism, Volume 4, 80-90.
 Vitamin D toxicity, known as Hypervitaminosis D, induces
abnormally high calcium levels (Hypercalcemia), which
could result in bone loss, kidney stones, and calcification of
organs like the heart and kidneys if untreated over a long
period of time. Excessive exposure to sunlight does not
lead to vitamin D toxicity. Excesses are usually attributed to
overdoses of dietary supplements.
Like Vitamin A, a
surplus of Vitamin D
is stored in the liver
and body fat.

An individual experiencing vitamin D poisoning

may complain of weakness, fatigue, loss of
appetite, nausea, and vomiting. In infants and
children there may be growth failure.
 In infants and children, severe
vitamin D deficiency results in the
failure of bone to mineralize, a disease
called Rickets. Rapidly growing bones
are most severely affected by rickets.
The growth plates of bones continue to
enlarge, but in the absence of adequate
mineralization, weight-bearing limbs
(arms and legs) become bowed.

Vitamin D deficiency causes muscle weakness and pain in

children and adults. In adults it may develop into osteomalacia, a
disease characterized by poorly calcified, softened bones.
Vitamin D deficiencies increase the risk of osteoporosis, which is a
progressive loss of bone density.
 Knock knee
Windswept deformity
deformity (genu valgum)
 VITAMIN K

Functions Food Sources

• Helps blood to clot so • Green leafy vegetables
wounds stop bleeding • Other vegetables
• Helps with bone health • Dairy products
• Some fruits

43
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K1, phyloquinone (in green vegetables)
K2, menaquinone (is synthesized by
intestinal bacteria)
 Biological functions
•Stimulates the synthesis of
coagulation factors in liver
•Increases the resistance of
capillaries
•Stimulates the synthesis of
albumins, pepsin, trypsis, lipase,
amilase
•Increases the peristalsis of
intestine
•Inhibits free radical oxidation
 The best dietary sources of
vitamin K are green leafy
vegetables such as spinach,
broccoli, Brussels sprouts,
cabbage and lettuce. Other rich
sources are certain vegetable oils.
Good sources include oats,
potatoes, tomatoes, asparagus
and butter. Lower levels are found
in beef, pork, ham, milk, carrots,
corn, most fruits and many other
vegetables.

A portion of the body's vitamin K

is produced by bacteria living in
the jejunum and ileum of the
intestine rather than by dietary
sources.
 Hypovitaminosis
Causes:
•Lipids malabsorption (lack of bile
acids)
•Disbacteriosis (vit. K is synthesized
by intestinal microflora)
•Taking of antivitamins (dicumarol)

dicumarol
Vitamin K deficiencies are rare for two reasons... 1. part of the body’s
needs of this vitamin are produced in the intestinal tract 2. Vitamin K
is “conserved” in the body. That means it is recycled… it can be used
over and over. The process is called the Vitamin K cycle.

Easy bruising
associated with
Vitamin K
deficiency.

Adults at risk of vitamin K deficiency include those taking vitamin K

anticoagulant drugs (warfarin, coumadin, heparin) that may be
prescribed for blood clots in the legs and lungs. Individuals with
significant liver damage or disease, and individuals with disorders of
fat malabsorption may also be at increased risk of vitamin K
deficiency. Large doses of vitamin A and vitamin E have been found to
counteract the function of vitamin K and interfere with Vitamin K
absorption. Long-term use of antibiotics may destroy the bacteria in
the intestine that produce Vitamin K.
 Hypovitaminosis
Symptoms:
•Hemorrhages (subcutaneous,
intramuscular, into inner organs)
•Increased coagulation time
Hemorrhages in heart.
Hemorrhages in the retina
 VITAMIN E

Functions Food Sources

• Powerful antioxidant • Nuts and seeds
• Protects cells from • Green leafy vegetables
oxidation damage • Wheat germ
• May reduce risk of • Vegetable oils
heart disease and • Soybean oils
some cancers

50
Copyright © Texas Education Agency, 2012. All rights reserved.
 VITAMIN E

• Vitamin E is found in both plant and animal foods. Plant

foods: especially oils from plants, are considered the richest
and main courses of vitamin E.
• Oils high in E include: canola, olive, sunflower. Also whole-
grain cereals, legumes and some fruits and vegies.
• The leaves and other green portions of plants contain mostly
E, with other tocopherols elsewhere.
• In foods of animal origin, it is found concentrated in fatty
tissues of the animal.
• Vitamin E is susceptible to destruction during food
preparation, processing, and storage. Tocopherols can be
oxidized with lengthy exposure to air.
• Exposure to light, heat, or metals also can lead to increased
destruction
VITAMIN E
Functions:
• Maintenance of membranes - prevents oxidation of unsaturated fatty acids contained in
the phospholipids (includes membranes of mitochondria and ER)
•Reduced LDL oxidation; decreased plaque formation
•Reduction in cataract formation
•Reduced oxidation in diabetics

• Suppression of activity of HMGcoA reductase (cholesterol synthesis)

Fig. 10-18, p. 356

 The main function of Vitamin E (alpha-tocopherol) is that of
an antioxidant. An antioxidant is a substance that reduces or
prevents damage.
Free radicals are very reactive
atoms or molecules that
typically possess a single
unpaired electron. They are
formed in the body during
normal metabolism and also
upon exposure to
environmental factors such as
cigarette smoke, stress,
alcohol, lack of sleep, poor
diet, or pollutants. These free Fats and some proteins are the target of
radicals cause destruction by
free radical destruction. The result is
trying to remove electrons
from other molecules so they damage to the cell membranes and
will have a matched pair. This accelerated aging. It is also linked to
destruction is called Alzheimer’s disease, cataracts, heart
oxidation. disease, Vitamin K usage, and cancer.
 Biological role
•Most potent antioxidant
•Active scavenger of free oxygen
and nitrogen radicals
•Protects vit.
A from
oxidation
•Prevents
oxidation of
Se
•Stabilizes the cell membranes
•Increases the resistance of membranes to
oxidation and toxic effects
•Improves cellular respiration stabilizing
ubiquinone
•Prevents oxidation of LDL
•Reduces risk of atherosclerosis
•Regulates transcription
•Maintains normal immune function
•Inhibits cholesterol biosynthesis
 Vitamin E deficiency has been
observed in individuals with severe
malnutrition, some genetic defects,
and fat malabsorption syndromes
such as cystic fibrosis or
cholestatic liver disease. Severe
vitamin E deficiency results mainly
in neurological symptoms,
including impaired balance and
coordination, injury to the sensory
nerves, muscle weakness, and
damage to the retina of the eye.

Vitamin E deficiencies are rare. In fact, a symptomatic

vitamin E deficiency in healthy individuals who consume
diets low in vitamin E has never been reported. Excess
Vitamin E can be stored in fatty tissues of the body.
Regeneration

Nutrient Interactions:
• Function closely linked to selenium (needed for GSH peroxidase), vitamin C, sulfur
containing amino acids,
• Inhibits carotene absorption and conversion to retinol; may impair vitamin K absorption;
may cause vitamin -D dependent bone mineralization problems
Deficiency:
Rare except in populations with fat malabsorption (cystic fibrosis)
myopathy and weakness, croid pigment accumulation, and degenerative neurologic
problems
Toxicity: one of the least toxic; bleeding problems

Fig. 10-19, p. 356

Digestion and Transport:
• Synthetic forms are de-
esterified
• Free alcohol forms are
absorbed passively in micelles;
non-saturable
• 20-80% absorption; better
with fats
• Incorporated into chylomicrons
in intestinal cell and sent out
into lymph
• Transfer between
chylomicrons, HDLs and LDLs
occurs in the blood. HDLs and
LDLs contain highest
concentration of the vitamin
• Half-life of about 48 hrs.
• Some stored in adipose, liver,
lung, heart, muscle, adrenals

Table 10-3, p. 354

 Vitamin F
Polyunsaturated
fatty acids
Antisclerotic
 Biological functions
•Participate in the organism growth
and development
•Components of phospholipids (cell
membranes)
•Regeneration of skin epithelium
•Synthesis of prostaglandins
•Decrease cholesterol level
•Increase the organism resistance
 Hypovitaminosis
Causes:
•Growth retardation Dermatitis

•Dermatitis
•Dry skin
•Exema
•Atherosclerosis
Exema Dry skin

Atherosclerosis
 B COMPLEX VITAMINS

• Co-enzymes (activate enzymes)

• Found in the same foods
• Single deficiency rare
• Act together in metabolism
• Metabolic pathways used by protein, carbohydrate, and fat
• Broken down from coenzyme form into free vitamins in the
stomach and small intestine
• Absorbed, primarily in the small intestine (50%-90%)
• Once inside cells, coenzyme forms are resynthesized
B COMPLEX PRIMARY FUNCTIONS

• Energy metabolism
• Thiamin (B-1), Riboflavin (B-2), Niacin (B-3), Pyridoxine (B-6),
Biotin, Pantothenic Acid
• Red blood cell synthesis
• Folate, B12
• Homocysteine metabolism
• Folate, B12, B6
 VIT. B12

• Essential roles in folate metabolism and synthesis of citric

acid cycle intermediate, succinyl- coA.
• Important for homocysteine metabolism
• Preservation of DNA integrity dependent on folate and
vitamin B12 availability
• Poor vit B status has been linked to increased risk of
breast cancer
• Vit B12 is essential for the preservation of the myelin
shealth around neurons and for the synthesis of
neurotransmitters
• hyperhomocysteinemia may increase risk of cognitive
impairment
 FUNCTION VIT B12

• Cofactor for methionine synthase

• Required for the synthesis of amino acid methionine
from homocysteine
• Methionine in turn is required for the synthesis of s-
adenosylmethionine (SAM), methyl group donor
used in many biologycal methylation reactions,
including the methylation of number of sites within
DNA, RNA, and protein
• Cofactor for L-methylmalonyl-coenzyme A mutase
• 5- Deoxyadenosylcobalamin is required by the
enzyme that catalyzes the conversion of L-
methylmalonyl-coenzyme A to succinyl-coenzyme
A ( succinyl coA), which than enters the citric acid
cycle.
• Succinyl co A plays an important role in production
of energy from lipids and proteins and is also
required for the synthesis of hemoglobin
 DEFICIENCY OF VITAMIN B-12
• Pernicious anemia
• Nerve degeneration, weakness
• Tingling/numbness in the extremities (parasthesia)
• Paralysis and death
• Looks like folate deficiency
• Usually (95%) due to decreased absorption ability
• Achlorhydria especially in elderly
• Injection of B-12 needed
• Takes ~20 years on a deficient diet to see nerve
destruction
• Traps folate in a form that unusable by the body for
DNA synthesis  diminished capacity for methylation
• Elevated rate for DNA damage and alterated
methylation of DNA  risk factor for cancer
 CAUSES OF VITAMIN B12 DEFICIENCY

• Intestinal malabsorbtion
• Atrophic gastritis
• H. Pylori
• Bacterial overgrowth
• Food-bound vitamin B12 malabsorbtion
• Surgical resection of the stomach or portions of
small intestine
PATHOPHYSIOLOGY- DEF. VIT B12

• Megaloblastic anemia is a subgroup of

macrocytic anemias
• Megaloblastic erythropoiesis when defect in DNA
synthesis and the cells are arrested at the G2
phase
• Becomes a build up of cells that do not synthesize
DNA so nucleus develops at a slower rate than
the rest of the cell
• Cytoplasm continues to grow due to RNA
synthesis
• Cells become larger and megaloblastic
 FOOD SOURCES OF VITAMIN B-12

• Synthesized by bacteria, fungi and algae

• (Stored primarily in the liver)
• Animal products
• Organ meat
• Seafood
• Eggs
• Hot dogs
• Milk
 PYRIDOXINE (B6)

• Coenzyme
• Activate enzymes needed for metabolism of CHO,
fat , protein
• Synthesize nonessential amino acid via
transamination
• Synthesize neurotransmitters
• Synthesize hemoglobin and WBC
 B6 DEFICIENCY

Widespread symptoms
• Depression
• Vomiting
• Skin disorders
• Nerve irritation
• Impaired immune system
 B6 TOXICITY

• Nerve damage
• Difficulty walking
• Numbness in hands/feet
 RDA FOR VITAMIN B-6

• 1.3 mg/day for adults

• 1.7 mg/day for men over 50
• 1.5 mg/day for women over 50
• Daily Value set at 2 mg
• Average intake is more than the RDA
• Athletes may need more
• Alcohol destroys vitamin B6
 FOOD SOURCES OF VITAMIN B-6

Well absorbed
• Meat, fish, poultry
• Enriched cereals
• Potatoes
• Milk
Less well absorbed
• Fruits and vegetables: Banana, spinach,
avocado
Heat and alkaline sensitive
 FOLATE

• Coenzyme
• DNA synthesis
• Homocysteine metabolism
• Neurotransmitter formation
 DIGESTION & ABSORPTION

• dietary form: polyglutamyl folate

• glutamate gamma linked
• Folate conjugase
• Zinc deficiency
• alcoholism
• drug interactions
• folate absorbed as monoglutamate (free
folate)
• dietary supplement: free folate
 FOLATE FUNCTIONS
• Single carbon metabolism
 FOLATE FUNCTIONS
• Interconversion of serine and glycine
• ser + THF <---> gly + 5,10-Me-THF
• Degradation of histidine
• his->->->formiminoglutamate(FIGLU)
• FIGLU+THF -> glu + 5-forminino-THF
• Purine and Pyrimidine Synthesis
• dUMP + 5,10-Me-THF -> dTMP + THF
• Methionine Synthesis
• homocysteine + 5-Me-THF -> MET + THF
• MET as a methyl donor for choline synthesis
• histidine load test
• Functional test for folate status
 DEFICIENCY OF FOLATE

• Similar signs and symptoms of vitamin B-12

deficiency
• Anemia
• RBC grow, cannot divide
• Megaloblast: large, immature RBC
• Pregnant women
• Alcoholics
• Megaloblastic Anemia
 FOLATE DEFICIENCY

• Megaloblastic Anemia
• decreased DNA synthesisstrands of DNA more
susceptible to damage
• failure of bone marrow cells to divide
• normal protein synthesis
• results in large immature RBC’s
• contrast with microcytic hypochromic anemia
 NEURAL TUBE DEFECTS

• Neural tube closes first 28 days of pregnancy

• Forms brain and spinal cord
• By the time pregnancy is confirmed, damage
is done
 NEURAL TUBE DEFECTS

• Spina bifida
• Spinal malformation
• Paralysis
• Anencephaly
• No brain cortex
• Stillborn or die within hours
• Importance of folate before and during
pregnancy
• Government requires folate enrichment of
flour and cereal
• May prevent 50% neural tube defects
 FOOD SOURCES OF FOLATE

• Liver
• Fortified breakfast cereals
• Grains, legumes
• Foliage vegetables
• Susceptible to heat, oxidation, ultraviolet light
• Synthetic form better absorbed
 RDA FOR FOLATE

• 400 ug/day for adults

• (600 ug/day for pregnant women)
• Average intake below RDA
• FDA limits nonprescription supplements to 400 ug
per tablet for non-pregnant adults
• OTC Prenatal supplement contains 800 ug
• Excess can mask vitamin B-12 deficiency
• Upper Level set at 1 mg
 FOLATE DEFICIENCY

• Main manifestations
• glossitis, symptoms of anemia (weakness, pallor, shortness of
breath), and GI problems (weight loss and infertility)
• Lab work
• an increase in MCV-- larger than 96 fL
• Best test for folate levels is the red blood cell
level
• this is the level in tissues and is not affected by recent intake
• Recommended intake of folate for adults is 400
micrograms per day, and for women of
childbearing age is 600 micrograms per day
 ANTICONVULSANT DRUGS AND
FOLATE DEFICIENCY

• Recent Drug Study

• Epileptic patients split into control and experimental group
• Experimental group using Phenytoin, Carbamazepine, and
Valproic Acid
• Patients taking the antiepileptic medications had
increased homocysteine levels and decreased red
blood cell levels of folate
• Different Drugs
• No difference in level of homocysteine between all drugs
• Phenytoin shown to have lowest folic acid level
TERIMA KASIH