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Retinol

Drugs & Medication

Retinol

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Vitamin A (Retinol)
General
Chemical formula C20H30O
Molecular weight 286.456 g/mol
Vitamin properties
Solubility Fat
RDA (adult male) 900 g/day
RDA (adult female) 700 g/day
RDA upper limit (adult male) 3,000 g/day
RDA upper limit (adult female) 3,000 g/day
Deficiency symptoms
  • Night blindness
  • Keratomalacia
  • Pale, dry skin
Excess symptoms
  • Liver toxicity
  • Dry skin
  • Hair loss
  • Teratological effects
  • Osteoporosis (suspected, long-term)
Common sources
  • Liver
  • Dairy products
  • Darkly colored fruits
  • Leafy vegetables

Retinol, the animal form of vitamin A, is a yellow 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.

Contents

Discovery

In 1913, Elmer McCollum, a biochemist at the University of Wisconsin-Madison, 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 [1]. 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 and Jozef Ferdinand Arens in 1947. 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 and Jozef Ferdinand Arens 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 cells of this subtype of leukemia are sensitive to agonists of the retinoic acid receptors (RARs).

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 maintain intact epithelial tissues as a physical barrier to infection; it is also involved in maintaining a number of immune cell types from both the innate and acquired immune systems. These include the lymphocytes (B-cells, T-cells, and natural killer cells), as well as many myelocytes (neutrophils, macrophages, and myeloid dendritic 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 micrograms (300 nanograms).

Nutrition

This vitamin plays an essential role in vision, particularly night vision, normal bone and tooth development, reproduction, and the health of skin and mucous membranes (the mucus-secreting layer that lines body regions such as the respiratory tract). Vitamin A also acts in the body as an antioxidant, a protective chemical that may reduce the risk of certain cancers.

There are two sources of dietary vitamin A. Active forms, which are immediately available to the body are obtained from animal products. These are known as retinoids and include retinal and retinol. Precursors, also known as provitamins, which must be converted to active forms by the body, are obtained from fruits and vegetables containing yellow, orange and dark green pigments, known as carotenoids, the most well-known being beta-carotene. For this reason, amounts of vitamin A are measured in Retinal Equivalents (RE). One RE is equivalent to 0.001mg of retinal, or 0.006mg of beta-carotene, or 3.3 International Units of vitamin A.

In the intestine, vitamin A is protected from being chemically changed by vitamin E. Vitamin A is fat-soluble and can be stored in the body. Most of the vitamin A you eat is stored in the liver. When required by a particular part of the body, the liver releases some vitamin A, which is carried by the blood and delivered to the target cells and tissues.

Dietary intake

The Dietary Reference Intake (DRI) Recommended Daily Amount (RDA) for Vitamin A for a 25-year old male is 900 micrograms/day, or 3,000 IU.

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. Isotretinoin is also used orally (under the trade names Accutane and Roaccutane), generally for severe or recalcitrant acne.

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

Prevalence of vitamin A deficiency. Source: WHO
Prevalence of vitamin A deficiency. Source: WHO

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 (Toxicity)

The Tolerable Upper Intake Level (UL) for vitamin A, for a 25-year old male, is 3,000 micrograms/day, or about 10,000 IU.

Too much vitamin A can be harmful or fatal, resulting in what is known as hypervitaminosis A. 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. Thus, vitamin A toxicity is typically reported in arctic explorers and people taking large doses of synthetic vitamin A. 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. Just 0.3 grams of the liver of the polar bear contains the upper intake level.[2] If eaten in one meal, 30 to 90 grams is enough to kill a human being, or 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.

Excess preformed vitamin A during early pregnancy has also been associated with a significant increase in birth defects.[1] These defects may be severe, even life-threatening. Even twice the daily recommended amount can cause severe birth defects.[2] The FDA currently recommends that pregnant women get their Vitamin A from foods containing beta carotene and that they should ensure that they consume no more than 5,000 IU of preformed Vitamin A (if any) per day. Although Vitamin A is necessary for fetal development, most women carry stores of Vitamin A in their fat cells, so oversupplementation should be strictly avoided.

Good sources

Vitamin A is found naturally in many foods. Each of the following contains at least 0.15mg of Vitamin A or beta carotene per 1.75-7 oz. (50-200g):

  • Sweet potatoes
    Carrots
    Collard greens
    Kale
    Pumpkin
    Spinach
    Sweet peppers
    Winter squash
    Apricots
    Cantaloupe melon
    Mango
    Liver (polar bear, beef, pork, chicken, or turkey)
    Eggs
    Broccoli

Night vision

Night blindness - the inability to see well in dim light - is associated with a deficiency of vitamin A. This vitamin is needed for the formation of rhodopsin. This is a pigment located in the eye's retina, which is the light-sensitive tissue lining in the back of the eye.

When stimulated by light, rhodopsin splits into two proteins: opsin and retinal (a form of vitamin A); when it is dark the reverse reaction occurs - the retinal and opsin combine to re-form rhodopsin, a reaction that requires extra retinal.

Without adequate amounts of retinal, regeneration of rhodopsin is incomplete and night blindness occurs. Since carrots are a good source of beta-carotene, there is truth in the old belief that carrots help you see better in the dark.

Closely related chemicals

  • Isotretinoin (Tradename: Accutane(US), Roaccutane)
    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.

References

  1. ^ Semba RD. Vitamin A as "Anti-Infective" Therapy, 19201940. Journal of Nutrition. 1999;129:783-791. PMID 10203551. Full Text Available
  2. ^ A. Aggrawal, Death by Vitamin A

External links


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