Download Vitamin A

TUMS
Azin Nowrouzi, PhD
Vitamin classification
Name(Letter)
RDI
Retinol (A)
5000 IU
Calciferol (D)
400 IU
Tocopherol (E)
30 IU
Phylloquinone (K) 70 g
Fat-soluble Vitamins
• Absorbed with dietary fat in small intestine
• 40-90% absorption efficiency
• Absorption typically regulated by need
– need absorption
• Transported away from small intestine in
chylomicra via blood and lymph (depending on
size)
• They are not easily excreted through urine.
• Substantial amounts are stored in liver and fat
tissue.
• Therefore, toxicity is possible.
Vitamin A
Compounds with 20-carbon structure.
Contain a methyl substituted cyclohexenyl ring (-ionone ring),
and an isoprenoid side chain with either a hydroxyl group, and aldehyde
group, a carboxylic acid group, or an ester group (retinyl ester) at the
terminal C15.
All-trans-retinal
Retinol
11-cis-retinal
Retinoic Acid
Can’t be reduced to retinol or retinal in the body.
Vitamin A
1.
Active vitamin A- Preformed vitamin A can be obtained
either directly from foods that are substantial in vitamin
A (beef liver, fish liver oils, egg yolks and butter)
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2.
The active form of vitamin is retinol, an alcohol which can be
converted to other forms (e.g. vitamin A esters) for storage in liver
and tissues.
much the body's vitamin A is stored in the liver as retinyl palmitate
Provitamin A- provitamins, substances that are
transformed into vitamins in the body
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Beta-carotene is the most abundant and widespread provitamin A.
Beta-carotene comes from a group of compounds called the
"carotenoids (C40 polyisoprenoids).
One need to eat approximately six times as much beta-carotene
to get the same amount of vitamin A as in retinol.
Dark-green leafy vegetables (spinach) and yellow-orange
fruits (apricots and mango) and vegetables (carrots, yellow
squash and sweet potatoes) are high in beta-carotene and other
carotenoids (-carotene, -cryptoxathin, etc.)
Carotenoids are not toxic even at high doses for long times.
Vitamin A: Absorption and transport
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Micelle formation
Inside mucosal cell -carotene is
cleaved in the lumen of the intestine
by -carotene dioxygenase to yield
retinal.
Retinal is reduced to retinol by
retinal reductase, an NADPH
requiring enzyme within the
intestines.
Retinol is esterified to palmitic acid
and delivered to the liver with
chylomicrons via lymphatic system.
- Carotenoids which escape intestinal
conversion to retinol can be stored in
adipose tissue.
- Species in which this occurs include
humans, horses and cattle, which
have yellow-pigmented body fat when
carotenoid intake is high.
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Vitamin A absorption efficiency 7090%; carotenoids 9-22%.
Vitamin A: Biological functions
• Role in vision. Vitamin A (retinal) is an essential precursor for
formation of the visual pigment, rhodopsin, in the retina of the
eye. Retinal plays an important role in vision, especially night
vision. Lowers cataract incidence.
• Role in growth. Helps regulate cell development, cell
differentiation and cell division.
• Role in Bone and teeth formation. Promotes the proper growth
of bones and teeth. Bone cells (osteoblasts and osteoclasts)
depend on vitamin A for their normal functioning.
– Is important in the formation and maintenance of healthy hair, skin
and mucous membranes.
• Role in reproduction. Vitamin A holds an important place in
sexual reproduction. Adequate levels of vitamin A are needed for
normal sperm production. The female reproductive cycle
requires sufficient amounts of vitamin A.
• Boosts the body's immune system helping to increase body
resistance to infectious diseases.
Role of Vitamin A in Vision
(Wald’s visual cycle)
1. When the rhodopsin is exposed to light it is bleached releasing the
11-cis-retinal from opsin.
2. Isomerization of the cis-isomer of retinal to all-trans-retinal, causes
conformational changes in rhodopsin, hyperpolarization of the retinal
rod cell, and extremely rapid transmission of electrical activity to the
brain via the optic nerve
3. Trans-retinal is isomerized to cis-retinal in the dark, which
associates with opsin to regenerate rhodopsin.
All trans retinol
= main circulating
form of Vit A
Visual Pigment
Vitamin A: Biological functions
(Cell growth and differentiation)
• Regulation of gene expression by retinoic acid,
the acid form of vitamin A
• Retinoic acid is formed within the target cell from
retinol transported in the bloodstream.
• Retinoic acid, combined with protein receptor,
acts as transcription regulator by binding to
specific sequences of DNA in the nucleus
• Affected cells include epithelium of numerous
tissues, including skin and gut, and bone, ovary
and testis.
• Retinoic acid is an especially important regulator
of embryonic cell differentiation.
Problems associated with Vitamin A
Vit. A deficiency:
1. Night blindness" - lessened
ability to see in dim light.
2. Increased susceptibility to
infection and cancer and
anemia equivalent to iron
deficient.
3. Prolonged lack of vitamin A
(keratinization of the cornea,
a condition known as
xerophthalmia).
4. Abnormal bone development
in fetal and neonatal life.
Skeletal malformations
spontaneous fractures
internal hemorrhages
loss of appetite
slow growth or weight loss
5. Various congenital defects.
Vit A excess
• Hypervitaminosis A in humans
– Symptoms include dry, pruritic
skin with excessive itching and
increase in intracranial pressure.
– is becoming an increasing
problem in Western countries
because of self-medication and
overprescription.
– has occurred through eating
polar bear or seal liver by polar
explorers.
• Eat polar bear liver sparingly, 30
grams contain 450,000 IU of
retinol! Continued ingestion
causes peeling of the skin from
head to foot.
• It is possible that some early
Arctic explorers died from eating
their sled dogs in an attempt to
survive.
Vitamin A: Uses
Retinol and its precursors are used as dietary supplements to prevent
deficiency symptoms.
Retinoic acid is used in dermatology to cure acne and psoriasis:
1. Mild acne (Darier’s disease) and aging
Topical application of tretinoin (all-trans retinoic acid), along with
benzoyl peroxide and antibiotics.
2. severe recalcitrant cystic acne
Oral consumption of isotretinoin (13-cis retinoic acid). This drug is
teratogenic. Should not be prescribed during pregnancy. It may lead
to hyperlipidemia and increased LDL/HDL ratio (increased chance of
heart disease) in long term.
Vitamin D
• Vitamin D is a family of fat-soluble
sterol compounds:
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Vitamin D1 (lamisterol)
Vitamin D2 (ergocalciferol)
Vitamin D3 (cholecalciferol)
Vitamin D4 (dihydroergocalciferol)
Vitamin D5 (7-dehydrositosterol)
Vitamin D: Types and Sources
• For humans, the two most important forms of
vitamin D are:
– vitamin D2
– vitamin D3.
• Vitamin D2 (ergocalciferol) is derived from
plants and irradiated yeast and fungi.
• Vitamin D3 is synthesized in the body when
skin is exposed to sunlight
– Cholesterol + sunshine = Vitamin D3
– “sunshine vitamin” – UV-B rays (5-10 minutes arms
and legs, mid-day sun).
• Vitamin D3 can be obtained from foods like
milk, fortified cereals, tuna, salmon and fish
oils.
Sunlight
Vitamin D2
(Ergocalciferol)
Ergosterol
(in plants)
Diet
Sunlight
7-Dehydrocholesterol
Vitamin D3
Cholecalciferol)
Activation of Vitamin D
• Vitamin D2 and vitamin D3
are biologically inactive but
can have equal biological
activity:
• Both can be converted first to
calcifediol in the liver and then
to calcitriol, also known as
1,25-dihydroxycholecalciferol,
in the kidneys.
• Calcitriol, which is the most
active form of vitamin D3, is
then transported via a carrier
protein to the various sites in
the body where it is needed.
Calcitriol is also called
1,25-dihydroxy vitamin D3,
or (1,25-(OH)2D3.
1,25-dihydroxyvitamin D3
Conversion of 25-(OH)D3 to its
biologically active form, calcitriol,
occurs through the activity of a
specific D3-1-hydroxylase present
in the proximal convoluted tubules
of the kidneys, and in bone and
placenta. Cytochrome P450, O2
and NADPH are needed.
25-hydroxyvitamin D3
In the liver cholecalciferol is
hydroxylated at the 25 position
by a specific D3-25-hydroxylase
generating 25-hydroxy-D3 [25(OH)D3] which is the major
circulating form of vitamin D.
Functions of vitamin D
• Vitamin D regulates the calcium and phosphorus
levels in the blood by promoting their absorption
from food in the intestines, and by promoting reabsorption of calcium in the kidneys.
• It promotes bone formation and mineralization and
is essential in the development of an intact and
strong skeleton.
• It inhibits parathyroid hormone secretion from the
parathyroid gland.
• Vitamin D affects the immune system by promoting
immunosupression, phagocytosis, and anti-tumor
activity.
Vitamin D:
Hormone for Calcium and Phosphate regulation
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Calcium is vital for nerve cell transmissions and muscle
fiber contractions.
Calcitriol functions in concert with parathyroid hormone
(PTH) and calcitonin to regulate serum calcium and
phosphorous levels by:
1.
2.
3.
Increasing dietary calcium absorption from the small intestine.
Decreasing the urinary calcium excretion (increasing renal
reabsorption).
Stimulating resorption of calcium from bone
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Instrumental in the growth, hardening and repair of bones.
Too much vitamin D, however, can increase calcium losses from bone
Vitamin D is essential for normal insulin secretion by the
pancreas and therefore control of blood sugar levels.
Effects of PTH and Vit D3
When vitamin D goes abnormal
• Too little (northern latitudes) leads to Vit D
deficiency:
– Rickets (bone deformities in children)
– Osteoporosis
– Osteomalacia (weak bones)
– Demineralization of bones
• Too much (5 times the RDA, chronically): It
is most toxic of the vitamins.
– Nausea, thirst, loss of appetite, stupor
– Hypercalcemia: calcium gets deposited in soft
tissues, arteries and kidneys.
Diseases caused by deficiency
• Vitamin D malnutrition may also be linked to an increased
susceptibility to several chronic diseases such as
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High blood pressure
tuberculosis
cancer
periodontal disease
multiple sclerosis
chronic pain
depression
schizophrenia
several autoimmune diseases
• The American Pediatric Associations advises vitamin D
supplementation of 200 IU/day (5μg/d) from birth onwards.
• Liquid "drops" of vitamin D for infants.
Vitamin E
A family of eight different molecules. Four of the eight vitamin E molecules
are called tocopherols (alpha, beta, gamma and delta) [also known as
“Natural Tocopherols”] while the remaining four are called tocotrienols
(alpha, beta, gamma and delta). D-alpha-tocopherol is the most biologically
active in humans.
-Tocopherol
is the most potent
of the tocopherols.
Functions
• Vitamin E in the form of d-alpha-tocopherol is an important fat-soluble
antioxidant, scavenging oxygen free radicals, lipid peroxy radicals and
singlet oxygen molecules before these radicals can do further harm to
cells. [Free radicals are very reactive atoms or molecules that typically
possess a single unpaired electron.]
• New studies have revealed that the tocotrienol forms of vitamin E are
even more potent antioxidants than the tocopherol isomers.
• Vitamin E helps maintain the structural integrity of cell membranes
throughout the body.
• d-alpha-tocopherol has been shown to inhibit the "clumping" of blood
platelets (thus helping to avoid blood clots) and enhancing vasodilation
(the opening of blood vessels).
• d-alpha-tocopherol protects the fat component in low-density
lipoproteins (LDLs) from oxidation and has shown moderate
cholesterol-lowering capabilities. Studies have shown that gammaand delta-tocotrienols may be better suited than the tocopherols at
inhibiting the manufacture of cholesterol in the liver and hence in
contributing to a greater cholesterol lowering effect.
Vitamin E (deficiency)
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Deficiency: rare in adults usually due to impaired fat absorption or transport;
seen usually in children (anemia, edema in infants)
– Muscular dystrophy
– Hemolytic anemia
– Dietary hepatic necrosis
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Excess: very safe below 800 IU/day
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Source:
– Vitamin E is present in animal fats, meat, green vegetables, nuts/seeds.
– Alpha-tocopherol is found in a number of vegetable oils, including safflower and
sunflower. It is also found in wheat germ. Soybean and corn oils contain mainly
gamma-tocopherol.
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Storage of vitamin E is limited. Vitamin E is stored in high amounts in the
pituitary gland and the adrenals. The liver briefly stores vitamin E but only in
small quantities. Adipose tissue.
Estimated requirements: 5mg/day = 0.6mg/day of unsaturated fat.
Uses:
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Hemolytic anemia in premature infants, unresponsive to B12, Fe and folic acids.
Macrocytic megaloblastic anemia seen in children with severe protein-calorie malnutrition.
The symptoms of Vitamin E deficiency
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Muscle weakness
lethargy
apathy
a lack of
vitality
indigestion
muscle cramps
inability to concentrate
irritability
disinterest in physical
activity
red blood cell breakage
anemia
neurological problems
• An increasing body of
evidence is emerging to
implicate free radical
activity in the
pathogenesis of
periodontal breakdown.
• Inadequate antioxidant
availability could either
predispose the host to
the disease, or modify
the progression of a
pre-existing disease.
Free Radicals - the Metabolic Oxidizers
Free radical = unpaired electron very reactive
.
OH
OH
.
OH
OH
Oxygen radicals: Hydroxy (HO•) / Peroxy (HOO•)
An antioxidant is a chemical so easily
oxidized itself that it protects others from oxidation.
OH
and / or
Double Bond
eg. Vitamin A
Phenol
eg. Vitamin E or C
Antioxidant
The antioxidant
neutralizes a free
radical by donating an
electron.
Vitamin K
• The "K" in vitamin K comes from the German
word "koagulation," which refers to blood
clotting (coagulation).
• Vitamin K is essential for the functioning of
several proteins involved in normal blood
clotting.
• There are several forms K1-K7
Vitamin K1 (Phylloquinone)
• Naturally occurring vitamin K is absorbed from the
intestines only in the presence of bile salts and other lipids
through interaction with chylomicrons. Therefore, fat
malabsorptive diseases can result in vitamin K deficiency.
• Source: Present in green leafy vegetables like lettuce,
parsley, spinach and various greens (beet and mustard).
Broccoli and certain vegetable oils (soybean, cottonseed,
and olive).
are also a good source of vitamin K1.
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Vitamin K2 (Menaquinone)
• Vitamin K2 is a group of compounds called the "menaquinones."
• Synthesized by intestinal bacteria "n" can be 6, 7 or 9 isoprenoid
groups.
– The number of isoprene residues in the side chain of the vitamin
K2 molecule designate the individual menaquinone compounds,
e.g., menaquinone-4 (MK-4) has four isoprene units in the side
chain of vitamin K2; menaquinone-7 (MK-7) has seven isoprene
units in the side chain.
• Source: Vitamin K2, which is the most biologically active form of
vitamin K, is found in egg yolks, butter, liver, cheddar cheese and
yogurt.
• It has been suggested that products like yogurt, may help to increase
the functioning of these useful bacteria.
Vitamin K3 (Menadione)
• The synthetic (man-made)
vitamin K3 is water soluble
and absorbed irrespective
of the presence of
intestinal lipids and bile.
Uses : essential cofactor in blood clotting.
Excess: Dangerous if taking anti-coagulants.
Hemolytic anemia, jaundice in infants.
Functions
1. Blood coagulation
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Post-translational carboxylation of some glutamate
residues in blood factors.
Vitamin K is needed for the body to make four of the
blood's coagulation factors, including prothrombin
(also known as factor II), proconvertin (factor VII),
Christmas factor (factor IX) and the Stuart-Power
factor (factor X).
It occurs in the liver
Vitamin K has to change to Hydroquinoine to function
as coenzyme for carboxylase.
2. Calcium binding proteins
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Carboxylation of specific glutamate residues in
calcium binding proteins.
3. Role in oxidative phosphorylation
Prothrombin -Carboxylation
Vitamin K role in -Carboxylation
Causes of Deficiency
1. Prolonged use of antibiotics
2. Malabsorption and biliary tract obstruction
3. Spoilt sweet-clover hay
– Contains dicumarol (vit K antagonist)
4. Short circuiting of the bowel
5. In immediate post-natal infants
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(bruising/bleeding in infants).
Sterile bowels (no intestinal microflora)
Low Vit K in mothers milk
Hemorrhagic disease of the newborn.
Too Much Broccoli !
Two women with diseases characterized by abnormal blood
clotting did not improve when they were given Warfarin.
When questioned about their diets, one woman reported
that she ate at least a pound of broccoli every day, and the
other ate broccoli soup and a broccoli salad every day.
When broccoli was removed from their diets, warfarin
became effective in preventing the abnormal clotting of their
blood.
Because broccoli is high in vitamin K, these patients had
been getting enough dietary vitamin K to compete with the
drug, thereby making the drug ineffective.
What do vitamins do?
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Metabolically they have diverse functions as:
Coenzymes (B vitamins, vitamin K)
Hormones (retinoic acid, vitamin D)
Modulators or regulators of growth and
development (retinoic acid, folic acid)
• (apparently non-specific) antioxidants
(Vitamins C and E)
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Vitamin C:
Bleeding gums
Loose teeth
Poor healing
Cofactors and coenzymes
Other coenzymes
Coenzyme Q = Ubiquinone
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A lipid in inner membrane of mitochondria.
Moves freely within membrane.
Carries electrons.
Coenzyme Q10 (CoQ 10) or ubiquinone is essentially a vitamin or vitamin-like
substance.
– (1) fish; (2) organ meats, including liver, kidney and
heart; and (3) the germs of whole grains
– It is synthesized in all tissues.
– The biosynthesis of CoQ10 from the amino acid tyrosine requires at least eight
vitamins and several trace elements.
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Coenzyme Q10 is the coenzyme for at least three mitochondrial enzymes
(complexes I, II and III) as well as enzymes in other parts of the cell.
CoQ10 has been studied in its reduced form as a potent antioxidant.
2H++2e
Coenzyme Q
Coenzyme Q
Coenzyme Q - 'promoted' to a Vitamin?
O
CH3O
CH3
CH3
CH3O
O
C
H2 C
H
C
H2
H
10
A vital 'transport agent' in the use of oxygen to generate
energy, especially in the heart muscle.
Supplements do aid in many forms of heart disease,
gum disease, BUT >> slows Parkinsons/Alzheimers/
aging, relieves allergies, boosts athletic performance
and immunity, aids weight loss ?!
Causes of Deficiency
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Significantly decreased levels of CoQ10 have
been noted in a wide variety of diseases in
both animal and human studies.
CoQ10 deficiency may be caused by
1.
2.
3.
Insufficient dietary CoQ10.
Impairment in CoQ10 biosynthesis.
Excessive utilization of CoQ10 by the body
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excessive exertion
hypermetabolism
acute shock states
4. or any combination of the three.
5. Drugs can cause CoQ deficiency
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HMG-CoA reductase inhibitors used to treat elevated blood cholesterol levels by
blocking cholesterol biosynthesis also block CoQ10 biosynthesis.
The resulting lowering of blood CoQ10 level is due to the partially shared
biosynthetic pathway of CoQ10 and cholesterol.
Phytochemicals
Non-nutrient compound
Found in plant-derived foods and have biological activity
in the body.
Some categories:
Antioxidants (anti-aging/cancer/heart disease?) catechins (berries, green/black tea), lycopene
(tomatoes,watermelon), bioflavanoids (citrus
fruit, grapes), coenzyme Q (nuts,oils).
Estrogen mimics (cancer inhibitors?) indoles (broccoli, cauliflower), isoflavones
(legumes), lignans & omega-3- fatty acids
(canola, flaxseed), genistein (soy).
Lycopene = red pigment in tomatoes, red
grapefruit, watermelon
Plant Pigments = Potent Antioxidants
Almost 2000 known plant pigments. >800 flavonoids,
~450 carotenoids and ~150 anthocyanins.
Red (lycopene) – tomatoes, pink/red grapefruit,
watermelon, guava, red peppers.
Red/Blue/Purple (anthocyanins) – red/blue grapes,
blue-/straw-/raspberries, beets, cherries,
egg plant, plums, red cabbage.
Orange (carotene) – squash, pumpkin, yams,
carrots,
mango, cantaloupe.
Plant Pigments = Phytochemicals
Orange/Yellow (cryptoxanthin) – peach, orange,
nectarine, papaya.
Yellow/Green (lutein), zeaxanthin =
especially good for health of eyes) –
corn, cucumber skins, yellow/green
peppers, green beans/peas, spinach,
honeydew melon, kiwi, romaine lettuce,
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