VITAMIN A FOR MEDICAL STUDENTS

1. VITAMIN A
Dr. Ruchi Gokani

2. VITAMINS
Organic compounds required in the diet
in small amounts to perform specific
biological functions for normal
maintenance of optimum growth and
health of the organisms

3. • Funk (1913) coined the term Vitamine
• Vital + Amine
• Earlier identified ones had amino groups.
• It was later realized that only few of
them are Amines.
• The term Vitamin-continued without the
final letter ‘e’

4. Fat Soluble Vitamin Water soluble Vitamin
Solubility in
Fat
Soluble Not soluble
Water
Solubility
Not soluble Soluble
Absorption Along with lipids requires bile
salts
Absorption simple
Carrier Protein Present
Vitamin A –RBP – Pre albumin
Vitamin D- Specific D binding
Protein
No carrier protein
Storage Stored in liver No storage –Except vita. B12
Excretion Excreted In Stool Excreted in urine
Deficiency Manifests only when vitamin
stored in liver are depleted
Manifest rapidly as there is
no storage
Toxicity Hypervitaminosis Unlikely
Treatment of
Deficiency
Single large doses may prevent Regular Dietary supply is
required
Major Vitamins A D E K B and C

5. Vitamin A
• Vitamin A is a fat soluble Vitamin.
• Present only in foods of animal origin
• Its provitamins carotenes are found in plants
• Chemistry:
• Retinol, retinal and retinoic acid are termed as
vitamers of Vitamin A

6. • This is present in plant foods
• It is cleaved in the intestine to produce two moles
of retinal; but it may produce only one in biological
system
CH3
CH3
β - Carotene
CH3
β-Ionone
CH3 CH3 CH3 CH3 CH3 CH3
H3C
β – Carotene (Pro Vitamin)

7. • It is a primary alcohol containing β-ionone ring
• The side chain has two isoprenoid units, four
double bonds and one hydroxyl group
• Retinols present in animal tissues as retinyl ester
with long chain fatty acids
CH3
CH3
CH2OH
CH3
β-Ionone
CH3 CH3
Retinol
Retinol (Vitamin A Alcohol)

8. Retinal (Vitamin A aldehyde)
• This is an aldehyde form obtained by the oxidation
of retinol.
• Retinal and retinol are interconvertible
CH3
CH3
CHO
CH3
β-Ionone
CH3 CH3
Retinal

9. Retinoic acid (vitamin A acid)
• This is produced by the oxidation of retinal
• Retinoic acid cannot give rise to the formation of
retinal or retinol
CH3
CH3
COOH
CH3
β-Ionone
CH3 CH3

10. • All the compounds with vitamin A activity are
referred as retinoids
• They are poly-isoprenoid compounds having
beta-ionone ring system
• The retinal may be reduced to retinol by retinal
reductase and it is reversible
• Retinal is oxidized to retinoic acid , which cannot
be converted to the other forms
Retinol (alcohol) Retinal (aldehyde)
Retinoic acid
Reductase
NAD+ NADH + H+

11. Absorption of vitamin A
• Intestine is the major site of absorption
• Dietary retinyl esters are hydrolyzed by
pancreatic or intestinal brush border hydrolases,
releasing retinol and free fatty acids
• β- Carotene is cleaved by di-oxygenase of
intestinal cells to release 2 moles of retinal
• Retinal is reduced to retinol by an NADH or
NADPH dependent retinal reductase present in
intestinal mucosa

12. • In the intestinal mucosal cells, retinol is
reesterified to long chain fatty acids,
incorporated into chylomicrons and transferred
to the lymph
• Absorption is along with other fats and requires
bile salts
• In biliary tract obstruction and steatorrhoea,
vitamin A absorption is reduced
• The retinol esters of chylomicrons are taken up
by the liver and stored (As retinol palmitate)

13. • Transport from liver to tissues:
• Vitamin A is released from the liver as retinol
• Zn is essential for retinol metabolism
• Retinol is transported in the circulation by the
retinol binding protein(RBP) in association with
pre-albumin
• One molecule of RBP : One molecule of retinol

14. • The retinol-RBP complex binds to specific
receptors on the cell membrane of
peripheral tissue and enters the cells
• Target cell: Skin, Retina, Gonads and other
tissues

15. • Many cells of target tissues contain a cellular
retinol-binding protein (CRBP) that carries
retinol to the nucleus and binds to the chromatin
(DNA)
• Causing gene expression, results in synthesis
of specific proteins which carry out biochemical
functions of vitamin A.
• Retinol exerts its function in a manner to that of
a steroid hormone
• Retinoic acid is mainly transported in the blood
by binding to albumin

16. (Continued…
Summary of
kinetics

17. …Continues)

18. Intestinal cell
β-Carotene
Retinal
Retinol
Retinyl esters
Chylomicrons
All-trans-retinol
Retinyl palmitate (stored)
Retinol
Retinol-RBP
Target cell
Retinol
Retinoic acid
Nuclear receptor
m-RNA
Specific proteins
Cell differentiation
Retina
All-
transretinol
All-trans
retinal
Visual Cycle
Diet
β-carotene Retinylesters
FFA
Retinol

19. Biochemical functions
• Rods and cones
• The rods are in the periphery while cones are at
the centre of retina
• Rods are involved in dim light vision
• Cones are responsible for bright light and
colour vision
• The number of rods is more in cats, mice and
owls

20. Vitamin A and Vision ( Wald’s visual
cycle)
• Rhodopsin (mol.wt.35,000) is a conjugated
protein present in rods
• It contains 11-cis-retinal and the protein opsin
• The aldehyde group (of retinal) is linked to
ε –amino group of lysine(of opsin)

21. • When light falls on retina, absorption of
light by rhodopsin triggers a series of
biochemical events that leads to
generation of nerve impulse.
• These cyclic events are popularly known
as Wald’s visual cycle.

22. • When light falls on retina, 11-cis-retinal
is isomerized to all-trans-retinal
• This leads to a conformational change
in opsin
• The all-trans retinal is isomerized to 11-
cis-retinal by retinal isomerase (retinal
epithelium)
• This combines with opsin to regenerate
rhodopsin and complete the visual
cycle

23. • Most of the all-trans retinal is transported to
liver and converted to all-trans retinol by
alcohol dehydrogenase, contains Zinc.
• The all-trans retinol is undergoes
isomerization to 11-cis retinol which is
oxidized to 11-cis retinal to participate in the
visual cycle

26. Bleaching of Rhodopsin
• When exposed to light, the color of rhodopsin
changes from red to yellow by a process known as
bleaching
• Bleaching occurs in a few milliseconds and many
unstable intermediates are formed during this
process
• Rhodopsin Prelumirhodopsin Lumirhodopsin
• All-trans-retinal + Opsin metarhodopsin II Metarhodopsin I

27. Visual cascade and cGMP
• The protein Transducin is activated by
metarhodopsin II.
• Involves the exchange of GTP for GDP
on inactive transducin
• The activated transducin activates cyclic
GMP phosphodiesterase
• This enzyme degrades cGMP in rod cells

28. • A rapid decrease in cGMP closes Na+
channels in the membrane of the rod cells
• This results in hyperpolarization resulting in
neuronal signaling.
• it generates electric current, causes
Depolarization of Ganglion cells of Optic
Tract & results in visual impulse

29. Termination if signal
• Quick termination and regeneration of signal.
For fine tuning.
1. Transducin possess intrinsic GTPase activity
2. Rhodopsin kinase phosphorylates
metarhodopsin II
3. Binding of Inhibitory Protein Beta Arrestin to
metarhodopsin II.

31. Dark adaptation mechanism:
• Bright light depletes stores of rhodopsin in rods.
• Therefore when a person shifts suddenly from
bright light to a dimly lit area, there is difficulty in
seeing, for example, entering a cinema theater
• After few minutes rhodopsin is resynthesized
and vision is improved
• It is called as dark adaptation and is
increased in Vitamin-A deficiency
• Rhodopsin present in rods is made up of 11-
cis-retinal + opsin.
• Reduction in number of rodes increases dark adaptation time

32. • Cones are responsible for vision in bright light as
well as color vision
• They contain the photosensitive protein,
conopsin
• There are three types of cones, each is
characterized by a different conopsin, that is
maximally sensitive to either - blue (cyanopsin),
green (iodopsin), red (porphyropsin)
• Reduction in number of cones or cone proteins, will lead to color
blindness
Cones are for color vision

33. Biochemical Role of Vitamin A

34. 1. Retinol and retinoic acid act like steroid
hormones.
2. They regulate the synthesis of proteins (gene
expression) involved in cell growth and
differentiation.
• Retinoic acid receptors (RAR) bind all-trans-
retinoic acid, while retinoic x receptors (RXR)
bind to cis-retinoic acid. RXRs form dimers with
vitamin D-receptor also. This explains why
deficiency of vitamin A impairs vitamin D
function; when there is lack of 9-cis-retinoic acid
to form receptor dimers, vitamin D function is
OTHER BIOCHEMICAL FUNCTIONS OF
VITAMIN A

35. 3. Vitamin A is required for maintenance of healthy
epithelial tissue. It maintains moist and pliable
epithelium by inhibiting the synthesis of excess
keratin (responsible for horny surfaces).
4. Retinoyl phosphate synthesised from retinoic
acid participates in glycoprotein synthesis.
5. Vitamin A is essential for the formation of
mucopolysaccharides in the extracellular
matrix.
(Continued…

36. 6. Vitamin A is essential for the maintenance of
the immune system. Its deficiency causes
keratinisation of the mucosal lining of the
respiratory, gastrointestinal and genitourinary
tracts making them susceptible to frequent
infections.
7. Antioxidant property: carotenoids are natural
antioxidants, reduces incidence of MI, Lung Ca.

37. 8. Retinol and retinoic acid are essential for the
synthesis of transferrin, the iron transporting
protein. Iron deficiency anemia may occur in
vitamin A deficiency.
9. Vitamin A is required for normal reproduction.
Deficiency may lead to miscarriage , Atrophy of
Epithelium & Sterility

38. Recommended dietary
allowance(RDA)
• Children :400-600 μg /day
• Men : 750-1000 μg /day
• Women : 750 μg /day
• Pregnancy : 1000 μg /day

39. • Dietary sources of vitamin A:
• Animal sources: Include milk, butter, cream,
cheese, egg yolk and liver
• Fish liver oils ( cod liver oil and shark liver oil )
are very rich sources of the vitamin A
• Vegetable sources contain yellow pigment beta-
carotene
• Yellow and dark green vegetables and fruits are
good sources of carotenes e.g. carrots, spinach,
pumpkins, mango, papaya etc.
• The darker the green leaves, the higher is its carotene content

40. • Deficiency of vitamin A:
1. Night Blindness or Nyctalopia :
• Dark Adaptation time is increased
• Visual acuity is diminished in dim light

41. 2. Xerophthalmia
• The conjunctiva becomes dry, thick and
wrinkled
• The conjunctiva gets keratinized and loses its
normal transparency
• Dryness spreads to cornea
• It becomes glazy and lusterless due to
keratinization of corneal epithelium

43. 3. Bitot’s spots:
• These are seen as greyish-white triangular
plaques firmly adherent to the conjunctiva in
certain areas.
• This is due to increased thickness of
conjuctiva in certain areas.

44. 4. Keratomalacia:
• When the xerophthalmia persists for a long time,
it progress to keratomalacia (softening of
cornea)
• There is degeneration of corneal epithelium
which may get vascularised
• Later, corneal opacities develop
• Bacterial infection leads to corneal ulceration,
perforation of cornea and total blindness

45. 5. Preventable Blindness
• The deficiency of vitamin A is the most common cause
of blindness in Indian children below the age of 5
6. Skin and Mucous Membrane Lesions
i. Follicular hyperkeratosis or phrynoderma.
• epithelium of the respiratory, gastrointestinal and
genitourinary tract is atrophied. Keratinization of
urinary tract epithelium may lead to urinary calculi.
ii. The alterations in skin may cause increased
occurrence of generalized infections.
iii. Isoretinone, a synthetic variant of vitamin A is known
to reduce the sebaceous secretions, hence it is used to
prevent acne formation during adolescence.

46. Causes of Vitamin A Deficiency:
Decreased Intake
Obstructive Jaundice causing defective
absorption
Cirrhosis of liver leading to reduced synthesis of
RBP
Severe Malnutrition where amino acids are not
available for RBP synthesis
Chronic Nephrosis where RBP is excreted
through urine.

47. Assessment of Vitamin A Deficiency:
• Vitamin A level ( Normal – 25 to 50
microgram/dl)
• S.Vit A level : Car Price Reaction
• Retinol Binding Protein
• Dark Adaptation Test