View source for Chemistry:Vitamin A

{{Short description|Essential nutrient}}

{{Infobox drug
| drug_name         =
| INN               =
| type              =<!-- empty -->
| IUPAC_name        = (2''E'',4''E'',6''E'',8''E'')-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol
| image             = All-trans-Retinol2.svg
| width             =
| alt               =
| image2            = Retinol 3D balls.png
| width2            =
| alt2              =
| imageL            =
| widthL            =
| altL              =
| imageR            =
| widthR            =
| altR              =
| caption           = Retinol
<!-- Clinical data -->
| pronounce         =
| tradename         =
| Drugs.com         = {{Drugs.com|monograph|vitamin-a}}
| MedlinePlus       =
| licence_EU        = <!-- EMA requires brand name -->
| licence_US        = <!-- FDA may use generic name -->
| DailyMedID        = Retinol
| pregnancy_AU      = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment =
| pregnancy_US      = X
| pregnancy_US_comment =<ref name=AHFS2016/>
| pregnancy_category=
| dependency_liability =
| addiction_liability =
| routes_of_administration = by mouth, IM<ref name=AHFS2016>{{cite web|title=Vitamin A|url=https://www.drugs.com/monograph/vitamin-a.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161230232204/https://www.drugs.com/monograph/vitamin-a.html|archive-date=30 December 2016}}</ref>
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = OTC
| legal_US_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status      = <!--For countries not listed above-->
<!-- Pharmacokinetic data -->
| bioavailability   =
| protein_bound     =
| metabolism        =
| metabolites       =
| onset             =
| elimination_half-life =
| duration_of_action =
| excretion         =
<!-- Identifiers -->

| index2_label = mixture
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 =	11103-57-4
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 81G40H8B0T

| CAS_number        = 68-26-8
| CAS_supplemental  =
| class             = [[Chemistry:Vitamin|vitamin]]
| ATCvet            =
| ATC_prefix        = A11
| ATC_suffix        = CA01
| ATC_supplemental  = {{ATC|D10|AD02}}, {{ATC|R01|AX02}}, {{ATC|S01|XA02}}
| PubChem           = 1071
| PubChemSubstance  =
| IUPHAR_ligand     = 4053
| DrugBank          =
| ChemSpiderID      = 393012
| UNII              = G2SH0XKK91
| KEGG              =
| ChEBI             = 17336
| ChEMBL            = 986
| NIAID_ChemDB      =
| synonyms          =
<!-- Chemical and physical data -->
| chemical_formula  =
| C=20
| H=30
| O=1
| SMILES            = OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)/CCCC1(C)C
| Jmol              =
| StdInChI          = 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+
| StdInChI_Ref  = {{stdinchicite|correct|chemspider}}
| StdInChIKey       = FPIPGXGPPPQFEQ-OVSJKPMPSA-N
| density           =
| density_notes     =
| melting_point     = 62–64
| melting_high      =
| melting_notes     =
| boiling_point     = 137–138
| boiling_notes     = ({{val|e=-6|u=mm Hg}})
| solubility        =
| specific_rotation =
}}

'''Vitamin A''' is a fat-soluble [[Chemistry:Vitamin|vitamin]] and an essential nutrient for animals. The term "vitamin A" is mainly used as a simplified term for vitamin A1 while summarising different substance classes like vitamin A1, vitamin A2 and [[Chemistry:Vitamin A5|vitamin A5]].

The term "vitamin A", here specifically vitamin A1, encompasses a group of chemically related organic compounds that includes [[Chemistry:Retinol|retinol]], [[Chemistry:Retinal|retinal]] (also known as retinaldehyde), all-''trans''-[[Chemistry:Retinoic acid|retinoic acid]], and several [[Chemistry:Provitamin|provitamin]] (precursor) [[Biology:Carotenoid|carotenoid]]s, most notably all-''trans''-beta-carotene.<ref name="ods">{{cite web |title=Vitamin A Fact Sheet for Health Professionals|url=https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/ |publisher=Office of Dietary Supplements, US National Institutes of Health |date=March 2021|accessdate=8 August 2021}}</ref><ref name="lpi">{{cite web |url=http://lpi.oregonstate.edu/mic/vitamins/vitamin-A |title=Vitamin A |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis |date=1 July 2016 |access-date=21 December 2021}}</ref><ref name="DRI VitA"/><ref name=PKIN2020VitA>{{cite book |vauthors=Blaner WS |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Vitamin A |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 73–92 |isbn=978-0-323-66162-1}}</ref> 

Vitamin A has multiple functions: it is essential for [[Biology:Embryo|embryo]] development and growth, for maintenance of the [[Biology:Immune system|immune system]], and for vision, where it combines with the protein [[Biology:Opsin|opsin]] to form [[Biology:Rhodopsin|rhodopsin]] {{ndash}} the light-absorbing molecule necessary for both low-light (scotopic vision) and [[Color vision|color vision]].<ref name="Wolf2001">{{cite journal |vauthors=Wolf G |title=The discovery of the visual function of vitamin A |journal=The Journal of Nutrition |volume=131 |issue=6 |pages=1647–50 |date=June 2001 |pmid= 11385047|doi=10.1093/jn/131.6.1647|doi-access=free }}</ref>

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 [[Chemistry:Ester|ester]], and B) the carotenoids alpha-carotene, β-carotene, gamma-carotene, and the [[Chemistry:Xanthophyll|xanthophyll]] beta-cryptoxanthin (all of which contain β-ionone rings) that function as provitamin A in [[Earth:Herbivore|herbivore]] and [[Biology:Omnivore|omnivore]] animals which possess the enzymes that cleave and convert provitamin carotenoids to retinal and then to retinol.<ref name=Wu2016/> Some [[Biology:Carnivore|carnivore]] species lack this enzyme. The other carotenoids have no vitamin activity.<ref name=PKIN2020VitA/>

Dietary retinol is absorbed from the digestive tract via [[Physics:Passive transport|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.<ref name=PKIN2020VitA/> Storage of retinol is in [[Biology:Lipid droplet|lipid droplet]]s in the [[Biology:Liver|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.<ref name=lpi/> Only when the liver stores are nearly depleted will signs and symptoms of deficiency show.<ref name=lpi/> Retinol is reversibly converted to retinal, then irreversibly to retinoic acid, which activates hundreds of [[Biology:Gene|gene]]s.<ref name="Kedish2016"/>

Vitamin A deficiency is common in developing countries, especially in [[Place:Sub-Saharan Africa|Sub-Saharan Africa]] and [[Place:Southeast Asia|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 [[Medicine:Visual impairment|blindness]] and deaths from childhood diseases because of immune system failure.<ref name=UNICEFvitaminA/> Reversible [[Medicine:Nyctalopia|night blindness]] is an early indicator of low vitamin A status. Plasma retinol is used as a [[Biology:Biomarker|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.<ref name=PKIN2020VitA/>

The [[Social:European Union|European Union]] and various countries have set recommendations for dietary intake, and upper limits for safe intake. Vitamin A toxicity also referred to as [[Medicine:Hypervitaminosis A|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.<ref name=PKIN2020VitA/>

==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., [[Chemistry:Vitamer|vitamer]]s, that all contain a β-ionone ring.<ref name=lpi/> The primary dietary form is retinol, which may have a fatty acid molecule attached, creating a retinyl ester, when stored in the liver. Retinol {{ndash}} the transport and storage form of vitamin A {{ndash}} is interconvertible with retinal, catalyzed to retinal by [[Biology:Retinol dehydrogenase|retinol dehydrogenase]]s and back to retinol by retinaldehyde reductases.<ref>{{cite journal | vauthors = Lidén M, Eriksson U | title = Understanding retinol metabolism: structure and function of retinol dehydrogenases | journal = The Journal of Biological Chemistry | volume = 281 | issue = 19 | pages = 13001–13004 | date = May 2006 | pmid = 16428379 | doi = 10.1074/jbc.R500027200 | doi-access = free }}</ref>
:retinal + [[Chemistry:Nicotinamide adenine dinucleotide phosphate|NADPH]] + H<sup>+</sup> {{eqm}} retinol + NADP<sup>+</sup>
:retinol + [[Chemistry:Nicotinamide adenine dinucleotide|NAD]]<sup>+</sup> {{eqm}} retinal + NADH + H<sup>+</sup>
Retinal, (also known as retinaldehyde) can be irreversibly converted to ''all-trans''-retinoic acid by the action of [[Biology:Retinal dehydrogenase|retinal dehydrogenase]] 
:retinal + NAD<sup>+</sup> + H<sub>2</sub>O → retinoic acid + NADH + H<sup>+</sup>
Retinoic acid diffuses into the [[Biology:Cell nucleus|cell nucleus]] where it regulates more than 500 genes by binding directly to gene targets via [[Biology:Retinoic acid receptor alpha|retinoic acid receptors]].<ref name=PKIN2020VitA/>

In addition to retinol, retinal and retinoic acid, there are plant-, fungi- or bacteria-sourced [[Biology:Carotenoid|carotenoid]]s which can be metabolized to retinol, and are thus vitamin A vitamers.<ref name=PKIN2020Carotenoids/>

There are also what are referred to as 2nd, 3rd and 4th generation [[Chemistry:Retinoid|retinoid]]s 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 [[Chemistry:Etretinate|etretinate]], [[Chemistry:Acitretin|acitretin]], [[Chemistry:Adapalene|adapalene]], [[Chemistry:Bexarotene|bexarotene]], [[Chemistry:Tazarotene|tazarotene]] and [[Chemistry:Trifarotene|trifarotene]].<ref name=Becken2015/><ref name=Monograph/>

==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 [[Biology:Lumen (anatomy)|lumen]] of the small intestine to release free retinol. Retinol enters [[Biology:Enterocyte|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.<ref name="DRI VitA"/> 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 [[Biology:Lymphatic system|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.<ref name=PKIN2020VitA/> Also downregulated is the enzyme [[Biology:Beta-carotene 15,15'-dioxygenase|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.<ref name=Wu2016/> 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.<ref name="PKIN2020VitA"/><ref name="Chel2016">{{cite journal |vauthors=Chelstowska S, Widjaja-Adhi MA, Silvaroli JA, Golczak M |title=Molecular Basis for Vitamin A Uptake and Storage in Vertebrates |journal=Nutrients |volume=8 |issue=11 |date=October 2016 |page=676 |pmid=27792183 |pmc=5133064 |doi=10.3390/nu8110676 |url=|doi-access=free }}</ref>

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: [[Biology:Hepatocyte|hepatocyte]]s and [[Biology:Hepatic stellate cell|hepatic stellate cell]]s (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.<ref name="Chel2016"/>

===Carnivores===
Strict carnivores manage vitamin A differently than [[Biology:Omnivore|omnivore]]s and [[Earth:Herbivore|herbivore]]s. 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, [[Biology:Polar bear|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.<ref name=Green2016>{{cite journal |vauthors=Green AS, Fascetti AJ |title=Meeting the Vitamin A Requirement: The Efficacy and Importance of β-Carotene in Animal Species |journal=ScientificWorldJournal |volume=2016 |issue= |pages=7393620 |date=2016 |pmid=27833936 |pmc=5090096 |doi=10.1155/2016/7393620 |url=|doi-access=free }}</ref> 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.<ref name=Green2016/> In general, carnivore species are poor converters of ionone-containing carotenoids, and pure carnivores such as [[Biology:Felidae|felidae]] (cats) lack the cleaving enzyme entirely. They must have retinol or retinyl esters in their diet.<ref name=Green2016/>

===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.<ref name=Green2016/>

===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 [[Chemistry:Ethanol|ethanol]] to [[Chemistry:Acetaldehyde|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 [[Biology:Cytochrome P450|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. [[Chemistry:Glucuronic acid|Glucuronic acid]] forms water-soluble glucuronide conjugates with the oxidized metabolites, which are then excreted in urine and feces.<ref name="Kedish2016">{{cite journal |vauthors=Kedishvili NY |title=Retinoic Acid Synthesis and Degradation |journal=Subcell Biochem |series=Subcellular Biochemistry |volume=81 |issue= |pages=127–61 |date=2016 |pmid=27830503 |pmc=5551983 |doi=10.1007/978-94-024-0945-1_5 |isbn=978-94-024-0943-7 |url=}}</ref>

==Metabolic functions==
{{see|Vitamin A deficiency}}
Other than for vision, the metabolic functions of vitamin A are mediated by [[Chemistry:Retinoic acid|''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.<ref name="Roberts2020">{{cite journal |vauthors=Roberts C |title=Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes |journal=J Dev Biol |volume=8 |issue=1 |date=March 2020 |page=6 |pmid=32151018 |pmc=7151129 |doi=10.3390/jdb8010006 |url=|doi-access=free }}</ref><ref name="Isoherr2019">{{cite journal |vauthors=Isoherranen N, Zhong G |title=Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases |journal=Pharmacol Ther |volume=204 |issue= |pages=107400 |date=December 2019 |pmid=31419517 |pmc=6881548 |doi=10.1016/j.pharmthera.2019.107400 |url=}}</ref>

===Vision and eye health===
Vitamin A status involves eye health via two separate functions. Retinal is an essential factor in [[Biology:Rod cell|rod cell]]s and [[Biology:Cone cell|cone cell]]s in the retina responding to light exposure by sending nerve signals to the brain. An early sign of vitamin A deficiency is night blindness.<ref name=PKIN2020VitA/> 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 [[Medicine:Xerophthalmia|xerophthalmia]] characterized by dryness of the conjunctival epithelium and cornea. Untreated, xerophthalmia progresses to corneal ulceration and blindness.<ref name="Whitcher2001"/>

====Vision====
{{Main|Biology: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 [[Biology:Opsin|opsin]] to form [[Biology:Rhodopsin|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.<ref name=PKIN2020VitA/> 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.<ref name=PKIN2020VitA/><ref name="Combs2008">{{cite book |title=The Vitamins: Fundamental Aspects in Nutrition and Health | vauthors = Combs GF |year=2008 |edition=3rd |publisher=Elsevier Academic Press |location=Burlington, MA |isbn=978-0-12-183493-7}}</ref><ref name="Miller"/>

====Night blindness====
{{Main|Medicine:Nyctalopia}}
[[Medicine:Vitamin A deficiency|Vitamin A deficiency]] (VAD) caused [[Medicine:Nyctalopia|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 [[Biology:Adaptation (eye)|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.<ref name="Wolf2001"/> 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.<ref name="Miller">{{cite journal |url=https://apps.dtic.mil/sti/citations/ADA257059 |archive-url=https://web.archive.org/web/20220104192142/https://apps.dtic.mil/sti/citations/ADA257059 |url-status=live |archive-date=4 January 2022 |title=Night Vision Manual for the Flight Surgeon|vauthors=Miller RE, Tredici TJ |date=1 August 1992 |website=US Department of Defense, Defense Technical Information Center |access-date=4 January 2022}}</ref>

====Xerophthalmia and childhood blindness====
{{Main|Medicine:Xerophthalmia}}
[[File:Typical location of Bitot's spots.jpg|thumb|Typical location of Bitot's spots]]
Xerophthalmia, caused by a severe vitamin A deficiency, is described by pathologic dryness of the conjunctival epithelium and cornea. The conjunctiva becomes dry, thick, and wrinkled. Indicative is the appearance of Bitot's spots, which are clumps of keratin debris that build up inside the conjunctiva. If untreated, xerophthalmia can lead to dry eye syndrome, corneal ulceration and ultimately to blindness as a result of cornea and retina damage. Although xerophthalmia is an eye-related issue, prevention (and reversal) are functions of retinoic acid having been synthesized from retinal rather than the 11-''cis''-retinal to rhodopsin cycle.<ref name="Akhtar2013"/>

Throughout southeast Asia, estimates are that more than half of children under the age of six years have subclinical vitamin A deficiency and night blindness, with progression to  xerophthalmia being the leading cause of preventable childhood blindness.<ref name="Akhtar2013">{{cite journal |vauthors=Akhtar S, Ahmed A, Randhawa MA, Atukorala S, Arlappa N, Ismail T, Ali Z |title=Prevalence of vitamin A deficiency in South Asia: causes, outcomes, and possible remedies |journal=J Health Popul Nutr |volume=31 |issue=4 |pages=413–23 |date=December 2013 |pmid=24592582 |pmc=3905635 |doi=10.3329/jhpn.v31i4.19975 |url=}}</ref> Estimates are that each year there are 350,000 cases of childhood blindness due to vitamin A deficiency.<ref name="Whitcher2001">{{cite journal |vauthors=Whitcher JP, Srinivasan M, Upadhyay MP |title=Corneal blindness: a global perspective |journal=Bull World Health Organ |volume=79 |issue=3 |pages=214–21 |date=2001 |pmid=11285665 |pmc=2566379 |doi= |url=}}</ref> The causes are vitamin A deficiency during pregnancy, followed by low transfer of vitamin A during lactation and infant/child diets low in vitamin A or beta-carotene.<ref name="Akhtar2013"/><ref name="Whitcher2001"/> The [[Prevalence|prevalence]] of pre-school age children who are blind due to vitamin A deficiency is lower than expected from [[Medicine:Incidence (epidemiology)|incidence of new cases]] only because childhood vitamin A deficiency significantly increases all-cause mortality.<ref name="Whitcher2001"/>

According to a 2017 Cochrane review, vitamin A deficiency, using serum retinol less than 0.70&nbsp;µmol/L as a criterion, is a major public health problem affecting an estimated 190 million children under five years of age in low- and middle-income countries, primarily in Sub-Saharan Africa and Southeast Asia. In lieu of or in combination with food fortification programs, many countries have implemented public health programs in which children are periodically given very large oral doses of synthetic vitamin A, usually retinyl palmitate, as a means of preventing and treating VAD. Doses were 50,000 to 100,000 IU ([[International unit]]s) for children aged 6 to 11 months and 100,000 to 200,000 IU for children aged 12 months to five years, the latter typically every four to six months. In addition to a 24% reduction in all-cause mortality, eye-related results were reported. Prevalence of Bitot's spots at follow-up were reduced by 58%, night blindness by 68%, xerophthalmia by 69%.<ref name="Imdad2017"/>

===Gene regulation===
RA regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs; RARα, RARβ, RARγ) which are bound to [[Biology:DNA|DNA]] as heterodimers with retinoid "X" receptors (RXRs; RXRα, RXRβ, RXRγ). RARs and RXRs must dimerize before they can bind to the DNA. Expression of more than 500 genes is responsive to retinoic acid.<ref name=PKIN2020VitA/> The process is that RAR-RXR heterodimers recognize retinoic acid response elements on DNA.<ref>{{cite journal |vauthors=Duester G |title=Retinoic acid synthesis and signaling during early organogenesis |journal=Cell |volume=134 |issue=6 |pages=921–31 |date=September 2008 |pmid=18805086 |pmc=2632951 |doi=10.1016/j.cell.2008.09.002}}</ref> The receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery.<ref>{{cite book |title=Biochemical, Physiological and Molecular Aspects of Human Nutrition | vauthors = Stipanuk MH |year=2006 |edition=2nd |publisher=Saunders |location=Philadelphia |isbn=9781416002093}}</ref> This response upregulates or downregulates the expression of target genes, including the genes that encode for the receptors themselves.<ref name="Combs2008" /> To prevent excess accumulation of RA it must be metabolized and eliminated. Three cytochromes (Cyp26A1, Cyp26B1 Cyp26C1) catalyze the oxidation of RA. The genes for these proteins are induced by high concentrations of RA, thus providing a regulatory feedback mechanism.<ref name=PKIN2020VitA/>

===Embryology===
In vertebrates and invertebrate chordates, RA has a pivotal role during development. Altering levels of endogenous RA signaling during early embryology, both too low and too high, leads to birth defects,<ref>{{cite journal |vauthors=Metzler MA, Sandell LL |title=Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos |journal=Nutrients |volume=8 |issue=12 |date=December 2016 |page=812 |pmid=27983671 |pmc=5188467 |doi=10.3390/nu8120812 |url=|doi-access=free }}</ref><ref name=Marletaz2006>{{cite journal |vauthors=Marlétaz F, Holland LZ, Laudet V, Schubert M |title=Retinoic acid signaling and the evolution of chordates |journal=Int J Biol Sci |volume=2 |issue=2 |pages=38–47 |date=2006 |pmid=16733532 |pmc=1458431 |doi=10.7150/ijbs.2.38 |url=}}</ref> including congenital vascular and cardiovascular defects.<ref>{{cite journal |vauthors=Pawlikowski B, Wragge J, Siegenthaler JA |title=Retinoic acid signaling in vascular development |journal=Genesis |volume=57 |issue=7–8 |pages=e23287 |date=July 2019 |pmid=30801891 |pmc=6684837 |doi=10.1002/dvg.23287 |url=}}</ref><ref>{{cite journal |vauthors=Wang S, Moise AR |title=Recent insights on the role and regulation of retinoic acid signaling during epicardial development |journal=Genesis |volume=57 |issue=7–8 |pages=e23303 |date=July 2019 |pmid=31066193 |pmc=6682438 |doi=10.1002/dvg.23303 |url=}}</ref> Of note, fetal alcohol spectrum disorder encompasses congenital anomalies, including craniofacial, auditory, and ocular defects, neurobehavioral anomalies and mental disabilities caused by maternal consumption of alcohol during pregnancy. It is proposed that in the embryo there is competition between acetaldehyde, an ethanol metabolite, and retinaldehyde (retinal) for  aldehyde dehydrogenase activity, resulting in a retenoic acid deficiency, and attributing the congenital birth defects to the loss of RA activated gene activation. In support of this theory, ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol or retinal.<ref>{{cite journal |vauthors=Shabtai Y, Fainsod A |title=Competition between ethanol clearance and retinoic acid biosynthesis in the induction of fetal alcohol syndrome |journal=Biochem Cell Biol |volume=96 |issue=2 |pages=148–160 |date=April 2018 |pmid=28982012 |doi=10.1139/bcb-2017-0132 |url=}}</ref> As for the risks of too much RA, the prescription drugs tretinoin (''all-trans''-retinoic acid) and isotretinoin (13-cis-retinoic acid), used orally or topically for acne treatment, come with warnings to not be used by pregnant women or women who are anticipating becoming pregnant, as they are known human teratogens.<ref name="Draghici2021"/><ref name="Tretinoin"/>

=== Immune functions ===
Vitamin A deficiency (VAD) has been linked to compromised resistance to infectious diseases.<ref name="Ross2012">{{cite journal |vauthors=Ross AC |title=Vitamin A and retinoic acid in T cell-related immunity |journal=Am J Clin Nutr |volume=96 |issue=5 |pages=1166S–72S |date=November 2012 |pmid=23053562 |pmc=3471201 |doi=10.3945/ajcn.112.034637 |url=}}</ref><ref name="Pino2010">{{cite journal |vauthors=Pino-Lagos K, Guo Y, Noelle RJ |title=Retinoic acid: a key player in immunity |journal=Biofactors |volume=36 |issue=6 |pages=430–36 |date=2010 |pmid=20803520 |pmc=3826167 |doi=10.1002/biof.117 |url=}}</ref> In countries where early childhood VAD is common, vitamin A supplementation public health programs initiated in the 1980s were shown to reduce the incidence of diarrhea and measles, and all-cause mortality.<ref name="Imdad2017"/><ref name=Brown2015>{{cite journal |vauthors=Brown CC, Noelle RJ |title=Seeing through the dark: New insights into the immune regulatory functions of vitamin A |journal=Eur J Immunol |volume=45 |issue=5 |pages=1287–95 |date=May 2015 |pmid=25808452 |pmc=4426035 |doi=10.1002/eji.201344398 |url=}}</ref><ref name="Guo2015">{{cite journal |vauthors=Guo Y, Brown C, Ortiz C, Noelle RJ |title=Leukocyte homing, fate, and function are controlled by retinoic acid |journal=Physiol Rev |volume=95 |issue=1 |pages=125–48 |date=January 2015 |pmid=25540140 |pmc=4281589 |doi=10.1152/physrev.00032.2013 |url=}}</ref> VAD also increases the risk of immune system over-reaction, leading to chronic inflammation in the intestinal system, stronger allergic reactions and autoimmune diseases.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Bono2016/>

[[Biology:Lymphocyte|Lymphocyte]]s and [[Biology:Monocyte|monocyte]]s are types of [[Biology:White blood cell|white blood cell]]s of the [[Biology:Immune system|immune system]].<ref name=Janeway>{{cite book | vauthors = Janeway C, Travers P, Walport M, Shlomchik M |title = Immunobiology |edition=5th |publisher = Garland Science |year=2001 |location = New York and London|url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10|isbn = 0-8153-4101-6}}</ref> Lymphocytes include [[Biology:Natural killer cell|natural killer cell]]s, which function in [[Biology:Innate immune system|innate immunity]], [[Biology:T cell|T cell]]s for [[Biology:Adaptive immune system|adaptive cellular immunity]] and [[Biology:B cell|B cell]]s for [[Biology:Antibody|antibody]]-driven [[Biology:Adaptive immune system|adaptive humoral immunity]]. Monocytes differentiate into [[Biology:Macrophage|macrophage]]s and [[Biology:Dendritic cell|dendritic cell]]s. Some lymphocytes migrate to the [[Biology:Thymus|thymus]] where they differentiate into several types of T cells, in some instances referred to as "killer" or "helper" T cells and further differentiate after leaving the thymus. Each subtype has functions driven by the types of [[Biology:Cytokine|cytokine]]s secreted and organs to which the cells preferentially migrate, also described as trafficking or homing.<ref name=Omman>{{cite book | vauthors = Omman RA, Kini AR | veditors = Keohane EM, Otto CN, Walenga JN |title=Rodak's Hematology: Clinical Principles and Applications |date=2020 |publisher=Elsevier |location=St. Louis, Missouri |isbn=978-0-323-53045-3 |pages=117–35 |edition=6th |chapter=Leukocyte development, kinetics, and functions}}</ref><ref name=Cohn>{{cite book | title=Middleton's Allergy: Principles and Practice | date=2014| doi=10.1016/B978-0-323-08593-9.00013-9 | chapter-url=https://www.sciencedirect.com/science/article/pii/B9780323085939000139 | pages=203–14 | vauthors = Cohn L, Hawrylowicz C, Ray A | isbn=9780323085939|edition=8th|chapter=Biology of Lymphocytes|publisher=Saunders|location=Philadelphia}}</ref>

Reviews based on ''in vitro'' and animal research describe the role that retinoic acid (RA) has in the immune system. RA triggers receptors in bone marrow, resulting in generation of new white blood cells.<ref>{{cite journal |vauthors=Cañete A, Cano E, Muñoz-Chápuli R, Carmona R |title=Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis |journal=Nutrients |volume=9 |issue=2 |date=February 2017 |page=159 |pmid=28230720 |pmc=5331590 |doi=10.3390/nu9020159 |url=|doi-access=free }}</ref> RA regulates proliferation and differentiation of white blood cells, the directed movement of T cells to the [[Biology:Gastrointestinal tract|intestinal system]], and to the up- and down-regulation of lymphocyte function.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Brown2015/><ref name="Guo2015"/><ref name="Bono2016">{{cite journal |vauthors=Bono MR, Tejon G, Flores-Santibañez F, Fernandez D, Rosemblatt M, Sauma D |title=Retinoic Acid as a Modulator of T Cell Immunity |journal=Nutrients |volume=8 |issue=6 |date=June 2016 |page=349 |pmid=27304965 |pmc=4924190 |doi=10.3390/nu8060349 |url=|doi-access=free }}</ref><ref name="Czarn2017">{{cite journal |vauthors=Czarnewski P, Das S, Parigi SM, Villablanca EJ |title=Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity |journal=Nutrients |volume=9 |issue=1 |date=January 2017 |page=68 |pmid=28098786 |pmc=5295112 |doi=10.3390/nu9010068 |url=|doi-access=free }}</ref> If RA is adequate, T helper cell subtype Th1 is suppressed and subtypes Th2, Th17 and iTreg (for regulatory) are induced. Dendritic cells located in intestinal tissue have enzymes that convert retinal to ''all-trans''-retinoic acid, to be taken up by retinoic acid receptors on lymphocytes. The process triggers gene expression that leads to T cell types Th2, Th17 and iTreg moving to and taking up residence in mesenteric lymph nodes and Peyer's patches, respectively outside and on the inner wall of the small intestine.<ref name=Brown2015/><ref name="Guo2015"/> The net effect is a down-regulation of immune activity, seen as tolerance of food [[Biology:Allergen|allergen]]s, and tolerance of resident bacteria and other organisms in the [[Biology:Microbiome|microbiome]] of the large intestine.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Bono2016/> In a vitamin A deficient state, innate immunity is compromised and pro-inflammatory Th1 cells predominate.<ref name="Ross2012"/><ref name="Czarn2017"/>

===Skin===
Deficiencies in vitamin A have been linked to an increased susceptibility to skin infection and inflammation.<ref name="Roche2021">{{cite journal |vauthors=Roche FC, Harris-Tryon TA |title=Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review |journal=Nutrients |volume=13 |issue=2 |date=January 2021 |page=302 |pmid=33494277 |pmc=7909803 |doi=10.3390/nu13020302 |url=|doi-access=free }}</ref> Vitamin A appears to modulate the innate immune response and maintains homeostasis of epithelial tissues and mucosa through its metabolite, retinoic acid (RA). As part of the innate immune system, toll-like receptors in skin cells respond to pathogens and cell damage by inducing a pro-inflammatory immune response which includes increased RA production.<ref name="Roche2021"/> The epithelium of the skin encounters bacteria, fungi and viruses. Keratinocytes of the epidermal layer of the skin produce and secrete [[Biology:Antimicrobial peptides|antimicrobial peptides]] (AMPs). Production of AMPs [[Biology:Resistin|resistin]] and [[Biology:Cathelicidin|cathelicidin]], are promoted by RA.<ref name="Roche2021"/>

==Units of measurement==
As some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. The situation can be confusing because the accepted equivalences have changed over time

For many years, a system of equivalencies in which an [[International unit|international unit]] (IU) was equal to 0.3 [[Microgram|μg]] of retinol (~1&nbsp;nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.<ref>''[https://web.archive.org/web/20081002175906/http://www.nal.usda.gov/fnic/foodcomp/Data/SR20/SR20_doc.pdf Composition of Foods Raw, Processed, Prepared USDA National Nutrient Database for Standard Reference, Release 20]'' [[Organization:USDA|USDA]], Feb. 2008</ref> This relationship was alternatively expressed by the retinol equivalent (RE): one RE corresponded to 1 μg retinol, to 2 μg β-carotene dissolved in oil, to 6 μg β-carotene in foods, and to 12 μg of either α-carotene, γ-carotene, or β-[[Chemistry:Cryptoxanthin|cryptoxanthin]] in food.

Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.<ref name="DRI VitA">{{cite book|author=Institute of Medicine |chapter=Vitamin A |chapter-url=https://www.nap.edu/read/10026/chapter/6 |title=Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc |publisher=Food and Nutrition Board of the Institute of Medicine| pages=82–161 |year=2001|isbn=0-309-07290-5}}</ref>

{| class="wikitable"
|-
! Substance and its chemical environment (per 1 μg)
! IU (1989)
! μg {{abbr|RE|retinol equivalent}} (1989)<ref name="DRI VitA"/>
! μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/>
|-
| Retinol
| 3.33
| 1
| 1
|-
| [[Chemistry:Beta-Carotene|beta-Carotene]], dissolved in oil
| 1.67
| 1/2
| 1/2
|-
| beta-Carotene, common dietary
| 1.67
| 1/6
| 1/12
|-
| {{plainlist|
* [[Chemistry:Alpha-Carotene|alpha-Carotene]], common dietary
* gamma-Carotene, common dietary
* beta-Cryptoxanthin, common dietary
}}
| 0.83
| 1/12
| 1/24
|}

Animal models have shown that at the enterocyte cell wall, β-carotene is taken up by the membrane transporter protein scavenger receptor class B, type 1 (SCARB1). Absorbed β-carotene is converted to retinal and then retinol. The first step of the conversion process consists of one molecule of β-carotene cleaved by the enzyme
β-carotene-15, 15'-monooxygenase, which in humans and other mammalian species is encoded by the BCM01 gene,<ref name=Wu2016>{{cite journal |vauthors=Wu L, Guo X, Wang W, Medeiros DM, Clarke SL, Lucas EA, Smith BJ, Lin D |title=Molecular aspects of β, β-carotene-9', 10'-oxygenase 2 in carotenoid metabolism and diseases |journal=Exp Biol Med (Maywood) |volume=241 |issue=17 |pages=1879–87 |date=November 2016 |pmid=27390265 |pmc=5068469 |doi=10.1177/1535370216657900 |url=}}</ref> into two molecules of retinal. When plasma retinol is in the normal range, gene expression for SCARB1 and BC01 are suppressed, creating a feedback loop that suppresses β-carotene absorption and conversion.<ref name=PKIN2020Carotenoids/> Absorption suppression is not complete, as receptor 36 is not downregulated.<ref name=PKIN2020Carotenoids/>

==Dietary recommendations==
The US National Academy of Medicine updated [[Chemistry:Dietary Reference Intake|Dietary Reference Intake]]s (DRIs) in 2001 for vitamin A, which included Recommended Dietary Allowances (RDAs).<ref name="DRI VitA"/> For infants up to 12 months there was not sufficient information to establish a RDA, so Adequate Intake (AI) is shown instead. As for safety, tolerable upper intake levels (ULs) were also established. For ULs, carotenoids are not added when calculating total vitamin A intake for safety assessments.<ref name="DRI VitA"/>

{| class="wikitable"
|-
! colspan=2 | Life stage group
! US RDAs or AIs<br /> (μg RAE/day)<ref name="DRI VitA"/>
! US Upper limits<br /> (μg/day)<ref name="DRI VitA"/>
|-
| rowspan=2 | '''Infants'''
|  0–6 months || 400 (AI) || 600
|-
| 7–12 months || 500 (AI) || 600
|-
| rowspan=2 | '''Children'''
| 1–3 years || 300 || 600
|-
| 4–8 years || 400 || 900
|-
| rowspan=3 | '''Males'''
| 9–13 years  || 600 || 1700
|-
| 14–18 years || 900 || 2800
|-
| >19<!-- – >70--> years || 900 || 3000
|-
| rowspan=3 | '''Females'''
| 9–13 years || 600 || 1700
|-
| 14–18 years || 700 || 2800
|-
| >19<!--– >70--> years || 700 || 3000
|-
| rowspan=2 | '''Pregnancy'''
| <19 years || 750 || 2800
|-
| >19<!-- – >50--> years || 770 || 3000
|-
| rowspan=2 | '''Lactation'''
| <19 years || 1200 || 2800
|-
| >19<!-- – >50--> years || 1300 || 3000
|}

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men of ages 15 and older, the PRIs are set respectively at 650 and 750 μg&nbsp;RE/day. PRI for pregnancy is 700 μg&nbsp;RE/day, for lactation 1300/day. For children of ages 1–14 years, the PRIs increase with age from 250 to 600 μg&nbsp;RE/day. These PRIs are similar to the US RDAs.<ref>{{cite web |title=Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies |year=2017 |url=https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf}}</ref> The EFSA reviewed the same safety question as the United States, and set ULs at 800 for ages 1–3, 1100 for ages 4–6, 1500 for ages 7–10, 2000 for ages 11–14, 2600 for ages 15–17 and 3000 μg/day for ages 18 and older for preformed vitamin A, i.e., not including dietary contributions from carotenoids.<ref name=EFSA-UL>{{citation |title=Tolerable Upper Intake Levels For Vitamins And Minerals |publisher=European Food Safety Authority |year=2006 |url=http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf}}</ref>

===Safety===
Vitamin A toxicity ([[Medicine:Hypervitaminosis A|hypervitaminosis A]]) occurs when too much vitamin A accumulates in the body. It comes from consumption of preformed vitamin A but not of carotenoids, as conversion of the latter to retinol is suppressed by the presence of adequate retinol.

====Retinol safety====
{{Main|Medicine:Hypervitaminosis A}}

There are historical reports of acute hypervitaminosis from Arctic explorers consuming bearded seal or polar bear liver, both very rich sources of stored retinol,<ref>{{cite journal |vauthors=Rodahl K, Moore T |title=The vitamin A content and toxicity of bear and seal liver |journal=Biochem J |volume=37 |issue=2 |pages=166–68 |date=July 1943 |pmid=16747610 |pmc=1257872 |doi=10.1042/bj0370166 |url=}}</ref> and there are also case reports of acute hypervitaminosis from consuming fish liver,<ref>{{cite journal |vauthors=Schmitt C, Domangé B, Torrents R, de Haro L, Simon N |title=Hypervitaminosis A Following the Ingestion of Fish Liver: Report on 3 Cases from the Poison Control Center in Marseille |journal=Wilderness Environ Med |volume=31 |issue=4 |pages=454–456 |date=December 2020 |pmid=32861618 |doi=10.1016/j.wem.2020.06.003 |s2cid=221384282 |url=|doi-access=free }}</ref> but otherwise there is no risk from consuming too much via commonly consumed foods. Only consumption of retinol-containing dietary supplements can result in acute or chronic toxicity.<ref name=PKIN2020VitA/> Acute toxicity occurs after a single or short-term doses of greater than 150,000 μg. Symptoms include blurred vision, nausea, vomiting, dizziness and headache within 8 to 24 hours. For infants ages 0–6 months given an oral dose to prevent development of vitamin A deficiency, bulging skull fontanel was evident after 24 hours, usually resolved by 72 hours.<ref name="Imdad2016">{{cite journal |vauthors=Imdad A, Ahmed Z, Bhutta ZA |title=Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age |journal=The Cochrane Database of Systematic Reviews |volume=9 |page=CD007480 |date=September 2016 |issue=2 |pmid=27681486 |doi=10.1002/14651858.CD007480.pub3 |pmc=6457829}}</ref> Chronic toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU/day for several months.<ref name=lpi/> Excessive consumption of alcohol can lead to chronic toxicity at lower intakes.<ref name=ods/> 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 is stopped.<ref name="DRI VitA"/>

In 2001, for the purpose of determining ULs for adults, the US Institute of Medicine considered three primary adverse effects and settled on two: [[Chemistry:Teratogen|teratogen]]icity, i.e., causing birth defects, and liver abnormalities. Reduced bone mineral density was considered, but dismissed because the human evidence was contradictory.<ref name="DRI VitA"/> During pregnancy, especially during the first trimester, consumption of retinol in amounts exceeding 4,500 μg/day increased the risk of birth defects, but not below that amount, thus setting a "No-Observed Adverse-Effect Level" (NOAEL). Given the quality of the clinical trial evidence, the NOAEL was divided by an uncertainty factor of 1.5 to set the UL for women of reproductive age at 3,000 μg/day of preformed vitamin A. For all other adults, liver abnormalities were detected at intakes above 14,000 μg/day. Given the weak quality of the clinical evidence, an uncertainty factor of 5 was used, and with rounding, the UL was set at 3,000 μg/day. Despite a US UL set at 3,000 μg, it is possible to buy over-the-counter dietary supplement products which are 7,500 μg (25,000 IU), with a label caution statement "Not intended for long term use unless under medical supervision."<ref>{{cite web |url=https://www.nowfoods.com/products/supplements/vitamin-25000-softgels |title=Vitamin A 25,000 Softgels |date= |website=NOW Foods |access-date=23 December 2021}}</ref>

For children, ULs were extrapolated from the adult value, adjusted for relative body weight. For infants, several case studies reported adverse effects that include bulging fontanels, increased intracranial pressure, loss of appetite, hyperirritability and skin peeling after chronic ingestion of the order of 6,000 or more μg/day. Given the small database, an uncertainty factor of 10 divided into the "Lowest-Observed-Adverse-Effect Level" (LOAEL) led to a UL of 600 μg/day.<ref name="DRI VitA"/>

====β-carotene safety====
No adverse effects other than carotenemia have been reported for consumption of β-carotene rich foods. Supplementation with β-carotene does not cause hypervitaminosis A.<ref name=PKIN2020Carotenoids/> Two large clinical trials (ATBC and CARET) were conducted in tobacco smokers to see if years of β-carotene supplementation at 20 or 30&nbsp;mg/day in oil-filled capsules would reduce the risk of lung cancer.<ref name="DRItextBetaCarotene"/> These trials were implemented because observational studies had reported a lower incidence of lung cancer in tobacco smokers who had diets higher in β-carotene. Unexpectedly, this high-dose β-carotene supplementation resulted in a higher incidence of lung cancer and of total mortality.<ref name=PKIN2020Carotenoids/> Taking this and other evidence into consideration, the U.S. Institute of Medicine decided not to set a Tolerable Upper Intake Level (UL) for β-carotene.<ref name=PKIN2020Carotenoids/><ref name="DRItextBetaCarotene">{{cite book |title=Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids |chapter=Beta-carotene and other Carotenoids |publisher=The National Academies Press |year=2000 |location=Washington, DC |pages=325–82 |doi=10.17226/9810 |pmid=25077263 |chapter-url=https://www.nap.edu/read/9810/chapter/10 |access-date=19 December 2021 |isbn=978-0-309-06935-9 |url-status=live |archive-url=https://web.archive.org/web/20170902180153/https://www.nap.edu/read/9810/chapter/10 |archive-date=September 2, 2017|author1=Institute of Medicine (US) Panel on Dietary Antioxidants Related Compounds }}</ref> The European Food Safety Authority, acting for the European Union, also decided not to set a UL for β-carotene.<ref name=EFSA-UL/>
[[File:Carrots.JPG|thumb|upright|right|250px|Carrots are a rich source of beta-carotene]]

====Carotenosis====
Carotenoderma, also referred to as carotenemia, is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. It is associated with a high blood β-carotene value. This can occur after a month or two of consumption of beta-carotene rich foods, such as carrots, carrot juice, tangerine juice, mangos, or in Africa, red palm oil. β-carotene dietary supplements can have the same effect. The discoloration extends to palms and soles of feet, but not to the [[Biology:Sclera|white of the eye]], which helps distinguish the condition from [[Medicine:Jaundice|jaundice]].<ref>{{cite journal |vauthors=Maharshak N, Shapiro J, Trau H |title=Carotenoderma--a review of the current literature |journal=Int J Dermatol |volume=42 |issue=3 |pages=178–81 |date=March 2003 |pmid=12653910 |doi=10.1046/j.1365-4362.2003.01657.x |s2cid=27934066 |url=}}</ref> Consumption of greater than 30&nbsp;mg/day for a prolonged period has been confirmed as leading to carotenemia.<ref name=PKIN2020Carotenoids/><ref>{{cite journal|vauthors=Nasser Y, Jamal Z, Albuteaey M |title=Carotenemia |journal=StatPearls |volume= |issue=  |pages= |date= 11 August 2021 |pmid=30521299 |doi=10.1007/s00253-001-0902-7|s2cid=22232461 }}</ref>

===U.S. labeling===
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin A labeling purposes 100% of the Daily Value was set at 5,000 IU, but it was revised to 900 μg RAE on 27 May 2016.<ref name="FedReg">{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels}}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=18 December 2021 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}</ref> A table of the old and new adult daily values is provided at [[Chemistry:Reference Daily Intake|Reference Daily Intake]].

==Sources==
{| class="wikitable" style="float:right; clear:left; width:18em; text-align:center;"
|-
! Food ||  
μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/> 
per 100 g<ref name="USDAContent"/> 
|-
| cod liver oil || 30000 
|-
| beef liver (cooked) || 21145
|-
| chicken liver (cooked) || 4296 
|-
| [[Chemistry:Butter|butter]] (stick) || 684
|-
| cheddar cheese || 316 
|-
| egg (cooked) || 140 
|-
|}

Vitamin A is found in many foods.<ref name="USDAContent">{{cite web |url=https://fdc.nal.usda.gov/fdc-app.html#/?component=1106 |title=Rank order of vitamin A content in foods, retinol activity equivalent (RAE) in ug per 100 g |publisher=FoodData Central, US Department of Agriculture |date=1 October 2021 |access-date=20 December 2021}}</ref> Vitamin A in food exists either as preformed retinol {{ndash}} an active form of vitamin A {{ndash}} found in animal liver, dairy and egg products, and some fortified foods, or as provitamin A carotenoids, which are plant pigments digested into vitamin A after consuming carotenoid-rich plant foods, typically in red, orange, or yellow colors.<ref name=lpi/> Carotenoid pigments may be masked by [[Biology:Chlorophyll|chlorophyll]]s in dark green leaf vegetables, such as spinach. The relatively low [[Chemistry:Bioavailability|bioavailability]] of plant-food carotenoids results partly from binding to proteins {{ndash}} chopping, homogenizing or cooking disrupts the plant proteins, increasing provitamin A carotenoid bioavailability.<ref name=lpi/>

[[Philosophy:Vegetarianism|Vegetarian]] and [[Philosophy:Veganism|vegan]] diets can provide sufficient vitamin A in the form of provitamin A carotenoids if the diet contains carrots, carrot juice, sweet potatoes, green leafy vegetables such as spinach and kale, and other carotenoid-rich foods. In the U.S., the average daily intake of β-carotene is in the range 2–7&nbsp;mg.<ref>{{cite web|url=https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Content.pdf#search=%22beta-carotene%22 |title=USDA National Nutrient Database for Standard Reference, Release 28 |date=28 October 2015 |access-date=5 February 2022}}</ref>

Some [[Chemistry:Food fortification|manufactured foods]] and dietary supplements are sources of vitamin A or beta-carotene.<ref name=lpi/><ref name="DRI VitA"/>

Despite the US setting an adult upper limit of 3,000 μg/day, some companies sell vitamin A as a dietary supplement with amounts of 7,500 μg/day. Two examples are WonderLabs and Pure Prescriptions.<ref>{{cite web |url=https://www.wonderlabs.com/itemleft.php?itemnum=1253&ad=GF1253 |title=Vitamin A 25,000 IU (7,500 μg) |last= |first= |date= |website=WonderLabs |access-date=26 January 2022}}</ref><ref>{{cite web |url=https://pureprescriptions.com/product/vitamin-a-25000iu-vital-nutrients/ |title=Vital Nutrients Vitamin A 7,500 RAE |last= |first= |date= |website=Pure Prescriptions |access-date=26 January 2022}}</ref>

===Fortification===
Some countries require or recommend fortification of foods. As of January 2022, 37 countries, mostly in Sub-Saharan Africa, require food fortification of cooking oil, rice, [[Biology:Wheat|wheat]] flour or [[Biology:Maize|maize]] (corn) flour with vitamin A, usually as retinyl palmitate or retinyl acetate. Examples include Pakistan, oil, 11.7&nbsp;mg/kg and Nigeria, oil, 6&nbsp;mg/kg; wheat and maize flour, 2&nbsp;mg/kg.<ref name=FortifMap>{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Total number of nutrients in food vehicles, according to a country's fortification standard|website=Global Fortification Data Exchange|access-date=7 January 2022}}</ref> An additional 12 countries, mostly in southeast Asia have a voluntary fortification program. For example, the government of India recommends 7.95&nbsp;mg/kg in oil and 0.626&nbsp;mg/kg for wheat flour and rice. However, compliance in countries with voluntary fortification is lower than countries with mandatory fortification.<ref name=FortifMap/> No countries in Europe or North America fortify foods with vitamin A.<ref name=FortifMap/>

{| class="wikitable" style="float:right; clear:left; width:18em; text-align:center;"
|-
! Food
! 
μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/>
per 100 g<ref name="USDAContent"/>
|-
| [[Biology:Sweet potato|Sweet potato]], baked, no added fat 
| 957
|-
| [[Biology:Carrot|Carrot]], frozen, cooked, no added fat
| 843
|-
| [[Biology:Pumpkin|Pumpkin]], canned, cooked
| 767
|-
| [[Biology:Spinach|Spinach]], fresh, cooked, no added fat
| 341
|-
| Kale, fresh, cooked, no added fat 
| 245
|-
|}

Separated from fortification via addition of synthetic vitamin A to foods, means of fortifying foods via genetic engineering have been explored. Research on rice began in 1982.<ref>[http://www.goldenrice.org/Content3-Why/why3_FAQ.php#Inventors FAQ: Who invented Golden Rice and how did the project start?] Goldenrice.org.</ref> The first field trials of golden rice cultivars were conducted in 2004.<ref>{{cite web|author=LSU AgCenter Communications|date=2004|title='Golden Rice' Could Help Reduce Malnutrition|url=http://www.lsuagcenter.com/news_archive/2004/October/Headline+News/Golden+Rice+Could+Help+Malnutrition.htm|url-status=dead|archive-url=https://web.archive.org/web/20070928171832/http://www.lsuagcenter.com/news_archive/2004/October/Headline%2BNews/Golden%2BRice%2BCould%2BHelp%2BMalnutrition.htm|archive-date=September 28, 2007}}</ref> The result was "Golden Rice", a variety of ''[[Biology:Oryza sativa|Oryza sativa]]'' rice produced through genetic engineering to [[Biology:Biosynthesis|biosynthesize]] beta-carotene, a precursor of retinol, in the edible parts of rice.<ref>{{cite journal |vauthors=Kettenburg AJ, Hanspach J, Abson DJ, Fischer J |title=From disagreements to dialogue: unpacking the Golden Rice debate |journal=Sustain Sci |volume=13 |issue=5 |pages=1469–82 |date=2018 |pmid=30220919 |pmc=6132390 |doi=10.1007/s11625-018-0577-y |url=}}</ref><ref>{{cite journal |vauthors=Ye X, Al-Babili S, Klöti A, Zhang J, Lucca P, Beyer P, Potrykus I |title=Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm |journal=Science |volume=287 |issue=5451 |pages=303–5 |date=January 2000 |pmid=10634784 |doi=10.1126/science.287.5451.303 |bibcode=2000Sci...287..303Y |s2cid=40258379 |url=}}</ref> In May 2018, regulatory agencies in the United States, Canada, Australia and New Zealand had concluded that Golden Rice met food safety standards.<ref>{{Cite news|url=http://irri.org/news/media-releases/golden-rice-meets-food-safety-standards-in-three-global-leading-regulatory-agencies|title= Golden Rice meets food safety standards in three global leading regulatory agencies|work=International Rice Research Institute – IRRI|access-date=2018-05-30|language=en-gb}}</ref> On 21 July 2021, the Philippines became the first country to officially issue the biosafety permit for commercially propagating Golden Rice.<ref>{{Cite web| vauthors = Talavera C |title=Philippines OKs GMO 'golden rice' |url=https://www.philstar.com/headlines/2021/07/24/2114742/philippines-oks-gmo-golden-rice|access-date=2021-08-21|website=Philstar.com}}</ref><ref>{{Cite web|date=2021-07-23|title=Filipinos soon to plant and eat Golden Rice|url=https://www.philrice.gov.ph/filipinos-soon-to-plant-and-eat-golden-rice/|access-date=2021-08-21|website=Philippine Rice Research Institute|language=en-US}}</ref>

===Vitamin A supplementation (VAS)===
[[File:Vitamin A supplementation coverage rate (children ages 6-59 months), OWID.svg|thumb|upright=1.6|Vitamin A supplementation coverage rate (children ages 6–59 months), 2014<ref>{{cite web|title=Vitamin A supplementation coverage rate (children ages 6–59 months)|url=https://ourworldindata.org/grapher/vitamin-a-supplementation-coverage-rate-children-ages-6-59-months|website=Our World in Data|access-date=6 March 2020}}</ref>]]

Delivery of oral high-dose supplements remains the principal strategy for minimizing deficiency.<ref name="UNICEF 2007, p.3">{{cite book | publisher = UNICEF | url = http://www.unicef.org/publications/files/Vitamin_A_Supplementation.pdf | title = Vitamin A Supplementation: A Decade of Progress | location = New York | date = 2007 | page = 3 | isbn = 978-92-806-4150-9 | access-date = 23 January 2011 | archive-date = 31 October 2020 | archive-url = https://web.archive.org/web/20201031224103/https://www.unicef.org/publications/files/Vitamin_A_Supplementation.pdf | url-status = dead }}</ref> As of 2017, more than 80 countries worldwide are implementing universal VAS programs targeted to children 6–59 months of age through semi-annual national campaigns.<ref name="Wirth2017">{{cite journal |vauthors=Wirth JP, Petry N, Tanumihardjo SA, Rogers LM, McLean E, Greig A, Garrett GS, Klemm RD, Rohner F |title=Vitamin A Supplementation Programs and Country-Level Evidence of Vitamin A Deficiency |journal=Nutrients |volume=9 |issue=3 |date=February 2017 |page=190 |pmid=28245571 |pmc=5372853 |doi=10.3390/nu9030190 |url=|doi-access=free }}</ref> Doses in these programs are one dose of 50,000 or 100,000 IU for children aged 6 to 11 months and 100,000 to 200,000 IU for children aged 12 months to five years, every four to six months.<ref name="Imdad2017"/>

==Deficiency==
{{Main|Medicine:Vitamin A deficiency}}

===Primary causes===
Vitamin A deficiency is common in [[Finance:Developing country|developing countries]], especially in [[Place:Sub-Saharan Africa|Sub-Saharan Africa]] and [[Place:Southeast Asia|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. The causes are low intake of retinol-containing, animal-sourced foods and low intake of carotene-containing, plant-sourced foods. Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world,<ref>{{cite web |publisher=[[Organization:World Health Organization|World Health Organization]] |title=Global prevalence of vitamin A deficiency in populations at risk 1995–2005 |url=http://apps.who.int/iris/bitstream/10665/44110/1/9789241598019_eng.pdf |work=WHO global database on vitamin A deficiency |year=2009}}</ref> possibly leading to the deaths of 670,000 children under five annually.<ref>{{cite journal |vauthors=Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, Mathers C, Rivera J |title=Maternal and child undernutrition: global and regional exposures and health consequences |journal=The Lancet |volume=371 |issue=9608 |pages=243–260 |date=January 2008 |pmid=18207566 |doi=10.1016/S0140-6736(07)61690-0 |author9=Maternal and Child Undernutrition Study Group |s2cid=3910132 |url=https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=10965&content=PDF |archive-url=https://web.archive.org/web/20211016033636/https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=10965&content=PDF |archive-date=16 October 2021 |url-status=dead}}</ref>

Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency.<ref name="ods"/> Vitamin A deficiency is "the leading cause of preventable childhood blindness", according to UNICEF.<ref name=UNICEFvitaminA>[http://www.unicef.org/specialsession/about/sgreport-pdf/12_VitaminADeficiency_D7341Insert_English.pdf "Vitamin A Deficiency"], UNICEF. Retrieved 3 June 2015.</ref><ref>{{cite journal |vauthors=Akhtar S, Ahmed A, Randhawa MA, Atukorala S, Arlappa N, Ismail T, Ali Z |title=Prevalence of vitamin A deficiency in South Asia: causes, outcomes, and possible remedies |journal=Journal of Health, Population, and Nutrition |volume=31 |issue=4 |pages=413–423 |date=December 2013 |pmid=24592582 |pmc=3905635 |doi=10.3329/jhpn.v31i4.19975}}</ref> It also increases the risk of death from common childhood conditions, such as [[Medicine:Diarrhea|diarrhea]]. UNICEF regards addressing vitamin A deficiency as critical to reducing [[Social:Child mortality|child mortality]], the fourth of the {{wipe|United Nations}}' Millennium Development Goals.<ref name=UNICEFvitaminA/>

During diagnosis, night blindness and [[Medicine:Xerophthalmia|dry eyes]] are signs of vitamin A deficiency that can be recognized without requiring biochemical tests. Plasma retinol is used to confirm vitamin A status. A plasma concentration of about 2.0 μmol/L is normal; less than 0.70 μmol/L (equivalent to 20 μg/dL) indicates moderate vitamin A deficiency, and less than 0.35 μmol/L (10 μg/dL) indicates severe vitamin A deficiency. Breast milk retinol of less than 8 μg/gram milk fat is considered insufficient.<ref name=PKIN2020VitA/> One weakness of these measures is that they are not good indicators of liver vitamin A stores as retinyl esters in [[Biology:Hepatic stellate cell|hepatic stellate cell]]s. The amount of vitamin A leaving the liver, bound to retinol binding protein (RBP), is under tight control as long as there are sufficient liver reserves. Only when liver content of vitamin A drops below approximately 20 μg/gram will concentration in the blood decline.<ref name="DRI VitA"/><ref name=Tanumihardjo>{{cite journal |vauthors=Tanumihardjo SA |title=Vitamin A: biomarkers of nutrition for development |journal=The American Journal of Clinical Nutrition |volume=94 |issue=2 |pages=658S–665S |date=August 2011 |pmid=21715511 |pmc=3142734 |doi=10.3945/ajcn.110.005777}}</ref>

===Secondary causes===
There are causes for deficiency other than low dietary intake of vitamin A as retinol or carotenes. Adequate dietary protein and caloric energy are needed for a normal rate of synthesis of  RBP, without which, retinol cannot be mobilized to leave the liver. Systemic infections can cause transient decreases in RBP synthesis even if protein-calorie malnutrition is absent. Chronic alcohol consumption reduces liver vitamin A storage.<ref name="DRI VitA"/> [[Medicine:Non-alcoholic fatty liver disease|Non-alcoholic fatty liver disease]] (NAFLD), characterized by the accumulation of fat in the liver, is the hepatic manifestation of [[Medicine:Metabolic syndrome|metabolic syndrome]]. Liver damage from NAFLD reduces liver storage capacity for retinol and reduces the ability to mobilize liver stores to maintain normal circulating concentration.<ref name="Saeed2017">{{cite journal |vauthors=Saeed A, Dullaart RP, Schreuder TC, Blokzijl H, Faber KN |title=Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD) |journal=Nutrients |volume=10 |issue=1 |date=December 2017 |page=29 |pmid=29286303 |pmc=5793257 |doi=10.3390/nu10010029 |url=|doi-access=free }}</ref>

==Animal requirements==
All [[Biology:Vertebrate|vertebrate]] and [[Biology:Chordate|chordate]] species require vitamin A,<ref name=Marletaz2006/> either as dietary carotenoids or preformed retinol from consuming other animals. Deficiencies have been reported in laboratory-raised and pet dogs, cats, birds, reptiles and amphibians,<ref name=Hensel2010>{{cite journal |vauthors=Hensel P |title=Nutrition and skin diseases in veterinary medicine |journal=Clin Dermatol |volume=28 |issue=6 |pages=686–93 |date=2010 |pmid=21034992 |doi=10.1016/j.clindermatol.2010.03.031 |url=}}</ref><ref>{{cite journal |vauthors=Clugston RD, Blaner WS |title=Vitamin A (retinoid) metabolism and actions: What we know and what we need to know about amphibians |journal=Zoo Biol |volume=33 |issue=6 |pages=527–35 |date=2014 |pmid=24958673 |pmc=4685470 |doi=10.1002/zoo.21140 |url=}}</ref> also commercially raised chickens and turkeys.<ref>{{cite journal |vauthors=Shojadoost B, Yitbarek A, Alizadeh M, Kulkarni RR, Astill J, Boodhoo N, Sharif S |title=Centennial Review: Effects of vitamins A, D, E, and C on the chicken immune system |journal=Poult Sci |volume=100 |issue=4 |pages=100930 |date=April 2021 |pmid=33607314 |pmc=7900602 |doi=10.1016/j.psj.2020.12.027 |url=}}</ref> Herbivore species such as horses, cattle and sheep can get sufficient β-carotene from green pasture to be healthy, but the content in pasture grass dry due to drought and long-stored hay can be too low, leading to vitamin A deficiency.<ref name=Hensel2010/> Omnivore and carnivore species, especially those toward the top of the food chain, can accrue large amounts of retinyl esters in their livers, or else excrete retinyl esters in urine as a means of dealing with surplus.<ref name=Green2016/> Before the era of synthetic retinol, cod liver oil, high in vitamins A and D, was a commonly consumed dietary supplement.<ref>{{cite journal |vauthors=Semba RD |title=Vitamin A as "anti-infective" therapy, 1920-1940 |journal=J Nutr |volume=129 |issue=4 |pages=783–91 |date=April 1999 |pmid=10203551 |doi=10.1093/jn/129.4.783 |url=|doi-access=free }}</ref><ref>{{Cite web|url=https://www.iffo.com/system/files/downloads/Codex%20Standard%20for%20Fish%20Oils%20CXS_329e_Nov%202017.pdf |title=STANDARD FOR FISH OILS CODEX STAN 329-2017 |date=2017 |access-date = 28 January 2022|website=CODEX ALIMENTARIUS COMMISSION, World Health Organization}}</ref> [[Biology:Invertebrate|Invertebrate]]s cannot synthesize carotenoids or retinol, and thus must accrue these essential nutrients from consumption of algae, plants or animals.<ref>{{cite journal |vauthors=André A, Ruivo R, Gesto M, Castro LF, Santos MM |title=Retinoid metabolism in invertebrates: when evolution meets endocrine disruption |journal=Gen Comp Endocrinol |volume=208 |issue= |pages=134–45 |date=November 2014 |pmid=25132059 |doi=10.1016/j.ygcen.2014.08.005 |s2cid=44685529 |url=}}</ref><ref>{{cite journal |vauthors=Gutierrez-Mazariegos J, Schubert M, Laudet V |title=Evolution of retinoic acid receptors and retinoic acid signaling |journal=Subcell Biochem |series=Subcellular Biochemistry |volume=70 |issue= |pages=55–73 |date=2014 |pmid=24962881 |doi=10.1007/978-94-017-9050-5_4 |isbn=978-94-017-9049-9 |url=}}</ref><ref>{{cite journal |vauthors=Albalat R |title=The retinoic acid machinery in invertebrates: ancestral elements and vertebrate innovations |journal=Mol Cell Endocrinol |volume=313 |issue=1–2 |pages=23–35 |date=December 2009 |pmid=19737598 |doi=10.1016/j.mce.2009.08.029 |s2cid=41188476 |url=}}</ref>

==Medical uses==
===Preventing and treating deficiency===
{{Main|Medicine:Vitamin A deficiency}}

Recognition of its prevalence and consequences has led to governments and non-government organizations promoting vitamin A fortification of foods<ref name=FortifMap/> and creating programs that administer large bolus-size oral doses of vitamin A to young children every four to six months.<ref name="Wirth2017"/> In 2008, the [[Organization:World Health Organization|World Health Organization]] estimated that vitamin A supplementation over a decade in 40 countries averted 1.25 million deaths due to vitamin A deficiency.<ref>{{cite web |url=https://www.who.int/nutrition/topics/vad/en/index.html |title=Micronutrient Deficiencies-Vitamin A |access-date=9 April 2008 |publisher=World Health Organization |archive-url=https://web.archive.org/web/20110127030721/https://www.who.int/nutrition/topics/vad/en/index.html |archive-date=27 January 2011 |url-status=dead}}</ref> A Cochrane review reported that vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children ages six month to five years of age. All-cause mortality was reduced by 14%, and incidences{{verify spelling|date=September 2022|reason=''incidence'' is normally used only in the singular form, perhaps ''incidence'', ''incidents'',  or ''instances'' was intended}} of [[Medicine:Diarrhea|diarrhea]] by 12%.<ref name="Imdad2017">{{cite journal |vauthors=Imdad A, Mayo-Wilson E, Herzer K, Bhutta ZA |title=Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age |journal=Cochrane Database Syst Rev |volume=3 |issue= 11|pages=CD008524 |date=March 2022 |pmid=35294044 |pmc=8925277 |doi=10.1002/14651858.CD008524.pub4 }}</ref> However, a Cochrane review by the same group concluded there was insufficient evidence to recommend blanket vitamin A supplementation for infants one to six months of age, as it did not reduce infant mortality or morbidity.<ref name="Imdad2016"/>

===Oral retinoic acid===
Orally consumed retinoic acid (RA), as ''all-trans''-tretinoin or 13-''cis''-isotretinoin has been shown to improve facial skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells. RA reduces the size and secretion of the sebaceous glands, and by doing so reduces bacterial numbers in both the ducts and skin surface. It reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils. In the US, isotretinoin was released to the market in 1982 as a revolutionary treatment for severe and refractory acne vulgaris. It was shown that a dose of 0.5‑1.0&nbsp;mg/kg body weight/day is enough to produce a reduction in sebum excretion by 90% within a month or two, but the recommended treatment duration is 4 to 6 months.<ref name="Draghici2021">{{cite journal |vauthors=Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu MC, Șandru F |title=Teratogenic effect of isotretinoin in both fertile females and males (Review) |journal=Exp Ther Med |volume=21 |issue=5 |pages=534 |date=May 2021 |pmid=33815607 |pmc=8014951 |doi=10.3892/etm.2021.9966 |url=}}</ref> Isotretinoin is a known teratogen, with an estimated 20‑35% risk of physical birth defects to infants that are exposed to isotretinoin ''in utero'', including numerous congenital defects such as craniofacial defects, cardiovascular and neurological malformations or thymic disorders. Neurocognitive impairments in the absence of any physical defects has been established to be 30‑60%. For these reasons, physician- and patient-education programs were initiated, recommending that for women of child-bearing age, contraception be initiated a month before starting oral (or topical) isotretinoin, and continue for a month after treatment ended.<ref name="Draghici2021"/>

In addition to the approved use for treating acne vulgaris, researchers have investigated off-label applications for dermatological conditions, such as rosacea, psoriasis, and other conditions.<ref name="Nickle2014">{{cite journal |vauthors=Nickle SB, Peterson N, Peterson M |title=Updated Physician's Guide to the Off-label Uses of Oral Isotretinoin |journal=J Clin Aesthet Dermatol |volume=7 |issue=4 |pages=22–34 |date=April 2014 |pmid=24765227 |pmc=3990537 |doi= |url=}}</ref> [[Medicine:Rosacea|Rosacea]] was reported as responding favorably to doses lower than used for acne. Isotretinoin in combination with ultraviolet light was shown affective for treating [[Medicine:Psoriasis|psoriasis]]. Isotretinoin in combination with injected interferon-alpha showed some potential for treating genital warts. Isotretinoin in combination with topical [[Chemistry:Fluorouracil|fluorouracil]] or injected interferon-alpha showed some potential for treating precancerous skin lesions and skin cancer.<ref name="Nickle2014"/>

===Topical retinoic acid and retinol===
[[File:Retinoids.svg|thumb|Retinoids: [[Chemistry:Tretinoin|Tretinoin]] is ''all-trans''-retinoic acid; initial tradename: Retin-A. Isotretinoin is 13-''cis''-retinoic acid; initial tradename: Accutane. Etretinate and Acitretin, its non-esterified metabolite, are used orally to treat severe psoriasis.<ref name=Becken2015>{{cite journal |vauthors=Beckenbach L, Baron JM, Merk HF, Löffler H, Amann PM |title=Retinoid treatment of skin diseases |journal=Eur J Dermatol |volume=25 |issue=5 |pages=384–91 |date=2015 |pmid=26069148 |doi=10.1684/ejd.2015.2544 |s2cid=408725 |url=|doi-access=free }}</ref>]]

Retinoic acids [[Chemistry:Tretinoin|tretinoin]] (''all-trans''-retinoic acid) and [[Chemistry:Isotretinoin|isotretinoin]] (13-''cis''-retinoic acid) are prescription [[Medicine:Topical medication|topical medication]]s used to treat moderate to severe cystic acne and acne not responsive to other treatments.<ref>{{cite web |title=Tretinoin |url=https://www.drugs.com/monograph/tretinoin.html |publisher=The American Society of Health-System Pharmacists |date=22 March 2021 |access-date=23 December 2021 }}</ref><ref>{{cite journal | vauthors = Merritt B, Burkhart CN, Morrell DS | title = Use of isotretinoin for acne vulgaris | journal = Pediatric Annals | volume = 38 | issue = 6 | pages = 311–20 | date = June 2009 | pmid = 19588674 | doi = 10.3928/00904481-20090512-01 }}</ref><ref>{{cite journal | vauthors = Layton A | title = The use of isotretinoin in acne | journal = Dermato-Endocrinology | volume = 1 | issue = 3 | pages = 162–9 | date = May 2009 | pmid = 20436884 | pmc = 2835909 | doi = 10.4161/derm.1.3.9364 }}</ref><ref name="Leyden2017">{{cite journal |vauthors=Leyden J, Stein-Gold L, Weiss J |title=Why Topical Retinoids Are Mainstay of Therapy for Acne |journal=Dermatol Ther (Heidelb) |volume=7 |issue=3 |pages=293–304 |date=September 2017 |pmid=28585191 |pmc=5574737 |doi=10.1007/s13555-017-0185-2 |url=}}</ref> These are usually applied as a [[Medicine:Cream (pharmacy)|skin cream]] to the face after cleansing to remove make-up and skin oils. Tretinoin and isotretinoin act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR).<ref name="Kang S 2008" /> These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.<ref>Fernandez [Graber] EM, Zaenglein A, Thiboutot D. Acne Treatment Methodologies. In: Cosmetic Formulation of Skin Care Products, Taylor and Francis Group, New York 2006. p.273.</ref> The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.<ref name="Kang S 2008">Kang S, Voorhees JJ. Topical retinoids. In: Fitzpatrick's Dermatology in General Medicine, 7th ed, Wolff K, Goldsmith LA, Katz SI, et al (Eds), McGraw Hill, New York 2008. p.2106.</ref> Retinoic acid products also reduce sebum secretion, a nutrient source for bacteria, from facial pores.{{citation needed|date=April 2022}}

These drugs are US-designated Pregnancy Category C (animal reproduction studies have shown an adverse effect on the fetus), and should not be used by pregnant women or women who are anticipating becoming pregnant.<ref name="Tretinoin">{{cite web |title=Tretinoin topical Use During Pregnancy |website=Drugs.com |date=1 July 2019 |url=https://www.drugs.com/pregnancy/tretinoin-topical.html |access-date=16 January 2020}}</ref> Many countries established a physician- and patient- education pregnancy prevention policy.<ref>{{cite journal |vauthors=Kovitwanichkanont T, Driscoll T |title=A comparative review of the isotretinoin pregnancy risk management programs across four continents |journal=Int J Dermatol |volume=57 |issue=9 |pages=1035–1046 |date=September 2018 |pmid=29508918 |doi=10.1111/ijd.13950 |s2cid=3726217 |url=}}</ref>

[[Chemistry:Trifarotene|Trifarotene]] is a prescription retinoid for the topical treatment acne vulgaris.<ref name=Monograph>{{cite web | title=Trifarotene Monograph for Professionals | website=Drugs.com | date=28 October 2019 |url=https://www.drugs.com/monograph/trifarotene.html | access-date=23 May 2021}}</ref> It functions as a [[Biology:Retinoic acid receptor gamma|retinoic acid receptor (RAR)-γ]] [[Biology:Agonist|agonist]].<ref name=Scott2019>{{cite journal |vauthors = Scott LJ |title = Trifarotene: First Approval |journal=Drugs |volume=79 |issue=17 |pages=1905–09 |date = November 2019 |pmid = 31713811 |doi = 10.1007/s40265-019-01218-6 |s2cid = 207964653 |url=}}</ref>

Non-prescription [[Medicine:Cream (pharmacy)|topical products]] that have health claims for reducing facial acne, combating skin dark spots and reducing wrinkles and lines associated with aging often contain [[Chemistry:Retinyl palmitate|retinyl palmitate]]. The hypothesis is that this is absorbed and desterified to free retinol, then converted to retinaldehyde and further metabolized to ''all-trans''-retinoic acid, whence it will have the same effects as prescription products with fewer side effects.<ref>{{cite journal|vauthors=Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G |title=Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety.|journal=Clinical Interventions in Aging|date=2006|volume=1|issue=4|pages=327–48| pmid=18046911|doi=10.2147/ciia.2006.1.4.327|pmc=2699641}}</ref> There is some ''ex vivo'' evidence with human skin that esterified retinol is absorbed and then converted to retinol.<ref>{{cite journal|vauthors=Boehnlein J, Sakr A, Lichtin JL, Bronaugh RL |journal=Pharmaceutical Research|title=Characterization of Esterase and Alcohol Dehydrogenase Activity in Skin. Metabolism of Retinyl Palmitate to Retinol (Vitamin A) During Percutaneous Absorption|volume=11|issue=8|year=1994|pages=1155–59|issn=0724-8741 |doi=10.1023/A:1018941016563|pmid=7971717|s2cid=25458156}}</ref> In addition to esterified retinol, some of these products contain hydroxypinacolone retinoate, identified as esterified 9-''cis''-retinoic acid.<ref>{{cite journal |vauthors=Villani A, Annunziata MC, Cinelli E, Donnarumma M, Milani M, Fabbrocini G |title=Efficacy and safety of a new topical gel formulation containing retinol encapsulated in glycospheres and hydroxypinacolone retinoate, an antimicrobial peptide, salicylic acid, glycolic acid and niacinamide for the treatment of mild acne: preliminary results of a 2-month prospective study |journal=G Ital Dermatol Venereol |volume=155 |issue=5 |pages=676–79 |date=October 2020 |pmid=32869963 |doi=10.23736/S0392-0488.20.06581-5 |s2cid=221402891 |url=}}</ref>

==Synthesis==
===Biosynthesis===
Carotenoid synthesis takes place in plants, certain fungi, and bacteria. Structurally carotenes are [[Chemistry:Tetraterpene|tetraterpene]]s, meaning that they are synthesized biochemically from four 10-carbon [[Biology:Terpene|terpene]] units, which in turn were formed from eight 5-carbon [[Chemistry:Isoprene|isoprene]] units. Intermediate steps are the creation of a 40-carbon [[Chemistry:Phytoene|phytoene]] molecule, conversion to [[Chemistry:Lycopene|lycopene]] via desaturation, and then creation of [[Chemistry:Ionone|ionone]] rings at both ends of the molecule. β-carotene has a β-ionone ring at both ends, meaning that the molecule can be divided symmetrically to yield two retinol molecules. α-Carotene has a β-ionone ring at one end and an Ɛ-ionone ring at the other, so it has half the retinol conversion capacity.<ref name=PKIN2020Carotenoids>{{cite book |vauthors=von Lintig J |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Carotenoids |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 531–49 |isbn=978-0-323-66162-1}}</ref>

[[File:Chem 157 vitamin a synthesis project.png|thumb|Vitamin A biosynthesis from β-carotene]]
In most animal species, retinol is synthesized from the breakdown of the plant-formed provitamin, β-carotene. First, the enzyme [[Biology:Beta-carotene 15,15'-dioxygenase|beta-carotene 15,15'-dioxygenase]] (BCO-1) 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 NAD<sup>+</sup>. The resultant retinal is then quickly reduced to retinol by the enzyme [[Biology:Retinol dehydrogenase|retinol dehydrogenase]].<ref name=PKIN2020VitA/> Omnivore species such as [[Biology:Canidae|dogs, wolves, coyotes and foxes]] in general are low producers of BCO-1. The enzyme is lacking in [[Biology:Felidae|felids]] (cats), meaning that vitamin A requirements are met from the retinyl ester content of prey animals.<ref name=Green2016/>

===Industrial synthesis===
[[File:Ionone beta.svg|thumb|left|β-ionone ring]]
β-carotene can be extracted from fungus ''Blakeslea trispora'', marine algae ''Dunaliella salina'' or genetically modified yeast ''Saccharomyces cerevisiae'', starting with xylose as a substrate.<ref name="Sun2020">{{cite journal |vauthors=Sun L, Atkinson CA, Lee YG, Jin YS |title=High-level β-carotene production from xylose by engineered Saccharomyces cerevisiae without overexpression of a truncated HMG1 (tHMG1) |journal=Biotechnol Bioeng |volume=117 |issue=11 |pages=3522–32 |date=November 2020 |pmid=33616900 |doi=10.1002/bit.27508 |osti=1651205 |s2cid=222411819 |url=}}</ref> Chemical synthesis uses either a method developed by BASF<ref name="β-Carotin-1">Wittig G.; Pommer H.: ''DBP 954247'', 1956</ref><ref name="β-Carotin-2">Wittig G.; Pommer H. (1959). ''Chem. Abstr''. 53: 2279</ref> or a [[Chemistry:Grignard reaction|Grignard reaction]] utilized by Hoffman-La Roche.<ref>{{cite patent|country = US |number = 2609396 |title = Compounds with the carbon skeleton of beta-carotene and process for the manufacture thereof |pubdate = 1952-09-02 |invent1 = Inhoffen Hans Herloff |invent2 = Pommer Horst }}</ref>

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.<ref name="Parker2016"/> Industrial methods for the production of retinol rely on chemical synthesis. The first industrialized synthesis of retinol was achieved by the company Hoffmann-La Roche in 1947. In the following decades, eight other companies developed their own processes. β-ionone, synthesized from acetone, is the essential starting point for all industrial syntheses. Each process involves elongating the unsaturated carbon chain.<ref name="Parker2016">{{cite journal|vauthors=Parker GL, Smith LK, Baxendale IR |title=Development of the industrial synthesis of vitamin A |journal=Tetrahedron |volume=72 |issue=  13|pages=1645–52 |date=February 2016 |pmid= |doi=10.1016/j.tet.2016.02.029}}</ref> Pure retinol is extremely sensitive to oxidization and is prepared and transported at low temperatures and oxygen-free atmospheres. When prepared as a dietary supplement or food additive, retinol is stabilized as the [[Chemistry:Ester|ester]] derivatives [[Chemistry:Retinyl acetate|retinyl acetate]] or [[Chemistry:Retinyl palmitate|retinyl palmitate]]. Prior to 1999, three companies, Roche, BASF and Rhone-Poulenc controlled 96% of global vitamin A sales. In 2001, the European Commission imposed total fines of 855.22 million [[Finance:Euro|euro]]s on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989.<ref>{{cite news |url=https://www.nytimes.com/2001/11/21/business/vitamin-makers-fined-record-7551-million-in-pricefixing-case.html#:~:text=BRUSSELS%20%2D%2D%20The%20European%20Commission,Holding%20AG's%20(RHHBY)%20F |author=<!--not stated--> |collaboration=Dow Jones Business News |title=Vitamin Makers Fined Record $755.1 Million in Price-Fixing Case |newspaper=The New York Times |date=21 November 2001  |access-date=24 March 2022}}</ref> Roche sold its vitamin division to DSM in 2003. DSM and BASF have the major share of industrial production.<ref name="Parker2016"/> A biosynthesis alternative utilizes genetically engineered yeast species ''Saccharomyces cerevisiae'' to synthesize retinal and retinol, using xylose as a starting substrate. This was accompished by having the yeast first synthesize β-carotene and then the cleaving enzyme β-carotene 15,15'-dioxygenase to yield retinal.<ref name="Sun2019">{{cite journal |vauthors=Sun L, Kwak S, Jin YS |title=Vitamin A Production by Engineered Saccharomyces cerevisiae from Xylose via Two-Phase in Situ Extraction |journal=ACS Synth Biol |volume=8 |issue=9 |pages=2131–40 |date=September 2019 |pmid=31374167 |doi=10.1021/acssynbio.9b00217 |osti=1547320 |s2cid=199389319 |url=}}</ref>

==Research==
===Brain===
Animal research (on mice), which is pre-clinical, also found Retinoid acid, the bioactive metabolite of vitamin A, to have an effect on brain areas responsible for memory and learning.<ref>{{Cite news |title=Significance of vitamin A to brain function, behavior and learning |last=Olson and Mello |first=Claudio V. and Christopher R. |date=8 September 2011 |work=ncbi |volume=54 |issue=4 |pages=489–495 |doi=10.1002/mnfr.200900246 |pmid=20077419 |pmc=3169332 }}</ref>

===Cancer===
Meta-analyses of intervention and observational trials for various types of cancer report mixed results. Supplementation with β-carotene did not appear to decrease the risk of cancer overall, nor specific cancers including: pancreatic, colorectal, prostate, breast, melanoma, or skin cancer generally.<ref name=Druesne2010>{{cite journal | vauthors = Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S | title = Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials | journal = International Journal of Cancer | volume = 127 | issue = 1 | pages = 172–84 | date = July 2010 | pmid = 19876916 | doi = 10.1002/ijc.25008 | s2cid = 24850769 | doi-access = free }}</ref> High-dose β-carotene supplementation unexpectedly resulted in a higher incidence of lung cancer and of total mortality in people who were cigarette smokers.<ref name=PKIN2020Carotenoids/>

For dietary retinol, no effects were observed for high dietary intake and [[Medicine:Breast cancer|breast cancer]] survival,<ref>{{cite journal |vauthors=He J, Gu Y, Zhang S |title=Vitamin A and Breast Cancer Survival: A Systematic Review and Meta-analysis |journal=Clin Breast Cancer |volume=18 |issue=6 |pages=e1389–e1400 |date=December 2018 |pmid=30190194 |doi=10.1016/j.clbc.2018.07.025 |s2cid=52169953 |url=}}</ref> risk of [[Medicine:Liver cancer|liver cancer]],<ref>{{cite journal |vauthors=Leelakanok N, D'Cunha RR, Sutamtewagul G, Schweizer ML |title=A systematic review and meta-analysis of the association between vitamin A intake, serum vitamin A, and risk of liver cancer |journal=Nutr Health |volume=24 |issue=2 |pages=121–31 |date=June 2018 |pmid=29792083 |doi=10.1177/0260106018777170 |s2cid=43944154 |url=}}</ref> risk of [[Medicine:Bladder cancer|bladder cancer]]<ref>{{cite journal |vauthors=Tang JE, Wang RJ, Zhong H, Yu B, Chen Y |title=Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies |journal=World J Surg Oncol |volume=12 |issue= |pages=130 |date=April 2014 |pmid=24773914 |pmc=4030017 |doi=10.1186/1477-7819-12-130 |url=}}</ref> or risk of [[Medicine:Colorectal cancer|colorectal cancer]],<ref>{{cite journal |vauthors=Liu Y, Yu Q, Zhu Z, Zhang J, Chen M, Tang P, Li K |title=Vitamin and multiple-vitamin supplement intake and incidence of colorectal cancer: a meta-analysis of cohort studies |journal=Med Oncol |volume=32 |issue=1 |pages=434 |date=January 2015 |pmid=25491145 |doi=10.1007/s12032-014-0434-5 |s2cid=25904916 |url=}}</ref><ref name="Xu2013">{{cite journal |vauthors=Xu X, Yu E, Liu L, Zhang W, Wei X, Gao X, Song N, Fu C |title=Dietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta-analysis of observational studies |journal=Eur J Cancer Prev |volume=22 |issue=6 |pages=529–39 |date=November 2013 |pmid=24064545 |doi=10.1097/CEJ.0b013e328364f1eb |s2cid=36958552 |url=}}</ref> although the last review did report lower risk for higher beta-carotene consumption.<ref name="Xu2013"/> In contrast, an inverse association was reported between retinol intake and relative risk of [[Medicine:Esophageal cancer|esophageal cancer]],<ref>{{cite journal |vauthors=Li K, Zhang B |title=The association of dietary β-carotene and vitamin A intake on the risk of esophageal cancer: a meta-analysis |journal=Rev Esp Enferm Dig |volume=112 |issue=8 |pages=620–26 |date=August 2020 |pmid=32543872 |doi=10.17235/reed.2020.6699/2019 |s2cid=219724574 |url=|doi-access=free }}</ref> gastric cancer,<ref>{{cite journal |vauthors=Wu Y, Ye Y, Shi Y, Li P, Xu J, Chen K, Xu E, Yang J |title=Association between vitamin A, retinol intake and blood retinol level and gastric cancer risk: A meta-analysis |journal=Clin Nutr |volume=34 |issue=4 |pages=620–6 |date=August 2015 |pmid=25008141 |doi=10.1016/j.clnu.2014.06.007 |url=}}</ref> [[Medicine:Ovarian cancer|ovarian cancer]],<ref>{{cite journal |vauthors=Wang Q, He C |title=Dietary vitamin A intake and the risk of ovarian cancer: a meta-analysis |journal=Biosci Rep |volume=40 |issue=4 |pages= |date=April 2020 |pmid=32149329 |pmc=7138903 |doi=10.1042/BSR20193979 |url=}}</ref> [[Medicine:Pancreatic cancer|pancreatic cancer]],<ref>{{cite journal |vauthors=Zhang T, Chen H, Qin S, Wang M, Wang X, Zhang X, Liu F, Zhang S |title=The association between dietary vitamin A intake and pancreatic cancer risk: a meta-analysis of 11 studies |journal=Biosci Rep |volume=36 |issue=6 |pages= |date=December 2016 |pmid=27756825 |pmc=5293573 |doi=10.1042/BSR20160341 |url=}}</ref> lung cancer,<ref name="Yu2015">{{cite journal |vauthors=Yu N, Su X, Wang Z, Dai B, Kang J |title=Association of Dietary Vitamin A and β-Carotene Intake with the Risk of Lung Cancer: A Meta-Analysis of 19 Publications |journal=Nutrients |volume=7 |issue=11 |pages=9309–24 |date=November 2015 |pmid=26569298 |pmc=4663591 |doi=10.3390/nu7115463 |url=|doi-access=free }}</ref> [[Medicine:Melanoma|melanoma]],<ref>{{cite journal |vauthors=Zhang YP, Chu RX, Liu H |title=Vitamin A intake and risk of melanoma: a meta-analysis |journal=PLOS ONE |volume=9 |issue=7 |pages=e102527 |date=2014 |pmid=25048246 |pmc=4105469 |doi=10.1371/journal.pone.0102527 |bibcode=2014PLoSO...9j2527Z |url=|doi-access=free }}</ref> and [[Medicine:Cervical cancer|cervical cancer]].<ref>{{cite journal |vauthors=Zhang X, Dai B, Zhang B, Wang Z |title=Vitamin A and risk of cervical cancer: a meta-analysis |journal=Gynecol Oncol |volume=124 |issue=2 |pages=366–73 |date=February 2012 |pmid=22005522 |doi=10.1016/j.ygyno.2011.10.012 |url=}}</ref> For lung cancer, an inverse association was also seen for beta-carotene intake, separate from the retinol results.<ref name="Yu2015"/> When high dietary intake was compared to low dietary intake, the decreases in relative risk were in the range of 15 to 20%. For gastric cancer, a meta-analysis of prevention trials reported a 29% decrease in relative risk from retinol supplementation at 1500 μg/day.<ref name="Kong2014">{{cite journal |vauthors=Kong P, Cai Q, Geng Q, Wang J, Lan Y, Zhan Y, Xu D |title=Vitamin intake reduce the risk of gastric cancer: meta-analysis and systematic review of randomized and observational studies |journal=PLOS ONE |volume=9 |issue=12 |pages=e116060 |date=2014 |pmid=25549091 |pmc=4280145 |doi=10.1371/journal.pone.0116060 |bibcode=2014PLoSO...9k6060K |url=|doi-access=free }}</ref>

===Fetal alcohol spectrum disorder===
[[Medicine:Fetal alcohol spectrum disorder|Fetal alcohol spectrum disorder]] (FASD), formerly referred to as fetal alcohol syndrome, presents as craniofacial malformations, neurobehavioral disorders and mental disabilities, all attributed to exposing human embryos to alcohol during fetal development.<ref name="Fainsod2020"/><ref name="Petrelli2019"/> The risk of FASD depends on the amount consumed, the frequency of consumption, and the points in pregnancy at which the alcohol is consumed.<ref>{{cite web|title=Fetal Alcohol Exposure |url=http://pubs.niaaa.nih.gov/publications/FASDFactsheet/FASDfact.htm|access-date=16 December 2021|date=April 2015|url-status=live|archive-url=https://web.archive.org/web/20150610050738/http://pubs.niaaa.nih.gov/publications/FASDFactsheet/FASDfact.htm|archive-date=10 June 2015|df=dmy-all}}</ref> [[Chemistry:Ethanol|Ethanol]] is a known [[Chemistry:Teratogen|teratogen]], i.e., causes birth defects. Ethanol is metabolized by [[Biology:Alcohol dehydrogenase|alcohol dehydrogenase]] enzymes into [[Chemistry:Acetaldehyde|acetaldehyde]].<ref name="Farrés">{{cite journal | vauthors = Farrés J, Moreno A, Crosas B, Peralba JM, Allali-Hassani A, Hjelmqvist L, Jörnvall H, Parés X | display-authors = 6 | title = Alcohol dehydrogenase of class IV (sigma sigma-ADH) from human stomach. cDNA sequence and structure/function relationships | journal = European Journal of Biochemistry | volume = 224 | issue = 2 | pages = 549–557 | date = September 1994 | pmid = 7925371 | doi = 10.1111/j.1432-1033.1994.00549.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Edenberg HJ, McClintick JN | title = Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review | journal = Alcoholism: Clinical and Experimental Research | volume = 42 | issue = 12 | pages = 2281–2297 | date = December 2018 | pmid = 30320893 | doi = 10.1111/acer.13904 | pmc = 6286250 }}</ref> The subsequent oxidation of acetaldehyde into acetate is performed by [[Biology:Aldehyde dehydrogenase|aldehyde dehydrogenase]] enzymes. Given that retinoic acid (RA) regulates numerous embryonic and differentiation processes, one of the proposed mechanisms for the teratogenic effects of ethanol is a competition for the enzymes required for the biosynthesis of RA from vitamin A. Animal research demonstrates that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for aldehyde dehydrogenase activity. In this model, acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Thus, animal research supports the reduction of retinoic acid activity as an etiological trigger in the induction of FASD.<ref name="Fainsod2020">{{cite journal |vauthors=Fainsod A, Bendelac-Kapon L, Shabtai Y |title=Fetal Alcohol Spectrum Disorder: Embryogenesis Under Reduced Retinoic Acid Signaling Conditions |journal=Subcell Biochem |series=Subcellular Biochemistry |volume=95 |pages=197–225 |date=2020 |pmid=32297301 |doi=10.1007/978-3-030-42282-0_8|isbn=978-3-030-42280-6 |s2cid=215793789 }}</ref><ref name="Petrelli2019">{{cite journal |vauthors=Petrelli B, Bendelac L, Hicks GG, Fainsod A |title=Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder |journal=Genesis |volume=57 |issue=1 |page=e23278 |date=January 2019 |pmid=30614633 |doi=10.1002/dvg.23278|s2cid=58603210 }}</ref><ref name="Shabtai2018A">{{cite journal |vauthors=Shabtai Y, Fainsod A |title=Competition between ethanol clearance and retinoic acid biosynthesis in the induction of fetal alcohol syndrome |journal=Biochem Cell Biol |volume=96 |issue=2 |pages=148–160 |date=April 2018 |pmid=28982012 |doi=10.1139/bcb-2017-0132}}</ref><ref name="Shabtai2018B">{{cite journal |vauthors=Shabtai Y, Bendelac L, Jubran H, Hirschberg J, Fainsod A |title=Acetaldehyde inhibits retinoic acid biosynthesis to mediate alcohol teratogenicity |journal=Sci Rep |volume=8 |issue=1 |page=347 |date=January 2018 |pmid=29321611 |pmc=5762763 |doi=10.1038/s41598-017-18719-7|bibcode=2018NatSR...8..347S }}</ref>

===Malaria===
Malaria and vitamin A deficiency are both common among young children in sub-Saharan Africa. Vitamin A supplementation to children in regions where vitamin A deficiency is common has repeatedly been shown to reduce overall mortality rates, especially from measles and diarrhea.<ref name="Sanj2009"/> For malaria, clinical trial results are mixed, either showing that vitamin A treatment did not reduce the incidence of probable malarial fever, or else did not affect incidence, but did reduce slide-confirmed parasite density and reduced the number of fever episodes.<ref name="Sanj2009">{{cite journal |vauthors=Sanjoaquin MA, Molyneux ME |title=Malaria and vitamin A deficiency in African children: a vicious circle? |journal=Malar J |volume=8 |page=134 |date=June 2009 |pmid=19534807 |pmc=2702350 |doi=10.1186/1475-2875-8-134}}</ref> The question was raised as to whether malaria causes vitamin A deficiency, or vitamin A deficiency contributes to the severity of malaria, or both. Researchers proposed several mechanisms by which malaria (and other infections) could contribute to vitamin A deficiency, including a fever-induced reduction in synthesis of retinal-binding protein (RBP) responsible for transporting retinol from liver to plasma and tissues, but reported finding no evidence for a transient depression or restoration of plasma RBP or retinol after a malarial infection was eliminated.<ref name="Sanj2009"/>

==In history==
[[File:Frederick Gowland Hopkins nobel.jpg|thumb|Frederick Gowland Hopkins, 1929 Nobel Prize for Physiology or Medicine]]
In 1912, [[Biography:Frederick Gowland Hopkins|Frederick Gowland Hopkins]] demonstrated that unknown accessory factors found in milk, other than [[Chemistry:Carbohydrate|carbohydrate]]s, [[Biology:Protein|protein]]s, and [[Chemistry:Fat|fat]]s were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.<ref name="Wolf2001"/><ref name=Semba>{{cite journal |vauthors=Semba RD |title=On the 'discovery' of vitamin A |journal=Annals of Nutrition & Metabolism |volume=61 |issue=3 |pages=192–198 |year=2012 |pmid=23183288 |doi=10.1159/000343124|s2cid=27542506 }}</ref> By 1913, one of these substances was independently discovered by Elmer McCollum and Marguerite Davis at the [[Organization:University of Wisconsin–Madison|University of Wisconsin–Madison]], and Lafayette Mendel and Thomas Burr Osborne at [[Organization:Yale University|Yale University]]. McCollum and Davis ultimately received credit because they submitted their paper three weeks before Mendel and Osborne. Both papers appeared in the same issue of the ''[[Biology:Journal of Biological Chemistry|Journal of Biological Chemistry]]'' in 1913.<ref>{{cite journal |vauthors=Rosenfeld L |title=Vitamine—vitamin. The early years of discovery |journal=Clinical Chemistry |volume=43 |issue=4 |pages=680–685 |date=April 1997 |pmid=9105273 |doi=10.1093/clinchem/43.4.680|doi-access=free }}</ref> The "accessory factors" were termed "fat soluble" in 1918, and later "vitamin A" in 1920. In 1919, Harry Steenbock (University of Wisconsin–Madison) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin A. In 1931, Swiss chemist [[Biography:Paul Karrer|Paul Karrer]] described the chemical structure of vitamin A.<ref name=Semba/> Retinoic acid and retinol were first synthesized in 1946 and 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.<ref>{{cite journal |vauthors=Arens JF, Van Dorp DA |title=Synthesis of some compounds possessing vitamin A activity |journal=Nature |volume=157 |issue= 3981|pages=190–191 |date=February 1946 |pmid=21015124 |doi=10.1038/157190a0 |bibcode=1946Natur.157..190A |s2cid=27157783 |url=}}</ref><ref>{{cite journal |vauthors=Van Dorp DA, Arens JF |title=Synthesis of vitamin A aldehyde |journal=Nature |volume=159 |issue=4058 |pages=189 |date=August 1947 |pmid=20256189 |doi=10.1038/160189a0 |bibcode=1947Natur.160..189V |s2cid=4137483 |url=}}</ref>

[[File:George Wald nobel.jpg|thumb|left|George Wald, 1967 Nobel Prize for Physiology or Medicine]]
During [[Social:World War II|World War II]], German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-board Airborne Intercept Radar system secret from Germany, the British Ministry of Information told newspapers an unproven claim that the nighttime defensive success of {{wipe|Royal Air Force}} pilots was due to a high dietary intake of carrots rich in beta-carotene, successfully convincing many people.<ref>{{cite web |url=https://www.sciencefocus.com/the-human-body/do-carrots-really-help-you-see-in-the-dark/ |title=Do carrots really help you see in the dark?
 |author=Luis Villazon |date= |publisher=sciencefocus.com |access-date=}}</ref>


In 1967, [[Biography:George Wald|George Wald]] shared the Nobel Prize in Physiology and Medicine for his work on chemical visual processes in the eye.<ref name="nobel-1967">{{cite web|title=The Nobel Prize in Physiology or Medicine 1967|url=http://www.nobelprize.org/nobel_prizes/medicine/laureates/1967/index.html|publisher=Nobel Foundation|access-date=28 July 2007|archive-url=https://web.archive.org/web/20131204095703/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1967/index.html|archive-date=4 December 2013|url-status=live}}</ref> Wald had demonstrated in 1935 that [[Biology:Photoreceptor cell|photoreceptor cell]]s in the eye contain rhodopsin, a [[Chemistry:Chromophore|chromophore]] composed of the protein [[Biology:Opsin|opsin]] and [[Biology:11-cis retinal|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 reconjugated to opsin.<ref name="Wolf2001"/><ref>{{cite journal | vauthors = Ebrey T, Koutalos Y | title = Vertebrate photoreceptors | journal = Progress in Retinal and Eye Research | volume = 20 | issue = 1 | pages = 49–94 | date = January 2001 | pmid = 11070368 | doi = 10.1016/S1350-9462(00)00014-8 | s2cid = 2789591 }}</ref> Wald's work was the culmination of nearly 60 years of research. In 1877, Franz Christian Boll identified a light-sensitive pigment in the outer segments of [[Biology:Rod cell|rod cell]]s of the retina that faded/bleached when exposed to light, but was restored after light exposure ceased. He suggested that this substance, by a photochemical process, conveyed the impression of light to the brain.<ref name="Wolf2001"/> The research was taken up by Wilhelm Kühne, who named the pigment rhodopsin, also known as "visual purple." Kühne confirmed that rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions, and that it was this chemical decomposition that stimulated nerve impulses to the brain.<ref name="Wolf2001"/> Research stalled until after identification of "fat-soluble vitamin A" as a dietary substance found in milkfat but not lard, would reverse night blindness and xerophthalmia. In 1925, Fridericia and Holm demonstrated that vitamin A deficient rats were unable to regenerate rhodopsin after being moved from a light to a dark room.<ref>{{cite journal| vauthors = Fridericia LS, Holm E |title=Experimental contribution to the study of the relation between night blindness and malnutrition |journal=Am J Physiol |volume=73 |issue= |pages=63–78 |date=1925 |pmid= |doi=10.1152/ajplegacy.1925.73.1.63}}</ref>

== References ==
{{reflist}}

== External links ==
* {{MeSH name|Vitamin A}}
*[https://web.archive.org/web/20061215060250/http://www.who.int/nutrition/publications/vitamin_a_pub/en/index.html WHO publications on Vitamin A Deficiency]

{{Vitamins}}
{{Antioxidants}}
{{Dietary supplement}}

[[Category:Biomolecules]]
[[Category:Unsaturated compounds]]

{{Sourceattribution|Vitamin A}}