Vitamin A

Gandham. Rajeev

Department of Biochemistry,Akash Institute of Medical Sciences & Research Centre,Devanahalli, Bangalore, Karnataka, India.

eMail: gandhamrajeev33@gmail.com

VITAMINSVitamins may be regarded as 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

Hopkins coined the term Accessory factors to

the unknown and essential nutrients

present in the natural foods

• Funk (1913) is isolated an active principle

(an amine) from rice polishings and , later

yeast, which could cure beri-beri in pigeons.

• He 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’

Classification

• All vitamins are broadly divided into two

groups according to solubility.

• Fat-soluble

• Vitamin-A

• Vitamin-D

• Vitamin-E

• Vitamin-K

Water-soluble

• A) Vitamin-C (Ascorbic acid)• B) Vitamin B-Complex group includes:– Vitamin - B1 (Thiamine)– Vitamin – B2 (Riboflavin)– Niacin (Nicotinic Acid)– Vitamin – B6 (Pyridoxine)– Pantothenic Acid– Folic acid– Vitamin – B12 (Cyanocobalamine)– Biotin– Α- Lipoic acid

VITAMINS

Fat SolubleWATER SOLUBLE

- Vitamin-A

-Vitamin-D

-Vitamin-E

-Vitamin-K

NON B - COMPLEX

Vitamin-C

B-Complex

ENERGY-RELEASING Hemopoietic-Thiamine

(B1)-Riboflavin

(B2)-Niacin

(B3)-Pyridoxine (B6)-Biotin

(B7)-Pantothenic Acid (B5)

-Folic Acid (B9)

-Vitamin B12(Cyanocobalam

in

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

Retinol (vitamin A alcohol)

• 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 acidsCH3CH3 CH2OH

CH3β-Ionone

CH3 CH3

Retinol

Retinal (Vitamin A aldehyde)

• This is an aldehyde form obtained by the

oxidation of retinol.

• Retinal and retinol are interconvertible

CH3CH3CHO

CH3β-Ionone

CH3 CH3

Retinal

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

CH3CH3COOH

CH3β-Ionone

CH3 CH3

β- Carotene (provitamin A)

• 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

CH3CH3

β - CaroteneCH3β-Ionone

CH3 CH3 CH3 CH3 CH3 CH3

H3C

• 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 formsRetinol

(alcohol)

Retinal (aldehyde)

Retinoic acid

Reductase

NAD+NADH +

H+

Absorption of vitamin A

• 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

• In the intestinal mucosal cells, retinol is

reesterified to long chain fatty acids,

incorporated into chylomicrons and

transferred to the lymph

• Intestine is the major site of absorption

• 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)

• 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 binds one molecule of

retinol

• The retinol-RBP complex binds to specific

receptors on the cell membrane of peripheral

tissue and enters the cells

• Many cells of target tissues contain a

cellular retinol-binding protein (CRBP) that

carries retinol to the nucleus and binds to

the chromatin (DNA)

• 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

• Small amounts of retinoic acid in the blood

is also transported in combination with

apo-retinol binding protein

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-transretin

ol

All-trans retinal

Visual Cycle

Diet

β-carotene Retinylesters

Retinol

FFA

Biochemical functions

• Rods and cones

• The retina of the eye possesses two types of cells

– rods and cones

• The human eye has about 10 million rods and 5

million 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

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)

• When light falls on retina, 11-cis-retinal is

isomerised to all-trans-retinal

• This leads to a conformational change in opsin

• Responsible for the generation of nerve impulse

• 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

• Most of the all-trans retinal is transported to liver

and converted to all-trans retinol by alcohol

dehydrogenase

• The all-trans retinol is undergoes

isomerization to 11-cis retinol which is

oxidized to 11-cis retinal to participate in

the visual cycle

Rhodopsin(11-cis-

retinal+opsin)

Opsin

All-trans-retinal

All-trans-retinol

NAD+

NADH + H+

ADH (liver)

11-cis-retinol

11-cis-retinal

NAD

NADH + H+

ADH(liver)

Isomerase (liver)

Retinal isomerase

Wald’s visual cycle

Light

Dark adaptation mechanism:

• When a person shifts from a bright light to

a dim light, rhodopsin stores are depleted

and vision is impaired

• After few minutes rhodopsin is

resynthesized and vision is improved

• Called as dark adaptation and is increased

in Vitamin-A deficiency

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

Visual cascade and cGMP

• When light strikes the retina, a number of

biochemical changes leading to membrane

hyperpolarization occur resulting in

genesis of nerve impulse

• When a photon (from light) is absorbed by

rhodopsin, metarhodopsin II is produced

• 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

• A rapid decrease in cGMP closes Na+

channels in the membrane of the rod cells

• This results in hyperpolarization which is an

excitatory response transmitted through the

neuron network to the visual cortex of brain

Cones are for color vision

• 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)

• In cones, 11-cis-retinal is the

chromoprotein

• Reduction in number of cones or cone

proteins, will lead to color blindness

• One eye contains about 6 million cones

Other biochemical functions of vitamin A

• Retinol and retinoic acid function like

steroid hormones

• They regulate protein synthesis and

involved in cell growth and differentiation

• Vitamin A is essential to healthy epithelial

tissue

• Vitamin A is considered to be essential for

maintenance of proper immune system

ROLE OF VITAMIN A IN REPRODUCTION

• Active form: The active form of vitamin A

which is involved in reproduction is retinol

• Mechanism: retinol binds to specific

intracellular receptor

• Retinol receptor complex binds to DNA and

regulates the expression of genes required

for reproductive function

ROLE IN GROWTH AND DIFFERENTIATION

• Active form: The active form of vitamin A

involved in growth and differentiation is

retinoic acid

• Mechanism: retinoic acid (present as either

all trans-retinoic acid or 9 cis-retinoic acid)

binds to specific cellular retinoic acid

binding protein (receptor)

• Retinoic acid receptor complex binds to DNA

and regulate the expression of genes

required for growth and differentiation

• In cancer treatment all-trans retinoic acid

has been shown to cause differentiation of

tumors, and has a potential for the

treatment of cancer

• All-trans retinoic acid also induces

apoptosis (programmed cell death) of

cancer cells

Role in maintenance of epithelial integrity and glycoprotein synthesis

• Active form: Retinol is involved in the

maintenance of epithelial integrity and

glycoprotein synthesis

• Retinol prevents the excess keratin synthesis

• Retinyl phosphate formed from retinol is

required for glycoprotein synthesis

• Glycosyl retinyl phosphate acts as donor of

carbohydrates for synthesis of glyco-proteins

and GAGs

• Collagen breakdown: Retinoic acid inhibits

the enzyme collagenase and thus prevents

the breakdown of collagen

• Role of β- Carotene as an antioxidant:

• The antioxidant effect of beta-carotene is

due to the stabilization of peroxide free

radicals within the conjugated alkyl

structure of beta-carotene

• Significance:

• The antioxidant properties of beta –

carotene is partly responsible for its

anticancer activity, protective effect

against coronary heart disease, and

prevention of cataract formation

Recommended dietary allowance(RDA)

• The daily requirement of vitamin A is

expressed as retinol equivalents (RE) rather

than International Units (IU)

• 1 retinol equivalent = 1 μg retinol

• = 6 μg beta-carotene

• = 12 μg other

carotinoids

• Children = 400 – 600 μg /day

• Men = 750 – 1000 μg /day

• Women = 750 μg /day

• Pregnancy = 1000 μg /day or 1 mg/day

• 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.

+ Deficiency of vitamin A: • Visual acuity is diminished in dim light

(nyctalopia or night blindness)

• The dark adaptation time is increased

• 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

• Bitot’s spots:• These are seen as greyish-white triangular

plaques firmly adherent to the conjunctiva

in certain areas

• 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

Other deficiency manifestations

• Effect on growth:

• Vitamin A deficiency results in growth

retardation due to impairment in skeletal

formation

• On reproduction:

• The reproductive system is adversely

affected in vitamin A deficiency

• Degeneration of germinal epithelium leads

to sterility in males

Effect on skin and epithelial cells:

• The skin becomes rough and dry

• Keratinization of epithelial cells of GIT,

urinary tract and respiratory tract

• Vitamin A deficiency is associated with

formation of urinary stones

• Hypervitaminosis:

• Excessive consumption of vitamin A leads

to toxicity

• Symptoms: Dermatitis (drying and redness

of skin), enlargement of liver, skeletal

decalcification, tenderness of long bones,

loss of weight, irritability, loss of hair, joint

pains

• Normal range: 20 -50 μg/dl

References

• Harper’s Biochemistry 25th Edition.

• Fundamentals of Clinical Chemistry by Tietz.

• Text Book of Medical Biochemistry-A R Aroor.

• Text Book of Biochemistry-DM Vasudevan

• Text Book of Biochemistry-MN Chatterjea

• Text Book of Biochemistry-Dr.U.Satyanarana