vitamin a vitamin a vitamin a is a fat-soluble vitamin and an essential nutrient for animals. the term "vitamin a" encompasses a group of chemically related organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. vitamin a has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light (scotopic vision) and color vision. this article is about the family of vitamers. for the form usually used as a supplement, see retinol. vitamin aretinolclinical dataahfs/drugs.commonographlicense data us dailymed: retinol routes ofadministrationby mouth, imdrug classvitaminatc codea11ca01 (who) d10ad02 (who), r01ax02 (who), s01xa02 (who)legal statuslegal status us: otc identifiers iupac name (2e,4e,6e,8e)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol cas number68-26-8mixture: 11103-57-4 ypubchem cid1071iuphar/bps4053chemspider393012uniig2sh0xkk91mixture: 81g40h8b0t ychebichebi:17336chemblchembl986echa infocard100.031.195 chemical and physical dataformulac20h30omolar mass286.459 g·mol−13d model (jsmol)interactive imagemelting point62–64 °c (144–147 °f)boiling point137–138 °c (279–280 °f) (10−6 mm hg) smiles oc/c=c(c)/c=c/c=c(c)/c=c/c1=c(c)/cccc1(c)c inchi 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+ ykey:fpipgxgpppqfeq-ovsjkpmpsa-n vitamin a occurs as two principal forms in foods: a) retinol, found in animal-sourced foods, either as retinol or bound to a fatty acid to become a retinyl ester, and b) the carotenoids alpha-carotene, β-carotene, gamma-carotene, and the xanthophyll beta-cryptoxanthin (all of which contain β-ionone rings) that function as provitamin a in herbivore and omnivore animals which possess the enzymes that cleave and convert provitamin carotenoids to retinal and then to retinol. some carnivore species lack this enzyme. the other carotenoids have no vitamin activity. dietary retinol is absorbed from the digestive tract via passive diffusion. unlike retinol, β-carotene is taken up by enterocytes by the membrane transporter protein scavenger receptor b1 (scarb1), which is upregulated in times of vitamin a deficiency. storage of retinol is in lipid droplets in the liver. a high capacity for long-term storage of retinol means that well-nourished humans can go months on a vitamin a- and β-carotene-deficient diet, while maintaining blood levels in the normal range. only when the liver stores are nearly depleted will signs and symptoms of deficiency show. retinol is reversibly converted to retinal, then irreversibly to retinoic acid, which activates hundreds of genes. vitamin a deficiency is common in developing countries, especially in sub-saharan africa and southeast asia. deficiency can occur at any age but is most common in pre-school-age children and pregnant women, the latter due to a need to transfer retinol to the fetus. vitamin a deficiency is estimated to affect approximately one-third of children under the age of five around the world, resulting in hundreds of thousands of cases of blindness and deaths from childhood diseases because of immune system failure. reversible night blindness is an early indicator of low vitamin a status. plasma retinol is used as a biomarker to confirm vitamin a deficiency. breast milk retinol can indicate a deficiency in nursing mothers. neither of these measures indicates the status of liver reserves. the european union and various countries have set recommendations for dietary intake, and upper limits for safe intake. vitamin a toxicity also referred to as hypervitaminosis a, occurs when there is too much vitamin a accumulating in the body. symptoms may include nervous system effects, liver abnormalities, fatigue, muscle weakness, bone and skin changes, and others. the adverse effects of both acute and chronic toxicity are reversed after consumption of high dose supplements is stopped. definition vitamin a is a fat-soluble vitamin, a category that also includes vitamins d, e and k. the vitamin encompasses several chemically related naturally occurring compounds or metabolites, i.e., vitamers, that all contain a β-ionone ring. the primary dietary form is retinol, which may have a fatty acid molecule attached, creating a retinyl ester, when stored in the liver. retinol – the transport and storage form of vitamin a – is interconvertible with retinal, catalyzed to retinal by retinol dehydrogenases and back to retinol by retinaldehyde reductases. retinal + nadph + h+ ⇌ retinol + nadp+ retinol + nad+ ⇌ retinal + nadh + h+ retinal, (also known as retinaldehyde) can be irreversibly converted to all-trans-retinoic acid by the action of retinal dehydrogenase retinal + nad+ + h2o → retinoic acid + nadh + h+ retinoic acid diffuses into the cell nucleus where it regulates more than 500 genes by binding directly to gene targets via retinoic acid receptors. in addition to retinol, retinal and retinoic acid, there are plant-, fungi- or bacteria-sourced carotenoids which can be metabolized to retinol, and are thus vitamin a vitamers. there are also what are referred to as 2nd, 3rd and 4th generation retinoids which are not considered vitamin a vitamers because they cannot be converted to retinol, retinal or all-trans-retinoic acid. some are prescription drugs, oral or topical, for various indications. examples are etretinate, acitretin, adapalene, bexarotene, tazarotene and trifarotene. absorption, metabolism and excretion retinyl esters from animal-sourced foods (or synthesized for dietary supplements for humans and domesticated animals) are acted upon by retinyl ester hydrolases in the lumen of the small intestine to release free retinol. retinol enters intestinal absorptive cells by passive diffusion. absorption efficiency is in the range of 70 to 90%. humans are at risk for acute or chronic vitamin a toxicity because there are no mechanisms to suppress absorption or excrete the excess in urine. within the cell, retinol is there bound to retinol binding protein 2 (rbp2). it is then enzymatically reesterified by the action of lecithin retinol acyltransferase and incorporated into chylomicrons that are secreted into the lymphatic system. unlike retinol, β-carotene is taken up by enterocytes by the membrane transporter protein scavenger receptor b1 (scarb1). the protein is upregulated in times of vitamin a deficiency. if vitamin a status is in the normal range, scarb1 is downregulated, reducing absorption. also downregulated is the enzyme beta-carotene 15,15'-dioxygenase (formerly known as beta-carotene 15,15'-monooxygenase) coded for by the bcmo1 gene, responsible for symmetrically cleaving β-carotene into retinal. absorbed β-carotene is either incorporated as such into chylomicrons or first converted to retinal and then retinol, bound to rbp2. after a meal, roughly two-thirds of the chylomicrons are taken up by the liver with the remainder delivered to peripheral tissues. peripheral tissues also can convert chylomicron β-carotene to retinol. the capacity to store retinol in the liver means that well-nourished humans can go months on a vitamin a deficient diet without manifesting signs and symptoms of deficiency. two liver cell types are responsible for storage and release: hepatocytes and hepatic stellate cells (hscs). hepatocytes take up the lipid-rich chylomicrons, bind retinol to retinol-binding protein 4 (rbp4), and transfer the retinol-rbp4 to hscs for storage in lipid droplets as retinyl esters. mobilization reverses the process: retinyl ester hydrolase releases free retinol which is transferred to hepatocytes, bound to rbp4, and put into blood circulation. other than either after a meal or when consumption of large amounts exceeds liver storage capacity, more than 95% of retinol in circulation is bound to rbp4. carnivores strict carnivores manage vitamin a differently than omnivores and herbivores. carnivores are more tolerant of high intakes of retinol because those species have the ability to excrete retinol and retinyl esters in urine. carnivores also have the ability to store more in the liver, due to a higher ratio of liver hscs to hepatocytes compared to omnivores and herbivores. for humans, liver content can range from 20 to 30 μg/gram wet weight. notoriously, polar bear liver is acutely toxic to humans because content has been reported in range of 2,215 to 10,400 μg/g wet weight. as noted, in humans, retinol circulates bound to rbp4. carnivores maintain r-rbp4 within a tight range while also having retinyl esters in circulation. bound retinol is delivered to cells while the esters are excreted in the urine. in general, carnivore species are poor converters of ionone-containing carotenoids, and pure carnivores such as felidae (cats) lack the cleaving enzyme entirely. they must have retinol or retinyl esters in their diet. herbivores herbivores consume ionone-containing carotenoids and convert those to retinal. some species, including cattle and horses, have measurable amounts of beta-carotene circulating in the blood, and stored in body fat, creating yellow fat cells. most species have white fat and no beta-carotene in circulation. activation and excretion in the liver and peripheral tissues of humans, retinol is reversibly converted to retinal by the action of alcohol dehydrogenases, which are also responsible for the conversion of ethanol to acetaldehyde. retinal is irreversibly oxidized to retinoic acid (ra) by the action of aldehyde dehydrogenases. ra regulates the activation or deactivation of genes. the oxidative degradation of ra is induced by ra - its presence triggers its removal, making for a short-acting gene transcription signal. this deactivation is mediated by a cytochrome p450 (cyp) enzyme system, specifically enzymes cyp26a1, cyp26b1 and cyp26c1. cyp26a1 is the predominant form in the human liver; all other human adult tissues contained higher levels of cyp26b1. cyp26c1 is expressed mainly during embryonic development. all three convert retinoic acid into 4-oxo-ra, 4-oh-ra and 18-oh-ra. glucuronic acid forms water-soluble glucuronide conjugates with the oxidized metabolites, which are then excreted in urine and feces. metabolic functions further information: vitamin a deficiency other than for vision, the metabolic functions of vitamin a are mediated by all-trans-retinoic acid (ra). the formation of ra from retinal is irreversible. to prevent accumulation of ra it is oxidized and eliminated fairly quickly, i.e., has a short half-life. three cytochromes catalyze the oxidation of retinoic acid. the genes for cyp26a1, cyp26b1 and cyp26c1 are induced by high levels of ra, providing a self-regulating feedback loop. vision and eye health vitamin a status involves eye health via two separate functions. retinal is an essential factor in rod cells and cone cells in the retina responding to light exposure by sending nerve signals to the brain. an early sign of vitamin a deficiency is night blindness. vitamin a in the form of retinoic acid is essential to normal epithelial cell functions. severe vitamin a deficiency, common in infants and young children in southeast asia causes xerophthalmia characterized by dryness of the conjunctival epithelium and cornea. untreated, xerophthalmia progresses to corneal ulceration and blindness. vision main article: visual cycle the role of vitamin a in the visual cycle is specifically related to the retinal compound. retinol is converted by the enzyme rpe65 within the retinal pigment epithelium into 11-cis-retinal. within the eye, 11-cis-retinal is bound to the protein opsin to form rhodopsin in rod cells and iodopsin in cone cells. as light enters the eye, the 11-cis-retinal is isomerized to the all-trans form. the all-trans-retinal dissociates from the opsin in a series of steps called photo-bleaching. this isomerization induces a nervous signal along the optic nerve to the visual center of the brain. after separating from opsin, the all-trans-retinal is recycled and converted back to the 11-cis-retinal form by a series of enzymatic reactions, which then completes the cycle by binding to opsin to reform rhodopsin in the retina. in addition, some of the all-trans-retinal may be converted to all-trans-retinol form and then transported with an interphotoreceptor retinol-binding protein to the retinal pigmented epithelial cells. further esterification into all-trans-retinyl esters allow for storage of all-trans-retinol within the pigment epithelial cells to be reused when needed. it is for this reason that a deficiency in vitamin a will inhibit the reformation of rhodopsin, and will lead to one of the first symptoms, night blindness. night blindness main article: nyctalopia vitamin a deficiency (vad) caused night blindness is a reversible difficulty for the eyes to adjust to dim light. it is common in young children who have a diet inadequate in retinol and beta-carotene. a process called dark adaptation typically causes an increase in photopigment amounts in response to low levels of illumination. this increases light sensitivity by up to 100,000 times compared to normal daylight conditions. significant improvement in night vision takes place within ten minutes, but the process can take up to two hours to reach maximal effect. people expecting to work in a dark environment wore red-tinted goggles or were in a red light environment to not reverse the adaptation because red light does not deplete rhodopsin versus what occurs with yellow or green light. xerophthalmia and childhood blindness main article: xerophthalmia typical location of bitot's spots xerophthalmia, caused by a severe vitamin a deficiency, is described by pathologic