Biochemical Functions and Deficiency

Two retinoids, retinoic acid and retinal, appear to have most of the biochemical functions attributed to vitamin A. Retinoic acid is required for cell differentiation and is the ligand for two families of nuclear receptors, RAR^ 7 and RXRa 3 These receptors are part of a family of superreceptors that include the steroid hormones and cholecalciferol. Vitamin A deficiency can lead to a variety of symptoms depending on the age of the deficient person. The most serious syndrome is keratomalacia, which results in desiccation, ulceration, and xerophthalmia of the cornea and conjunctiva. It is one of the leading causes of blindness in infants and children.

Retinoic acid is required for the development of goblet mucous cells. A deficiency results in basal cell proliferation with increased keratini-zation of the epithelial structures. Mucus is one of the essential physical barriers (part of innate immunity) that prevents pathogens from entering the body. Therefore, a retinol deficiency increases the risk of infection.

The aldehyde form, retinal, is an essential component of the visual pigment found in the rods of the eye. A very brief outline of the rho-dopsin cycle is shown in Fig. 8.4. Retinol is transported from the liver to the eye, where it is converted to 11-cis-retinal. In the rod, the aldehyde forms an enamine (Schiffs base) with a lysine on opsin forming rhodopsin (Fig. 8.5). In the presence of light, trans-retinal forms with cleavage of the enamine, sending a nerve impulse to the brain along the optic nerve. In the dark, 11-cts-retinol re-forms followed by oxidation to 11-cis-retinal and the cycle repeats.

A deficiency causes night blindness, which is considered an early symptom of retinol deficiency. Night blindness refers to decreased ability to see in very dim light because there is an inadequate amount of retinal in the eye to fully "stock" the rods with functional rhodopsin. There is some evidence that as retinol levels in the liver decrease, the equilibrium favors the movement of retinol from the eye back to the liver.

3.1.4 Dosage Forms. Retinol is unstable. It easily dehydrates (Fig. 8.6), forming a stable ion. Therefore, the two most common forms for both oral and parenteral administration are the acetate or palmitate esters. With the extensive conjugation retinol is light sensitive and subject to oxidation. Therefore, the vitamin formulator must protect the product from light and air.

3.1.5 Hypervitamininosis A. In high doses, can be toxic. Acute poisoning is rare and dependent on the dosage form. Nausea and vomiting are the most common symptoms. Most rapidly absorbed are the "clear" emulsions (usually formulated with a Tween or other surfactant). Next in order are the standard emulsions, usually produced from fish liver oils. The most slowly absorbed are ■ the dry tablet formulations or an oil solution j in a capsule. Chronic hypervitaminosis is

Rhodopsin (visual pigment)

Changes in the conformation cf the Rhodopsin complex impulse to the brain

Sight

11 -c/s-Retinal + Opsin trans-Retinal + Opsin

frans-Retinol

(transported to the eye fom the liver on a retino! binding protein)

Liver stores cf retinol esters

Figure 8.4. Outline of the rhodopsin cycle.

jaore common and is more commonly seen $rhen people consume fish liver oil concen-ites. The symptoms are nondescript and inlude fatigue, malaise, lethargy, abdominal comfort, bone/joint pain, severe and throbbing headache, insomnia, restlessness, dry and scaly skin, loss of body hair, brittle nails, nstipation, and irregular menses, symptoms ight make users conclude that they are Itamin A deficient. Depending on the health person's liver, there is risk of developing hosis. There is a daily Tolerable Upper In-:e Level (UL) of 3000 /xg for this vitamin. rhe UL to RDA ratio is narrow (3-5), relative that of most vitamins. This is somewhat imparable to vitamins D.

3.1.6 Hypercarotenosis. This occurs from ;ive doses of carotene that exceed the ca-ity of the mucosa cells to cleave the mole-.e to retinal derivatives. The excess carotene omes deposited in the body tissues. Except ir the yellow or bronze-orange skin, there seem to be no other symptoms. The skin coloration slowly disappears when carotene intake stops. A commercial form of carotene is indicated for the photosensitivity seen in erythropoietic porphyria. Carotene capsules are also sold with the claim that a person can have a tanned appearance without the need of UV radiation. Patients who drink large amounts of carrot juice sometimes show signs of hypercarotenosis.

3.1.7 Dietary Reference Intakes (as Retinoic Acid Equivalents).

Infants (1-12 months) EAR

Children (1-8 years) Boys (9-18 years) Girls (9-18 years) Men (19-70+ years) Women (19-70-t years) Lactating

400-500 /xg/day

210-275 /big/day 445-630 jag/day 420485 /xg/day 625 jug/day 500 /xg/day 885-900 jag/day

Opsin

Rhodopsin Figure 8.5. Rhodopsin.

Children (1-8 years)

Boys (9-18 years)

Girls (9-18 years)

Women

Pregnant

Lactating

300-400 jug/day 600-900 jug/day 600-700 fJLg/day 900 jug/day 700 jLcg/day 750-770 jug/day 1200-1300 ¡xgí day

3000 ju.g/day for all adults including pregnant women. There is some concern of teratogenic effects based on the experience of the retinoids used in therapy.

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