2. Vitamin A is a fat soluble vitamin
Required for vision, repair, reproduction, growth
and tissue differentiation
Two groups of compounds have vitamin A activity
Retinoids and
Carotenoids
07/30/15Biochemistry for medics- Lecture Notes 2
3. Vitamin A, in the strictest sense, refers to retinol.
However, the oxidized metabolites, retinaldehyde
and retinoic acid, are also biologically active
compounds.
The term Retinoids includes all molecules
(including synthetic molecules) that are chemically
related to retinol.
07/30/15Biochemistry for medics- Lecture Notes 3
4. • There are more than 600 carotenoids in
nature, and approximately 50 of these can
be metabolized to vitamin A.
• β-Carotene is the most prevalent carotenoid
in the food supply that has provitamin A
activity.
• In humans, significant fractions of
carotenoids are absorbed intact and are
stored in liver and fat.
• The α-, β-, and γ-carotenes and
cryptoxanthin are quantitatively the most
important provitamin A carotenoids.
07/30/15Biochemistry for medics- Lecture Notes 4
6. 07/30/15Biochemistry for medics- Lecture Notes 6
•Site of β cleavage of carotene is shown by *
•Although it would appear that one molecule of β carotene should
yield two of retinol, this is not so in practice
•6 μg of β carotene is equivalent to 1μ g of preformed retinol.
•The total amount of vitamin A in foods is therefore expressed as
micrograms of retinol equivalents.
7. • Liver, fish, and eggs are excellent
food sources for preformed vitamin
A;
• Vegetable sources of provitamin A
carotenoids include dark green and
deeply colored fruits and
vegetables.
• Moderate cooking of vegetables
enhances carotenoid release for
uptake in the gut.
• Carotenoid absorption is also aided
by some fat in a meal.
07/30/15Biochemistry for medics- Lecture Notes 7
8. Dietary Vitamin A, from
animal sources is available in
the form of Retinyl esters,
which is hydrolyzed to retinol
and fatty acid by pancreatic
hydrolases
The absorption of retinol
requires the presence of bile
salts
In the intestinal cells, retinol
is esterified back and
secreted with chylomicrons
07/30/15Biochemistry for medics- Lecture Notes 8
Retinyl esters
Fatty acid + Retinol
9. • β-Carotene is cleaved in the
intestinal mucosa by carotene
dioxygenase, yielding retinaldehyde,
which is reduced to retinol,
esterified and secreted in
chylomicrons together with esters
formed from dietary retinol.
• The intestinal activity of carotene
dioxygenase is low, so that a
relatively large proportion of
ingested β -carotene may appear in
the circulation unchanged.
07/30/15Biochemistry for medics- Lecture Notes 9
10. • The liver contains approximately 90% of the
vitamin A reserves and secretes vitamin A in the
form of retinol, which is bound to retinol-
binding protein.
• The retinol-binding protein complex interacts
with a second protein, Transthyretin.
• This trimolecular complex functions to prevent
vitamin A from being filtered by the kidney
glomerulus, to protect the body against the
toxicity of retinol and to allow retinol to be
taken up by specific cell-surface receptors that
recognize retinol-binding protein.
07/30/15Biochemistry for medics- Lecture Notes 10
12. • Vitamin A is essential for vision (especially
dark adaptation),
• Immune response,
• Bone growth,
• Reproduction,
• Maintenance of the surface linings of the
eyes, epithelial cell growth and repair, and
the epithelial integrity of the respiratory,
urinary, and intestinal tracts.
• Vitamin A is also important for embryonic
development and the regulation of adult
genes.
07/30/15Biochemistry for medics- Lecture Notes 12
13. • In the retina, retinaldehyde functions as the
prosthetic group of the light-sensitive opsin
proteins, forming Rhodopsin (in rods) and
iodopsin (in cones).
• Any one cone cell contains only one type of
opsin, and is sensitive to only one color.
• The absorption of light by Rhodopsin causes
isomerization of the retinaldehyde from 11-cis to
all-trans, and a conformational change in opsin.
• This results in the release of retinaldehyde from
the protein, and the initiation of a nerve
impulse.
07/30/15Biochemistry for medics- Lecture Notes 13
14. The formation of the initial excited form of
Rhodopsin, bathorhodopsin, occurs within
picoseconds of illumination.
There are then a series of conformational
changes leading to the formation of
metarhodopsin II, which initiates a guanine
nucleotide amplification cascade and then a
nerve impulse.
07/30/15Biochemistry for medics- Lecture Notes 14
15. The final step is hydrolysis to release all-
trans-retinaldehyde and opsin.
The key to initiation of the visual cycle is the
availability of 11-cis-retinaldehyde, and
hence vitamin A.
In deficiency, both the time taken to adapt
to darkness and the ability to see in poor
light are impaired.
07/30/15Biochemistry for medics- Lecture Notes 15
17. Retinoic acid is a ligand for certain nuclear
receptors that act as transcription factors.
The retinoid receptors play an important role in
controlling cell proliferation and differentiation.
Like vitamin D, retinoic acid interacts with
nuclear receptors that bind to control elements
which are specific regions on the DNA to
regulate the expression of specific genes.
07/30/15Biochemistry for medics- Lecture Notes 17
18. Two families of receptors (RAR and RXR receptors) are
active in retinoid-mediated gene transcription. RAR
binds all-trans retinoic acid and 9-cis retinoic acid,
whereas RXR binds only 9-cis retinoic acid.
07/30/15Biochemistry for medics- Lecture Notes 18
19. All-trans-RA and 9-cis-RA are transported
to the nucleus of the cell bound to
cytoplasmic retinoic acid-binding
proteins.
Within the nucleus, all-trans-RA binds to
retinoic acid receptors (RAR) and 9-cis-RA
binds to retinoid receptors (RXR).
RAR and RXR form RAR/RXR heterodimer,
which bind to regulatory regions of the
chromosome called retinoic acid
response elements (RARE).
07/30/15Biochemistry for medics- Lecture Notes 19
20. Binding of all-trans-RA and 9-cis-RA to RAR
and RXR respectively allows the complex to
regulate the rate of gene transcription.
Nuclear Receptors in the Gonads increase
gene expression and maintain reproductive
tissues while nuclear receptors in epithelial
cells regulate cell differentiation.
07/30/15Biochemistry for medics- Lecture Notes 20
21. 1) Vitamin A and retinoic acid (RA) play a central role
in the development and differentiation of white
blood cells, such as lymphocytes, which play critical
role in the immune response.
2) The skin and mucosal cells (function as a barrier
and form the body's first line of defense against
infections. Retinol and its metabolites are required to
maintain the integrity and functioning of these cells.
Keratinization of mucous membranes in vitamin A
deficiency add up to the risk to infections.
3)Retinol binding protein (RBP) is a negative ‘Acute
phase protein’, that results in decreased circulatory
concentration of the vitamin with further
deterioration of the immune system.
07/30/15Biochemistry for medics- Lecture Notes 21
22. Vitamin A is required for-
General body growth
Bone and
Brain development
07/30/15Biochemistry for medics- Lecture Notes 22
23. Vitamin A deficiency can result from
inadequate intake, fat malabsorption, or
liver disorders.
Deficiency impairs immunity and
hematopoiesis and causes skin rashes and
typical ocular effects (e.g., xerophthalmia,
night blindness).
Diagnosis is based on typical ocular findings
and low vitamin A levels.
Treatment consists of vitamin A given orally
or, if symptoms are severe or malabsorption
is the cause, parenterally.
07/30/15Biochemistry for medics- Lecture Notes 23
24. Primary vitamin A deficiency
o Prolonged dietary deprivation
o Vegetarians,
o Refugees, and
o Chronic alcoholics,
o Toddlers and
o Preschool children
07/30/15Biochemistry for medics- Lecture Notes 24
25. Secondary vitamin A deficiency
o Sprue,
o Cystic fibrosis,
o Pancreatic insufficiency,
o Duodenal bypass,
o Chronic diarrhea,
o Bile duct obstruction,
o Giardiasis, and cirrhosis.
07/30/15Biochemistry for medics- Lecture Notes 25
26. Bitot spots - Areas of abnormal
squamous cell proliferation and
keratinization of the conjunctiva
can be seen in young children with
VAD.
Blindness due to retinal injury -
Vitamin A has a major role in
photo transduction. VAD leads to a
lack of visual pigments;
this reduces the absorption
of various wavelengths of light,
resulting in blindness.
07/30/15Biochemistry for medics- Lecture Notes 26
27. Poor adaptation to darkness (nyctalopia),
which can lead to night blindness, is an early
symptom.
Xerophthalmia results from keratinization of
the conjunctiva.
Keratomalacia- In advanced deficiency; the
cornea becomes hazy and can develop
erosions, which can lead to its destruction
(Keratomalacia).
07/30/15Biochemistry for medics- Lecture Notes 27
28. Increased susceptibility to infections-
Keratinization of the mucous membranes of
respiratory tracts and urinary tract takes
place, increasing the susceptibility to
infections.
During infection the synthesis of retinol binding
protein is reduced in response to infection
since it is a negative ‘Acute phase protein’,
that results in decreased circulatory
concentration of the vitamin with further
deterioration of the immune system.
07/30/15Biochemistry for medics- Lecture Notes 28
29. Fatigue
Anemia
Diarrhea
Respiratory infections
Decreased growth rate
Decreased bone development
Infertility
07/30/15Biochemistry for medics- Lecture Notes 29
30. Serum retinol level-Normal range is 28 to 86
μg/dL (1 to 3 µmol/L). The level decreases in
vitamin A deficiency.
Serum RBP level
Serum zinc level is useful because zinc
deficiency interferes with RBP production.
An iron panel is useful because iron
deficiency can affect the metabolism of
vitamin A.
07/30/15Biochemistry for medics- Lecture Notes 30
31. Albumin levels are indirect measures of
vitamin A levels.
Complete blood count (CBC) with
differential if anemia, infection, or sepsis is
a possibility.
An electrolyte evaluation and liver function
studies should be performed to evaluate for
nutritional and volume status.
07/30/15Biochemistry for medics- Lecture Notes 31
32. In children, radiographic films of the long
bones may be useful when an evaluation is
being made for bone growth and for excessive
deposition of periosteal bone
07/30/15Biochemistry for medics- Lecture Notes 32
33. Any stage of xerophthalmia should be
treated with 60 mg of vitamin A in oily
solution, usually contained in a soft-gel
capsule.
Mothers with night blindness or Bitot's spots
should be given vitamin A orally.
A common approach to prevention is to
supplement young children living in high-risk
areas with 60 mg every 4–6 months, with a
half-dose given to infants 6–11 months of
age.
07/30/15Biochemistry for medics- Lecture Notes 33
34. Extremely low-birth-weight infants (<1000
g), are likely to be vitamin A–deficient and
should be supplemented with 1500 μg (or
RAE) of vitamin A, three times a week for 4
weeks.
Children hospitalized with measles should
receive two 60-mg doses of vitamin A on two
consecutive days.
The patients with malabsorption syndrome
require vitamin A supplements.
07/30/15Biochemistry for medics- Lecture Notes 34
35. The diet should include dark green leafy
vegetables, deep- or bright-colored fruits
(e.g., papayas, oranges), carrots, and yellow
vegetables (e.g., squash, pumpkin).
Vitamin A–fortified milk and cereals, liver,
egg yolks, and fish liver oils are helpful.
Carotenoids are absorbed better when
consumed with some dietary fat.
07/30/15Biochemistry for medics- Lecture Notes 35
36. In developing countries, prophylactic
supplements of vitamin A palmitate in oil
60,000 RAE (200,000 IU) po every 6 mo are
advised for all children between 1 and 5 years
of age
Infants < 6 mo can be given a one-time dose of
15,000 RAE (50,000 IU), and
those aged 6 to 12 mo can be given a one-time
dose of 30,000 RAE (100,000 IU).
07/30/15Biochemistry for medics- Lecture Notes 36
37. Vitamin A toxicity can be acute (usually due to
accidental ingestion by children) or chronic.
Both types usually cause headache and
increased intracranial pressure.
Acute toxicity also causes nausea and vomiting.
07/30/15Biochemistry for medics- Lecture Notes 37
38. Chronic toxicity also causes changes in skin,
hair, and nails; abnormal liver test results;
and, in a fetus, birth defects.
Diagnosis is usually clinical. Unless birth
defects are present, adjusting the dose
almost always leads to complete recovery.
07/30/15Biochemistry for medics- Lecture Notes 38
39. Vitamin A deficiency can result from
inadequate intake, fat malabsorption, or liver
disorders.
Deficiency impairs immunity and hematopoiesis
and causes skin rashes and typical ocular
effects (e.g., xerophthalmia, night blindness).
07/30/15Biochemistry for medics- Lecture Notes 39
40. Diagnosis is based on typical ocular findings
and low vitamin A levels.
Treatment consists of vitamin A given orally
or, if symptoms are severe or malabsorption
is the cause, parenterally.
Excessive intake can lead to toxicity since
the vitamin is stored in the body.
07/30/15Biochemistry for medics- Lecture Notes 40