Vitamin A belongs to the fat soluble vitamins. Its active form is present only in animal tissues meanwhile the pro-vitamin, beta-carotene is present in plant tissues. Beta carotene is made up of two beta ionone rings which are connected by a polyprenoid chain. Theoretically, one molecule of beta carotene can give rise to two molecules of vitamin A but it may produce only one in biological systems.
All the compounds with vitamin A activity are known as Retinoids. These are polyisoprenoid compounds having a beta-ionone ring system. Retinol (vitamin A alcohol), retinal (vitamin A aldehyde) and retinoic acid (vitamin A acid) are three different compounds with vitamin A activities.
Retinal may be reduced to retinol by the enzyme retinal reductase. The reaction is readily reversible. Retinal is also oxidized to retinoic acid, which cannot be converted back to the other forms. The side chain contains alternate double bonds, and hence many isomers are possible. The all-trans variety of retinal, also called vitamin A1 is most common as for Vitamin A2, it is found in fish oils and has an extra double bond in the ring. Biologically important compound is 11-cis-retinal
Absorption of Vitamin A
The major site for Vitamin A absorption is the Intestine. The absorption is along with other fats and requires bile salts. In the intestine, Beta carotene is cleaved by a di-oxygenase in order to form retinal which is then reduced to retinol by an enzyme (NADH or NADPH dependent retinal reductase) present in the intestinal mucosa.
Within the mucosal cell, retinol is re-esterified with fatty acids, incorporated into chylomicrons and transported to the liver. In the liver stellate cells, vitamin is stored as retinol palmitate.
Vitamin A absorption is reduced in condition such as biliary tract obstruction and steatorrhoea.
Transport of Vitamin A from Liver to Tissues
The vitamin A from the liver is then transported to peripheral tissues as trans-retinol by the retinol binding protein (RBP). A molecule of RBP binds one molecule of retinol. Therefore a drop in RBP blood level leads vitamin A deficiency.
Uptake of Vitamin A by Tissues
The retinol-RBP complex binds to specific receptors on the retina, skin, gonads and other tissues. The RBP does not enter in the cell. Inside the cytoplasm of cells, vitamin binds to cellular retinoic acid binding protein (CRBP) and finally to hormone responsive elements (HRE) of DNA. Thus, genes are activated
vitamin a function in the body
Wald’s Visual Cycle
Generation of Nerve Impulse
- The role of vitamin A in vision was identified by Wald in 1967. Rhodopsin plays the pivotal role in vision. Rhodopsin is a proteinous membrane found in the photoreceptor cells of the retina which plays the pivotal role in vision. It is made up of the protein opsin and 11-cis-retinal.
- When light falls on the retina, the 11-cis-retinal isomerizes to all-trans-retinal therefore a single photon can excite the rod cell. The photon produces immediate conformational change. The unstable intermediates produced are: Rhodopsin → Batho-rhodopsin → Lumirhodopsin → Metarhodopsin-I → Metarhodopsin-II → and finally Opsin + all-trans-retinal.
- Each of these intermediaries has a lifespan of only few picosecond to microseconds. The all-trans-retinal is then released from the protein.
- Visual pigments are G-protein-coupled receptors and 11-cis-retinal locks the receptor protein (opsin) in its inactive form. The isomerization and photo-excitation leads to activation of G-protein and generation of cyclic-GMP. The cyclic GMP acts as the gate for cation specific channels. Transducin is the G-protein in retina. The nerve impulse thus generated in the retina is transmitted to visual centres in the brain.
- The signal is terminated by phosphorylation of a serine residue of activated rhodopsin, by an enzyme rhodopsin kinase, so that the inhibitory protein beta-arrestin can bind and inactivate rhodopsin.
Regeneration of 11-cis-retinal
- After dissociation, opsin remains in retina; but trans-retinal enters the blood circulation. Later cis-retinal is generated, reaches retina. The re-attachment of 11-cis retinal to opsin is critical for shutting off the pigment’s catalytic activity.
- The all-trans-retinal is isomerized to 11-cisretinal in the retina itself in the dark by the enzyme retinal isomerase. The reaction takes place in the retinal pigment epithelium. The 11-cis retinal can recombine with opsin to regenerate rhodopsin.
- Alternatively, all-trans-retinal is transported to liver which is then reduced to all-trans-retinol by the enzyme (alcohol dehydrogenase (ADH), an NADH dependent enzyme). ADH contains zinc, and therefore, zinc is important in retinol metabolism. The all-trans-retinol is isomerized to 11-cis-retinol which is then oxidise to 11-cisretinal in liver. This is then transported to retina which completes the Wald’s visual cycle
Mechanism of Dark Adaptation
- When a person suddenly shifts from bright light to a dimly lit area, there is difficulty in seeing because bright light depletes stores of rhodopsin in rods. For example, entering a dark room. After a few minutes, rhodopsin is resynthesized in order to improve vision. This mechanism or period is called Dark Adaptation Time.
- Dark Adaption Time is increased in vitamin A deficiency. Red light bleaches rhodopsin to a lesser extent reason why red glasses are mostly used during fluoroscopic X-ray examination of the patients.
Rods for Vision in Dim Light
- The rods and cones are the two types of photosensitivity cells in the retina. Rods are responsible for dim light perception. The rhodopsin present in the rods consists of 11-cis-retinal + opsin. As a result, cis-retinal deficiency will lead to an increase in dark adaptation time and night blindness.In humans, one eye contains approximately 120 million rods and each rod contains 120 million molecules of rhodopsin.
Cones for Colour Vision
- There are about 6 million cones in one eye. Cones contain photosensitive protein, conospine and are accountable for vision in bright light and color vision.
- Three types of cones exist, each are characterized by a different conopsin, which is maximally sensitive to either green (iodopsin), red (porphyropsin) or blue (cyanopsin).
- 11-cis-retinal is the chromophore protein found in cones. Therefore a reduction in number of cones or the cone proteins, will lead to colour blindness.
Other Functions of Vitamin A
- Retinoic acid plays a part in the differentiation of tissues and the regulation of gene expression.All-trans-retinoic acid and 9-cisretinoic acid function as steroid hormones.They bind to nuclear receptors ; retinoic acid, along with the receptor, binds to DNA response elements.Retinoic acid (RAR) receptors bind all-trans-retinoic acid, while retinoic x (RXR) receptors bind to 9-cisretinoic acid.RXRs also form dimers with a vitamin D receptor.This illustrates why vitamin A deficiency impairs the function of vitamin D.
- Retinol is also needed for the reproductive system.It functions as a steroid hormone to control the expression of certain genes.This may account for the necessity of vitamin A for ordinary reproduction, therefore vitamin deficiency may lead to miscarriage or atrophy of germinal epithelium and sterility.
- Vitamin A has an anti-oxidant property reason why there is a correlation between the occurrence of epithelial cancers and vitamin A deficiency. This anticancer activity has been attributed to the natural antioxidant property of carotenoids as fresh vegetables containing carotenoids were shown to reduce the incidence of cancer.
- Beta carotenes may be useful in preventing heart attacks.
- Vitamin A is also very necessary for the maintenance of normal epithelium and skin.
Deficiency manifestations of Vitamin A
1. Bitot’s Spots
Bitot’s spot are seen as greyish-white triangular plaques firmly adherent to the conjunctiva. This is due to increased thickness of conjunctiva in certain areas. These changes are completely reversible when vitamin is supplemented.
2. Nyctalopia or Night Blindness
In dim light, Visual acuity is diminished. This make it difficult to read or drive in poor light. The dark adaptation time is increased.
Here, the conjunctiva becomes dry, thick and wrinkled. It gets keratinized and therefor loses its normal transparency. Dryness spreads to cornea. It becomes glazy and lustreless due to keratinization of corneal epithelium. Infections may supersede.
If xerophthalmia persists for a long time, it progresses to keratomalacia which is the softening of the cornea. These leads to degeneration of corneal epithelium which may get vascularized. Later, corneal opacities develop. Bacterial infection leads to corneal ulceration, perforation of cornea and followed by total blindness.
5. Preventable Blindness
Vitamin A deficient is the most common cause of blindness in Indian children below the age of 5. One-third of the world’s blind population are residing in India. About 40% of blindness is preventable. This makes Vitamin A deficiency a major public health problem. During immunization campaign, a single dose of vitamin A is given, as a prophylactic measure, to children below 1 year age.
6. Skin and Mucous Membrane Lesions
- Follicular hyperkeratosis or phrynoderma results from hyperkeratinization of the epithelium lining the follicles. This makes the skin rough. Keratinizing metaplasia of the epithelium of the respiratory, gastrointestinal and genitourinary tract have been observed. Epithelium is atrophied. The keratinization of urinary tract epithelium may also lead to urinary calculi.
- The alterations in skin may cause increased occurrence of generalized infections. In old literature, vitamin A is referred to as the anti-inflammatory vitamin.
- Isoretinone, a synthetic variant of vitamin A is known to reduce the sebaceous secretions, hence it is used to prevent acne formation during adolescence.
Causes of Vitamin A Deficiency
- Low intake.
- Obstructive jaundice leading to malabsorption.
- Cirrhosis of liver leading to reduced synthesis of RBP
- Severe malnutrition, where amino acids are not available for RBP synthesis
- Chronic nephrosis, leading to excretion of RBP through urine.
Daily Requirement of Vitamin A
Vitamin A recommended daily allowance (RDA) for
One international unit = 0.3 mg of retinol.
One retinol equivalent = 1 microgram of retinol or 6 microgram of beta carotene.
Dietary Sources of Vitamin A
- Animal sources of Vitamin A include butter, cream, cheese, milk, egg yolk and liver.
- Fish liver oils (cod liver oil and shark liver oil) are very rich sources of the vitamin.
- Vegetable sources contain the yellow pigment beta carotene. Carrot contains significant quantity of beta carotene. Pumpkins, Papaya, mango and green leafy vegetables (spinach, amaranth) are also other good sources for vitamin A activity. During cooking the activity is not destroyed.
Hypervitaminosis A or Toxicity
Excessive consumption of vitamin A can lead to toxicity as the vitamin is stored. It has been reported in kids where parents have been overzealous in supplementing their vitamins. Eskimos refrain from eating polar bear’s liver owing to its elevated content of vitamin A.
Symptoms of Vitamin A toxicity include anorexia, irritability, headache, skin peeling, somnolence and vomiting.Some of these indications are due to enhanced intracranial stress.Sometimes swelling over lengthy bones (bony exostosis) can happen with painful bones.Liver enlargement (hepatomegaly) is also seen in kids.Higher concentrations of retinol increase lysosomal enzymes, leading to cell death.
Hypercarotenemia can result from persistent excessive consumption of foods rich in carotenoids. The skin becomes yellow, but no staining of sclera as in jaundice is observed.
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