Retinol

Source: Wikipedia, the free encyclopedia.

Retinol
Retinol
Clinical data
AHFS/Drugs.comMonograph
License data
intramuscular[1]
Drug classvitamin
ATC code
Legal status
Legal status
Identifiers
  • (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol
JSmol)
Melting point62–64 °C (144–147 °F)
Boiling point137–138 °C (279–280 °F) (10−6 mm Hg)
  • OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)/CCCC1(C)C
  • InChI=1S/C20H30O/c1-16(8-6-9-17(2)13-15-21)11-12-19-18(3)10-7-14-20(19,4)5/h6,8-9,11-13,21H,7,10,14-15H2,1-5H3/b9-6+,12-11+,16-8+,17-13+
  • Key:FPIPGXGPPPQFEQ-OVSJKPMPSA-N

Retinol, also called vitamin A1, is a fat-soluble

by mouth or by injection into a muscle.[1] As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.[3]

Retinol at normal doses is well tolerated.[1] High doses may cause enlargement of the liver, dry skin, and hypervitaminosis A.[1][4] High doses during pregnancy may harm the fetus.[1] The body converts retinol to retinal and retinoic acid, through which it acts.[2]

Retinol was discovered in 1909, isolated in 1931, and first made in 1947.

over the counter.[1] In 2021, vitamin A was the 298th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.[8][9]

Medical uses

Retinol is used to treat vitamin A deficiency.

Three approaches may be used when populations have low vitamin A levels:[10]

  1. Through dietary modification involving the adjustment of menu choices of affected persons from available food sources to optimize vitamin A content.
  2. Enriching commonly eaten and affordable foods with vitamin A, a process called fortification. It involves addition of synthetic vitamin A to staple foods like margarine, bread, flours, cereals, and infant formula during processing.
  3. By giving high-doses of vitamin A to the targeted deficient population, a method known as supplementation. In regions where deficiency is common, a single large dose is recommended to those at high risk twice a year.[11]

Retinol is also used to reduce the risk of complications in measles patients.[11]

Side effects

The Recommended Daily Intake (RDA) for preformed supplemental Vitamin A for adult men and women is 900 and 700 Retinol Activity Units(RAE)/day, respectively, or about 3,000 IU and 2,300 IU. For pregnant people, the Vitamin A RDA is 750-770 RAE/day (about 2,500-2,550 IU). During lactation, the RDA increases to 1,200-1,300 RAE/day (about 4,000-4,300 IU).

Retinol Activity Units can only be converted to IU (International Units) when the source of the Vitamin A is known. The IU values listed above do not apply to food sources of Vitamin A.[12]

Too much vitamin A in retinoid form can be harmful. The body converts the dimerized form, carotene, into vitamin A as it is needed, so high levels of carotene are not toxic, whereas the ester (animal) forms are. The livers of certain animals, especially those adapted to polar environments, such as polar bears and seals,[13] 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 possibly caused by vitamin A poisoning was that of 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 may have consumed lethal amounts of vitamin A by eating the dogs' livers.[14]

Vitamin A acute toxicity occurs when a person ingests vitamin A in large amounts more than the daily recommended value in the threshold of 25,000 IU/kg or more. Often, the patient consumes about 3–4 times the RDA's specification.[15] Toxicity of vitamin A is believed to be associated with the methods of increasing vitamin A in the body, such as food modification, fortification, and supplementation, all of which are used to combat vitamin A deficiency.[16] Toxicity is classified into two categories: acute and chronic. The former occurs a few hours or days after ingestion of a large amount of vitamin A. Chronic toxicity takes place when about 4,000 IU/kg or more of vitamin A is consumed for a long time. Symptoms of both include nausea, blurred vision, fatigue, weight-loss, and menstrual abnormalities.[17]

Excess vitamin A is 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; but excessive uptake of carotenoids can cause carotenosis.

Excess preformed vitamin A during early pregnancy is associated with a significant increase in birth defects.[18] These defects may be severe, even life-threatening. Even twice the daily recommended amount can cause severe birth defects.[19] The FDA recommends that pregnant women get their vitamin A from foods containing beta carotene and that they 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 over-supplementation should be strictly avoided.

A review of all randomized controlled trials in the scientific literature by the

JAMA in 2007 found that supplementation with beta carotene or vitamin A increased mortality by 5% and 16%, respectively.[20]

Studies emerging from developing countries India, Bangladesh, and Indonesia strongly suggest that, in populations in which vitamin A deficiency is common and maternal mortality is high, dosing expectant mothers can greatly reduce maternal mortality.[21] Similarly, dosing newborn infants with 50,000 IU (15 mg) of vitamin A within two days of birth can significantly reduce neonatal mortality.[22][23]

Biological roles

Retinol or other forms of vitamin A are needed for eyesight, maintenance of the skin, and human development.[1] Other than for vision, the active compound is all-trans-retinoic acid, synthesized from retinal, in turn synthesized from retinol.

Embryology

Retinoic acid via the retinoic acid receptor influences the process of cell differentiation, hence, the growth and development of embryos. During development, there is a concentration gradient of retinoic acid along the anterior-posterior (head-tail) axis. Cells in the embryo respond to retinoic acid differently depending on the amount present. For example, in vertebrates, the hindbrain transiently forms eight

rhombomeres and each rhombomere has a specific pattern of genes being expressed. If retinoic acid is not present the last four rhombomeres do not develop. Instead, rhombomeres 1–4 grow to cover the same amount of space as all eight would normally occupy. Retinoic acid has its effects by turning on a differential pattern of Homeobox (Hox) genes that encode different homeodomain transcription factors which in turn can turn on cell type specific genes. Deletion of the Homeobox (Hox-1) gene from rhombomere 4 makes the neurons growing in that region behave like neurons from rhombomere 2. Retinoic acid is not required for patterning of the retina as originally proposed, but retinoic acid synthesized in the retina is secreted into surrounding mesenchyme where it is required to prevent overgrowth of perioptic mesenchyme which can cause microphthalmia, defects in the cornea and eyelid, and rotation of the optic cup.[24]

Stem cell biology

Retinoic acid is an influential factor used in differentiation of stem cells to more committed fates, echoing retinoic acid's importance in natural embryonic developmental pathways. It is thought to initiate differentiation into a number of different cell lineages by unsequestering certain sequences in the genome.

It has numerous applications in the experimental induction of stem cell differentiation; amongst these are the differentiation of human embryonic stem cells to posterior foregut lineages and also to functional motor neurons.

Vision

Retinol is an essential compound in the cycle of light-activated chemical reactions called the "

metarhodopsin
) and the cofactor all-trans-retinal. The regeneration of active opsin requires conversion of all-trans-retinal back to 11-cis-retinal via retinol. The regeneration of 11-cis-retinal occurs in vertebrates via conversion of all-trans-retinol to 11-cis-retinol in a sequence of chemical transformations that occurs primarily in the pigment epithelial cells.

Without adequate amounts of retinol, regeneration of rhodopsin is incomplete and

iodopsin, the opsins of the cones. The cones mediate color vision
, and vision in bright light (day vision).

Glycoprotein synthesis

Glycoprotein synthesis requires adequate vitamin A status. In severe vitamin A deficiency, lack of glycoproteins may lead to corneal ulcers or liquefaction.[26]

Immune system

Vitamin A is essential to maintain intact

dendritic cells
).

Skin

Deficiencies in vitamin A have been linked to an increased susceptibility to skin infection and inflammation.

sebum secretion, which is a nutrient source for bacteria.[28] Retinol has been the subject of clinical studies related to its ability to reduce the appearance of fine lines on the face and neck.[3][29]

Red blood cells

Vitamin A may be needed for normal

iron metabolism.[32] Vitamin A is needed to produce the red blood cells from stem cells through retinoid differentiation.[33]

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

Vitamin properties
Solubility Fat
RDA
(adult male)
900 µg/day
RDA (adult female) 700 µg/day
RDA upper limit (adult male) 3,000 µg/day
RDA upper limit (adult female) 3,000 µg/day
Deficiency symptoms
Excess symptoms
  • Liver toxicity
  • Dry skin
  • Hair loss
  • Teratological
    effects
  • Osteoporosis (suspected, long-term)
Common sources
  • Liver and other organs
  • fortified
    Dairy products

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 retinaldehyde 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 β-carotene. For this reason, amounts of vitamin A are measured in Retinol Equivalents (RE). One RE is equivalent to 0.001 mg of retinol, or 0.006 mg of β-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 consumed 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 3000 IU. National Health Service daily recommended values are slightly lower at 700 micrograms for men and 600 micrograms for women.[34]

During the absorption process in the

intracellularly
.

Deficiency

Prevalence of vitamin A deficiency in 1995

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.[37]

Sources

Retinoids are found naturally only in foods of animal origin. Each of the following contains at least 0.15 mg of retinoids per 1.75–7 oz (50–198 g):

Chemistry

Many different geometric isomers of retinol, retinal and retinoic acid are possible as a result of either a

cis configuration of four of the five 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 at the top of this page). 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 composed 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.

Many of the non-visual functions of vitamin A are mediated by retinoic acid, which regulates gene expression by activating nuclear retinoic acid receptors.[24] 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.

Synthesis

Biosynthesis

Vitamin A biosynthesis

Retinol is synthesized from the breakdown of

β-carotene. First, the β-carotene 15-15'-monooxygenase cleaves β-carotene at the central double bond, creating an epoxide. This epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. The cleavage occurs when these alcohols are oxidized to the aldehydes using NADH. This compound is called retinal. Retinal is then reduced to retinol by the enzyme retinol dehydrogenase. Retinol dehydrogenase is an enzyme that is dependent on NADH.[39]

Industrial synthesis

β-ionone ring

Retinol is made industrially via

Hoffman-La Roche.[42] The two major suppliers, DSM and BASF, are believed to use total synthesis.[43]

The world market for synthetic retinol is primarily for animal feed, leaving approximately 13% for a combination of food, prescription medication and dietary supplement use.

Rhone-Poulenc controlled 96% of global vitamin A sales. In 2001, the European Commission imposed total fines of 855.22 Euros on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989. Roche sold its vitamin division to DSM in 2003. DSM and BASF have the major share of industrial production.[43]

Production from natural β-carotene is possible, but is not industrially used.

History

Frederick Gowland Hopkins, 1929 Nobel Prize for Physiology or Medicine

In 1912, Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.[44] One year later, 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 Burr Osborne and Lafayette Mendel, at Yale, also in 1913, which suggested a fat-soluble nutrient in butterfat.[45] The "accessory factors" were termed "fat soluble" in 1918 and later "vitamin A" in 1920. In 1931, Swiss chemist Paul Karrer described the chemical structure of vitamin A.[44] Retinoic acid and retinol were first synthesized in 1946 and 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.[46][47]

George Wald, 1967 Nobel Prize for Physiology or Medicine

In 1967,

11-cis retinal. When struck by light, 11-cis retinal undergoes photoisomerization to all-trans retinal and via signal transduction cascade send a nerve signal to the brain. The all-trans retinal is reduced to all-trans retinol and travels back to the retinal pigment epithelium to be recycled to 11-cis retinal and conjugated to opsin.[49]

Although vitamin A was not confirmed as an essential nutrient and a chemical structure described until the 20th century, written observations of conditions created by deficiency of this nutrient appeared much earlier in history. Sommer classified historical accounts related to vitamin A and/or manifestations of deficiency as follows: "ancient" accounts; 18th- to 19th-century clinical descriptions (and their purported etiologic associations); early 20th-century laboratory animal experiments, and clinical and epidemiologic observations that identified the existence of this unique nutrient and manifestations of its deficiency.[21]

References

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