VITAMIN A Retinol

 Retinol, the dietary form of vitamin A, is a fat-soluble, antioxidant vitamin important in vision and bone growth. It belongs to the family of chemical compounds known as retinoids. Retinol is ingested in a precursor form; animal sources (milk and eggs) contain retinyl esters, whereas plants (carrots, spinach) contain pro-vitamin A carotenoids. Hydrolysis of retinyl esters results in retinol while pro-vitamin A carotenoids can be cleaved to produce retinal. Retinal, also known as retinaldehyde, can be reversibly reduced to produce retinol or it can be irreversibly oxidized to produce retinoic acid. The best described active retinoid metabolites are 11-cis-retinal and the all-trans and 9-cis-isomers of retinoic acid.

Discovery

In 1913, Elmer McCollum, a biochemist at the University of Wisconsin, and colleague Marguerite Davis identified a fat-soluble nutrient in butterfat and cod liver oil. Their work confirmed that of Thomas Osborne and Lafayette Mendel, at Yale, which suggested a fat-soluble nutrient in butterfat, also in 1913. Vitamin A was first synthesized in 1947.

Chemical structure and function

Many different geometric isomers of retinol, retinal and retinoic acid are possible as a result of either a trans or cis configuration of the four double bonds found in the polyene chain. The cis isomers are less stable and can readily convert to the all-trans configuration (as seen in the structure of all-trans-retinol shown here). Nevertheless, some cis isomers are found naturally and carry out essential functions. For example, the 11-cis-retinal isomer is the chromophore of rhodopsin, the vertebrate photoreceptor molecule. Rhodopsin is comprised of the 11-cis-retinal covalently linked via a Schiff base to the opsin protein (either rod opsin or blue, red or green cone opsins). The process of vision relies on the light-induced isomerisation of the chromophore from 11-cis to all-trans resulting in a change of the conformation and activation of the photoreceptor molecule. One of the earliest signs of vitamin A deficiency is night-blindness followed by decreased visual acuity.

As can be seen from the structure, retinol is derived from isoprene, and has an alcohol functional group. The first full synthesis route for the compound was found by David Adriaan van Dorp in 1947.

George Wald won the 1967 Nobel Prize in Physiology or Medicine for his work with retina pigments (also called visual pigments), which led to the understanding of the role of vitamin A in vision.

Many of the non-visual functions of vitamin A are mediated by retinoic acid, which regulates gene expression by activating intracellular retinoic acid receptors. The non-visual functions of vitamin A are essential in the immunological function, reproduction and embryonic development of vertebrates as evidenced by the impaired growth, susceptibility to infection and birth defects observed in populations receiving suboptimal vitamin A in their diet.

Retinol can also be used in the treatment of acne in a topical cream. A form of retinoic acid, all-trans retinoic acid (ATRA) is currently used as chemotherapy for acute promyelocytic leukemia, a subtype of acute myelogenous leukemia. This is because this transformed cells of this subtype respond in most cases to agonists of the retinoic acid receptor (RAR).

Vision

Vitamin A is required in the production of rhodopsin, the visual pigment used in low light levels. This is why eating foods rich in vitamin A is said to allow you to see in the dark.

Epithelial Cells

Vitamin A is essential for the correct functioning of epithelial cells. In Vitamin A deficiency, mucus-secreting cells are replaced by keratin producing cells, leading to xerosis.

Glycoprotein synthesis

Glycoprotein synthesis requires adequate Vitamin A status. In severe Vitamin A deficiency, lack of glycoproteins may lead to corneal ulcers or liquefaction.

Immune System

Vitamin A is essential to provide intact epithelial tissues as a physical barrier to infection; it is also involved in maintaining healthy lymphocytes and T-cells.

Formation of red blood cells(Haematopoiesis)

Vitamin A may be needed for normal haematopoiesis; deficiency causes abnormalities in iron metabolism.

Growth

Vitamin A affects the production of human growth hormone.

Units of measurement

When referring to dietary allowances or nutritional science, retinol is usually measured in international units (IU). IU refers to biological activity and therefore is unique to each individual compound, however 1 IU of retinol is equivalent to approximately 0.3 µg (300 nanograms).

 Dietary intake

During the absorption process in the intestines, retinol is incorporated into chylomicrons as the ester form, and it is these particles that mediate transport to the liver. Liver cells (hepatocytes) store vitamin A as the ester, and when retinol is needed in other tissues, it is de-esterifed and released into the blood as the alcohol. Retinol then attaches to a serum carrier, retinol binding protein, for transport to target tissues. A binding protein inside cells, cellular retinoic acid binding protein, serves to store and move retinoic acid intracellularly. Carotenoid bioavailability ranges between 1/5 to 1/10 of retinol's. Carotenoids are better absorbed when ingested as part of a fatty meal. Also, the carotenoids in vegetables, especially those with tough cell walls (e.g. carrots), are better absorbed when these cell walls are broken up by cooking or mincing.

Topical use

All retinoid forms of vitamin A are used in cosmetic and medical applications applied to the skin.

Retinoic acid, retinyl palmitate, isotretinoin, tretinoin and retinol are all used medicinally as a topical treatment for acne and keratosis pilaris.

In cosmetics, vitamin A derivatives are used as so-called antiaging chemicals- vitamin A is absorbed through the skin and increases the rate of skin turnover, and gives a temporary increase in collagen giving a more youthful appearance.

Vitamin A deficiency

 Vitamin A deficiency is common in developing countries but rarely seen in developed countries. Approximately 250,000 to 500,000 malnourished children in the developing world go blind each year from a deficiency of vitamin A. Night blindness is one of the first signs of vitamin A deficiency. Vitamin A deficiency contributes to blindness by making the cornea very dry and damaging the retina and cornea.

Vitamin A deficiency also diminishes the ability to fight infections. In countries where children are not immunized, infectious disease like measles have relatively higher fatality rates. As elucidated by Dr. Alfred Sommer, even mild, subclinical deficiency can also be a problem, as it may increase children's risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness.

In addition to dietary problems, there are other causes of vitamin A deficiency. Iron deficiency can affect vitamin A uptake. Excess alcohol consumption can deplete vitamin A, and a stressed liver may be more susceptible to vitamin A toxicity. People who consume large amounts of alcohol should seek medical advice before taking vitamin A supplements.

Treatment of vitamin A deficiency can be undertaken with both oral and injectable forms, generally as vitamin A palmitate.

Vitamin A overdose

Too much vitamin A can be harmful or fatal. The body converts the dimerized form, carotene, into vitamin A as it is needed, therefore high levels of carotene are not toxic compared to the ester (animal) forms. The livers of certain animals, especially those adapted to polar environments, often contain amounts of vitamin A that would be toxic to humans. The first documented death due to vitamin A poisoning was Xavier Mertz, a Swiss scientist who died in January 1913 on an Antarctic expedition that had lost its food supplies and fell to eating its sled dogs. Mertz consumed lethal amounts of vitamin A by eating the dogs' livers. The liver of the polar bear also has enough vitamin A to kill a human being, or enough to make even sled dogs very ill.

Excess vitamin A has also been suspected to be a contributor to osteoporosis. This seems to happen at much lower doses than those required to induce acute intoxication. Only preformed vitamin A can cause these problems, because the conversion of carotenoids into vitamin A is downregulated when physiological requirements are met. An excessive uptake of carotenoids can, however, cause carotenosis.

The carotenoid beta carotene was interestingly associated with an increase in lung cancer when it was studied in a lung cancer prevention trial in male smokers. In non-smokers, the opposite effect has been noted.

Although cases of vitamin A toxicity have been reported in arctic explorers and some people taking large doses of synthetic vitamin A for long periods of time, pregnant women require large amounts of vitamin A from preferably natural animal sources, such as liver, raw (non-pasteurized) butter, and cod liver oil. However excess in retinoid form must at all costs be avoided due to its well known teratogenic effects.

Closely related chemicals

• Isotretinoin (Tradename: Accutane)
• Retinyl palmitate ('vitamin A' aka. "pro-vitamin A")
• All-trans retinoic acid

Genetically engineered vitamin A enriched rice

Due to the high prevalence of vitamin A deficiency in developing countries, there are efforts to produce genetically modified rice rich in beta carotene. The idea is that this would help poor people, who can't afford a varied diet containing sufficient natural sources of vitamin A, meet their dietary needs. The golden rice  project is one such effort, and is already undergoing trials.