Vitamin A

Retinoids Precursors of vitamin A

1- RetinolIt is found in animal tissues as a retinyl ester with long-chain fatty acids.

2- Retinal The aldhyde derived from the oxidation of retinol.

Retinol and retinal can be interconverted.

3- Retinoic acid The acid derived from retinal. It can not be reduced in the body, and therefore, can not give rise to either retinal or retinol

4- b-carotene Plant foods contain b-carotene, which can be cleaved in the intestine to

two molecules of retinal In humans, the conversion is insufficient, and vitamin A activity of b-carotene is only about one sixth(1/6) of that of retinol

Retinol (Animal Source)

Retinal b-carotene (Plant Source)

Retinoic Acid

RETINOIDSPRECURSOR

OF VITAMIN A

Absorption & Transport of vitamin A

Transport to the Liver

I- Retinol is derived from (DIET SOURCES) 1- DIET Retinyl esters (animal source) which are hydrolyzed in the intestinal mucosa, releasing retinol and free fatty acids

2- DIET b-carotenes (plant source) which is cleaved 2 retinal retinol

II- Retinol is esterified with fatty acids to give retinyl esters

III- Retinyl esters are collected by the chylomicrons into the lymphatic system.

IV- Retinyl esters contained in the chylomicrons are taken up and stored by the liver

Release from the Liver

• When needed, retinol is released from the liver and transported to extra hepatic tissue by plasma retinol binding protein (RBP)

• The retinol - RBP complex attaches to specific receptors on the surface of the cells of peripheral tissues permitting retinol to enter

Mechanism of Action of vitamin A

• Retinol is oxidized to retinoic acid inside cells.

• Retinoic acid binds with high-affinity to specific receptor proteins present in the nucleus of target tissue, such as epithelial cell.

• The activated retinoic acid - receptor complex interacts with nuclear chromatin (genes) to stimulate retinoid-specific mRNA synthesis, resulting in the production of specific proteins that mediate several physiological functions.

e.g. retinoids control the expression of keratin gene in most epithelial tissues.

Physiological Functions of Vitamin A

• Vision• Growth• Reproduction• Epithelial cell maintenance

Functions of Vitamin A

1- Vision• Vitamin A is a component of the visual pigments of rod and cone cells.

• Rhodopsin, the visual pigment of the rod cells in the retina, (for vision in dim light)

consists of 11-cis retinal specially bound to the protein opsin. • When rhodopsin is exposed to light, a series of photochemical

isomerization occurs, which results in release of all trans retinal and opsin (with bleaching of the visual pigment).

• This process triggers a nerve impulse that is transmitted by the optic nerve to the brain.

• Regeneration of rhodopsin requires isomerization of all trans retinal back to 11-cis retinal, which spontaneously combines with opsin to form rhodopsin.

2- Growth• Vitamin A is essential for normal growth of

cells (by synthesis of important proteins)

• bone growth is slow in vitamin A deficiency.

• Animals deprived of vitamin A suffers keratinzation of taste buds leading to losing of their appetites.

3- Reproduction• Retinol & retinal are essential for normal reproduction 1- supporting spermatogenesis in males 2- preventing fetal resorption in females

• Retinoic acid is inactive in maintaining reproduction & the visual cycle, BUT promotes growth.

Thus, retinoic acids given only since birth to animals, leads to blindness & sterility.

4- Epithelial cells maintenance• Vitamin A is essential for normal differentiation of epithelial tissues and

mucus secretion.

Diet Sources of Vitamin A• Sources of retinol (retinyl esters) : animal source Liver, kidney, cream, butter & egg yolk

• Sources of carotenes (precursors of vitamin A) : plant source Yellow & dark green vegetables & fruits

Requirement for Vitamin A

• One RE (retinol equivalents) = 1 mg of retinol 12mg of b-carotene 24mg of other carotenoids• RDA for adults 900 RE for males 700 RE for females

Clinical indications of vitamin A

1- Dietary deficiency

Vitamin A, administered as retinol or retinyl esters, is used to treat patients deficient in the vitamin (not retinoic acid)

Night blindness

One of the earliest signs of vitamin A deficiency Difficulty in seeing in dim light. Prolonged deficiency leads to irreversible loss of visual cell. (affection of rods of retina)

Xerophthalmia

Severe deficiency of vitamin A Pathological dryness of the epithelium conjunctiva & cornea. It may end in corneal ulcerations and blindness.

2- Acne & Psoriasis

Dermatologic problems of acne and psoriasis are effectively treated with retinoic acid or its derivatives.

• Mild cases of acne is treated by topical application of tretinoin (All- trans retinoic acid) which is too toxic for systemic administration.

• Severe recalcitrant cystic acne unresponsive to conventional therapies, isotretinoin (13-cis retinoic acid) is administered orally

3- Prevention of chronic diseases

• Populations consuming diets high in b-carotene show decreased incidence of heart diseases & lung & skin cancer

• Consumption of foods rich in b-carotene is associated with reduced risk of cataracts and macular degeneration

Toxicity of Retinoids

I. Vitamin A excess (hypervitaminosis A syndrome) Amounts exceeding 7.5 mg/day of retinol

1- Excessive intake of vitamin A may cause the followings:

• dry skin & pruiritis are early signs• liver enlarged, cirrhotic• increased intracranial pressure (mimic symptoms of brain tumours

e.g. headache etc…) 2- Pregnant females should not ingest excessive amounts of vitamin A because of its potential for causing congenital malformations in developing fetus.

II. Isotretinoin drug (13-cis retinoic acid) 1- Teratogenic

• So, absolutely contraindicated in women with childbearing potential.

• Pregnancy should be excluded before initiation of treatment & adequate contraceptive (birth control) must be used

2- Risk of coronary heart diseases Prolonged treatment with 13-cis retinoic acid leads to hyperlipidemia & increase in LDL/HDL ratio with increased risk

of coronary heart diseases.