Editing Retinol

{{Short description|Chemical compound}}
{{Distinguish|Retinal}}
{{Use dmy dates|date=January 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image             = All-trans-Retinol.svg
| image_class       = skin-invert-image
| width             =
| alt               =
| image2            = Retinol 3D balls.png
| width2            =
| alt2              =
| caption           = Retinol

<!-- Clinical data -->
| pronounce         =
| tradename         =
| Drugs.com         = {{Drugs.com|monograph|vitamin-a}}
| MedlinePlus       =
| DailyMedID        = Retinol
| pregnancy_AU      = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = [[By mouth]], [[intramuscular]]<ref name=drugs/>
| class             = [[vitamin]]
| ATC_prefix        = A11
| ATC_suffix        = CA01
| ATC_supplemental  = {{ATC|D10|AD02}}, {{ATC|R01|AX02}}, {{ATC|S01|XA02}}

| 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_number        = 68-26-8
| CAS_number2       = 11103-57-4
| CAS_supplemental  =
| PubChem           = 445354
| IUPHAR_ligand     = 4053
| DrugBank          = DB00162
| ChemSpiderID      = 393012
| UNII              = G2SH0XKK91
| UNII2             = 81G40H8B0T
| KEGG              = D00069
| ChEBI             = 17336
| ChEMBL            = 986
| NIAID_ChemDB      = 
| PDB_ligand        = RTL
| synonyms          = 

<!-- Chemical and physical data -->
| 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
| C=20
| H=30
| O=1
| SMILES            = OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)/CCCC1(C)C
| 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+
| 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        =0.000017<ref>{{cite journal | vauthors = Bonrath W, Gao B, Houston P, McClymont T, Müller MA, Schäfer C, Schweiggert C, Schütz J, Medlock JA | title=75 Years of Vitamin A Production: A Historical and Scientific Overview of the Development of New Methodologies in Chemistry, Formulation, and Biotechnology | journal=Organic Process Research & Development | volume=27 | issue=9 | date=September 2023 | issn=1083-6160 | doi=10.1021/acs.oprd.3c00161 | pages=1557–84| doi-access=free }}</ref>
| specific_rotation =
}}

<!-- Definition and medical uses -->
'''Retinol''', also called '''vitamin A<sub>1</sub>''', is a fat-soluble [[vitamin]] in the [[vitamin A]] family that is found in food and used as a [[dietary supplement]].<ref name=ods/> Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and [[mucous membranes]], immune function and reproductive development.<ref name=ods/> Dietary sources include fish, [[dairy products]], and meat.<ref name=ods/> As a supplement it is used to treat and prevent [[vitamin A deficiency]], especially that which results in [[xerophthalmia]].<ref name="drugs">{{cite web|title=Vitamin A|url=https://www.drugs.com/monograph/vitamin-a.html|publisher=Drugs.com, The American Society of Health-System Pharmacists|date=12 December 2024|accessdate=10 September 2024}}</ref> It is taken [[by mouth]] or by [[intramuscular injection|injection into a muscle]].<ref name=drugs/> As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.<ref name="Kong 2015">{{cite journal | vauthors = Kong R, Cui Y, Fisher GJ, Wang X, Chen Y, Schneider LM, Majmudar G | title = A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin | journal = Journal of Cosmetic Dermatology | volume = 15 | issue = 1 | pages = 49–57 | date = March 2016 | pmid = 26578346 | doi = 10.1111/jocd.12193 | s2cid = 13391046 | doi-access = free }}</ref>

<!-- Side effects and mechanism -->
Retinol at normal doses is well tolerated.<ref name=drugs/> High doses may cause [[hepatomegaly|enlargement of the liver]], dry skin, and [[hypervitaminosis A]].<ref name=drugs/><ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=701|edition=69}}</ref> High doses during [[pregnancy]] may harm the fetus.<ref name=drugs/> The body converts retinol to [[retinal]] and [[retinoic acid]], through which it acts.<ref name=ods/> 

<!-- History and culture -->
Retinol was discovered in 1909, isolated in 1931, and first made in 1947.<ref>{{cite book| vauthors = Squires VR |title=The Role of Food, Agriculture, Forestry and Fisheries in Human Nutrition | volume = IV |date=2011 |publisher=EOLSS Publications|isbn=9781848261952|page=121|url=https://books.google.com/books?id=VJWoCwAAQBAJ&pg=PA121|language=en|url-status=live|archive-url=https://web.archive.org/web/20171105201706/https://books.google.com/books?id=VJWoCwAAQBAJ&pg=PA121|archive-date=5 November 2017}}</ref><ref>{{cite book|title=Ullmann's Food and Feed, 3 Volume Set|date=2016|publisher=John Wiley & Sons|isbn=9783527695522|page=Chapter 2|url=https://books.google.com/books?id=w1O9DQAAQBAJ&pg=PA2034|language=en|url-status=live|archive-url=https://web.archive.org/web/20171105201730/https://books.google.com/books?id=w1O9DQAAQBAJ&pg=PA2034|archive-date=5 November 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> Retinol is available as a [[generic medication]] and [[over the counter]].<ref name=drugs/> In 2021, vitamin A was the 298th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Vitamin A - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/VitaminA | access-date = 14 January 2024}}</ref>

==Medical uses==
Retinol is used to treat [[vitamin A deficiency]].

Three approaches may be used when populations have low vitamin A levels:<ref>{{cite journal | vauthors = Schultink W | title = Use of under-five mortality rate as an indicator for vitamin A deficiency in a population | journal = The Journal of Nutrition | volume = 132 | issue = 9 Suppl | pages = 2881S–2883S | date = September 2002 | pmid = 12221264 | doi = 10.1093/jn/132.9.2881S | doi-access = free }}</ref>

# Through dietary modification involving the adjustment of menu choices of affected persons from available food sources to optimize vitamin A content.
# Enriching commonly eaten and affordable foods with vitamin A, a process called fortification. It involves the addition of synthetic vitamin A to staple foods like [[margarine]], bread, flour, cereals, and infant formula during processing.
# By giving high doses of vitamin A to the targeted deficient population, a method known as supplementation. In regions where deficiency is common, a single large dose is recommended to those at high risk twice a year.<ref name=WHO2008/>

Retinol is also used to reduce the risk of complications in [[measles]] patients.<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization |page=500 }}</ref>

==Side effects==<!-- This section is linked from [[Cod liver oil]] -->
{{see also|Hypervitaminosis A}}
The [[Dietary Reference Intake|Recommended Daily Intake]] (RDA) for preformed supplemental vitamin A for adult men and women is 900 and 700 Retinol Activity Units(RAE)/day, respectively, or about 3,000 IU and 2,300 IU.<ref name=ods/> In pregnancy, the vitamin A RDA is 750–770 RAE/day (about 2,500–2,550 IU).<ref name=ods/> During [[lactation]], the RDA increases to 1,200–1,300 RAE/day (about 4,000–4,300 IU, with differences depending on age).<ref name=ods/> 

Retinol Activity Units can only be converted to IU (International Units) when the source of the vitamin A is known.<ref name=ods/> The IU values listed above do not apply to food sources of vitamin A.<ref name="ods">{{cite web|url=https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/|title=Vitamin A: Fact Sheet for Health Professionals |date=15 December 2023|publisher=Office of Dietary Supplements, National Institutes of Health|accessdate=10 September 2024}}</ref>

Too much vitamin A in retinoid form can be harmful. The body converts the dimerized form, [[carotene]], into vitamin A as it is needed, so high levels of carotene are not toxic, whereas the ester (animal) forms are. The livers of certain animals, especially those adapted to polar environments, such as polar bears and seals,<ref>{{cite journal | vauthors = Rodahl K, Moore T | title = The vitamin A content and toxicity of bear and seal liver | journal = The Biochemical Journal | volume = 37 | issue = 2 | pages = 166–168 | date = July 1943 | pmid = 16747610 | pmc = 1257872 | doi = 10.1042/bj0370166 }}</ref> often contain amounts of vitamin A that would be toxic to humans. Thus, vitamin A toxicity is typically reported in Arctic explorers and people taking large doses of synthetic vitamin A. The first documented death possibly caused by vitamin A poisoning was that of [[Xavier Mertz]], a [[Switzerland|Swiss]] scientist, who died in January 1913 on an [[Antarctica|Antarctic]] expedition that had lost its food supplies and fell to eating its sled dogs. Mertz may have consumed lethal amounts of vitamin A by eating the dogs' livers.<ref>{{cite web | vauthors = Nataraja A |title=Man's best friend? (An account of Mertz's illness) |url= http://www.studentbmj.com/back_issues/0502/life/158.html|archive-url= https://web.archive.org/web/20070129213607/http://www.studentbmj.com/back_issues/0502/life/158.html |archive-date=29 January 2007 }}</ref>

Vitamin A acute toxicity occurs when a person ingests vitamin A in large amounts more than the daily recommended value in the threshold of 25,000 IU/kg or more. Often, the patient consumes about 3–4 times the RDA's specification.<ref name=Gropper>{{cite book | vauthors = Gropper SS, Smith JL, Groff JL | date = 2009 | title = Advanced Nutrition and Human Metabolism | edition = 5th | pages = 373–1182 }}</ref> Toxicity of vitamin A is believed to be associated with the methods of increasing vitamin A in the body, such as food modification, fortification, and supplementation, all of which are used to combat vitamin A deficiency.<ref>{{cite book | vauthors = Thompson J, Manore M | date = 2005| chapter = Ch. 8: Nutrients involved in antioxidant function | pages = 276–283 | title = Nutrition: An Applied Approach | publisher = Pearson Education Inc. }}</ref> Toxicity is classified into two categories: acute and chronic. The former occurs a few hours or days after ingestion of a large amount of vitamin A. Chronic toxicity takes place when about 4,000 IU/kg or more of vitamin A is consumed for a long time. Symptoms of both include nausea, blurred vision, fatigue, weight loss, and menstrual abnormalities.<ref>{{cite journal | vauthors = Mohsen SE, Mckinney K, Shanti MS | date = 2008 | url = http://emedicine.medscape.com/article/819426-overview | title = Vitamin A toxicity | archive-url = https://web.archive.org/web/20130723040000/http://emedicine.medscape.com/article/819426-overview | archive-date = 23 July 2013 | url-status = live | journal = Medscape }}</ref>

Excess vitamin A is suspected to be a contributor to [[osteoporosis]]. This seems to happen at much lower doses than those required to induce acute intoxication. Only preformed vitamin A can cause these problems because the conversion of carotenoids or retinyl esters into vitamin A is downregulated when physiological requirements are met;<ref>{{cite journal | vauthors = Steinhoff JS, Wagner C, Dähnhardt HE, Košić K, Meng Y, Taschler U, Pajed L, Yang N, Wulff S, Kiefer MF, Petricek KM, Flores RE, Li C, Dittrich S, Sommerfeld M, Guillou H, Henze A, Raila J, Wowro SJ, Schoiswohl G, Lass A, Schupp M | title = Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting | journal = EMBO Reports | volume = 25 | issue = 7 | pages = 2878–2895 | date = July 2024 | pmid = 38769419 | pmc = 11239848 | doi = 10.1038/s44319-024-00158-x }}</ref> but excessive uptake of carotenoids can cause [[carotenosis]].

Excess preformed vitamin A during early pregnancy is associated with a significant increase in birth defects.<ref>{{cite web| vauthors = Challem J |title=Caution Urged With Vitamin A in Pregnancy: But Beta-Carotene is Safe|url=http://www.thenutritionreporter.com/A-vitamins.html|website=The Nutrition Reporter Newsletter|archive-url=https://web.archive.org/web/20040901090549/http://www.thenutritionreporter.com/A-vitamins.html|archive-date=1 September 2004|date=1995}}</ref> These defects may be severe, even life-threatening. Even twice the daily recommended amount can cause severe birth defects.<ref>{{cite web| vauthors = Stone B |title=Vitamin A and Birth Defects|url=https://www.fda.gov/bbs/topics/ANSWERS/ANS00689.html|publisher=United States FDA|archive-url=https://web.archive.org/web/20040204082441/https://www.fda.gov/bbs/topics/ANSWERS/ANS00689.html|archive-date=4 February 2004|date=6 October 1995}}</ref> The FDA recommends that pregnant women get their vitamin A from foods containing beta carotene and that they ensure that they consume no more than 5,000 IU of preformed vitamin A (if any) per day. Although vitamin A is necessary for fetal development, most women carry sufficient stores of vitamin A in their liver cells,<ref>{{cite journal | vauthors = Steinhoff JS, Wagner C, Dähnhardt HE, Košić K, Meng Y, Taschler U, Pajed L, Yang N, Wulff S, Kiefer MF, Petricek KM, Flores RE, Li C, Dittrich S, Sommerfeld M, Guillou H, Henze A, Raila J, Wowro SJ, Schoiswohl G, Lass A, Schupp M | title = Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting | journal = EMBO Reports | volume = 25 | issue = 7 | pages = 2878–2895 | date = July 2024 | pmid = 38769419 | pmc = 11239848 | doi = 10.1038/s44319-024-00158-x }}</ref> so over-supplementation should be strictly avoided.

A review of all randomized controlled trials in the scientific literature by the [[Cochrane Collaboration]] published in ''[[Journal of the American Medical Association|JAMA]]'' in 2007 found that supplementation with beta carotene or vitamin A ''increased'' mortality by 5% and 16%, respectively.<ref>{{cite journal | vauthors = Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C | title = Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis | journal = JAMA | volume = 297 | issue = 8 | pages = 842–857 | date = February 2007 | pmid = 17327526 | doi = 10.1001/jama.297.8.842 | url = http://dcscience.net/bjelakovic-supplements-07.pdf | url-status = live | archive-url = https://web.archive.org/web/20160204172729/http://dcscience.net/bjelakovic-supplements-07.pdf | archive-date = 4 February 2016 }}</ref> This effect has been attributed to the role of retinol and retinoic acid in increasing circulating cholesterol and triglycerides as well as promoting cancer incidence.<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}</ref>

Studies emerging from developing countries India, Bangladesh, and Indonesia strongly suggest that, in populations in which vitamin A deficiency is common and maternal mortality is high, dosing expectant mothers with retinol can greatly reduce maternal mortality.<ref name=Sommer>{{cite journal | vauthors = Sommer A | title = Vitamin a deficiency and clinical disease: an historical overview | journal = The Journal of Nutrition | volume = 138 | issue = 10 | pages = 1835–1839 | date = October 2008 | pmid = 18806089 | doi = 10.1093/jn/138.10.1835 | doi-access = free }}</ref> Similarly, dosing newborn infants with 50,000 IU (15&nbsp;mg) of vitamin A within two days of birth can significantly reduce neonatal mortality.<ref>{{cite journal | vauthors = Tielsch JM, Rahmathullah L, Thulasiraj RD, Katz J, Coles C, Sheeladevi S, John R, Prakash K | title = Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India | journal = The Journal of Nutrition | volume = 137 | issue = 11 | pages = 2470–2474 | date = November 2007 | pmid = 17951487 | doi = 10.1093/jn/137.11.2470 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP | title = Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh | journal = Pediatrics | volume = 122 | issue = 1 | pages = e242–e250 | date = July 2008 | pmid = 18595969 | doi = 10.1542/peds.2007-3448 | s2cid = 27427577 }}</ref>

==Biological roles==
Retinol or other forms of vitamin A are needed for eyesight, maintenance of the skin, and human development.<ref name=drugs/> Other than for vision, which requires 11-cis retinal, the active compound is retinoic acid, synthesized from retinal, in turn synthesized from retinol. The differing biological roles of retinoic acid depend on its [[stereochemistry]] and whether it is present in the all-trans, 9-cis, or 13-cis forms.<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}</ref>

===Embryology===
Retinoic acid via the retinoic acid receptor influences the process of cell differentiation and, hence, the growth and development of embryos. During development, there is a concentration gradient of retinoic acid along the anterior-posterior (head-tail) axis. Cells in the embryo respond to retinoic acid differently depending on the amount present. For example, in vertebrates, the hindbrain transiently forms eight [[rhombomeres]] and each rhombomere has a specific pattern of genes being expressed. If retinoic acid is not present the last four rhombomeres do not develop. Instead, rhombomeres 1–4 grow to cover the same amount of space as all eight would normally occupy. Retinoic acid has its effects by turning on a differential pattern of Homeobox (Hox) genes that encode different homeodomain transcription factors which in turn can turn on cell type-specific genes.<ref name=gd>{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–931 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref> Deletion of the Homeobox (Hox-1) gene from rhombomere 4 makes the neurons growing in that region behave like neurons from rhombomere 2.  Retinoic acid is not required for patterning of the retina as originally proposed, but retinoic acid synthesized in the retina is secreted into the surrounding [[mesenchyme]] where it is required to prevent overgrowth of perioptic mesenchyme which can cause microphthalmia, defects in the cornea and eyelid, and rotation of the optic cup.<ref name="Duester_2008"/>

===Stem cell biology===
Synthetic retinoic acid is used in [[Cellular differentiation|differentiation]] of stem cells to more committed fates, echoing retinoic acid's importance in natural embryonic developmental pathways. It is thought to initiate differentiation into several different cell lineages through activation of the [[Retinoic acid receptor]]. It has numerous applications in the experimental induction of stem cell differentiation; amongst these is the differentiation of human [[embryonic stem cell]]s to posterior foregut lineages.<ref name=gd/>

===Vision===
{{Main|Visual cycle}}
Retinol is an essential compound in the cycle of light-activated chemical reactions called the "[[visual cycle]]" that underlies vertebrate vision. Retinol is converted by the protein [[RPE65]] within the [[pigment epithelium]] of the [[retina]] into 11-''cis''-retinal. This molecule is then transported into the [[retina]]'s [[photoreceptor cell]]s (the [[rod cell|rod]] or [[cone cell|cone]] cells in mammals) where it binds to an [[opsin]] protein and acts as a light-activated molecular switch.  When 11-''cis''-retinal absorbs light it [[cis-trans isomerism|isomerizes]] into all-''trans''-retinal. The change in the shape of the molecule in turn changes the configuration of the opsin in a cascade that leads to the [[Action potential|neuronal firing]], which signals the detection of light.<ref>{{cite book | vauthors = Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, Williams SM |date=2001 | chapter = Phototransduction |chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK10806/ |title = Neuroscience |publisher=Sinauer Associates | edition = 2nd }}</ref> The opsin then splits into the protein component (such [[metarhodopsin]]) and the cofactor all-''trans''-retinal. The regeneration of active opsin requires conversion of all-''trans''-retinal back to 11-''cis''-retinal via retinol. The regeneration of 11-''cis''-retinal occurs in vertebrates via the conversion of all-''trans''-retinol to 11-''cis''-retinol in a sequence of chemical transformations that occurs primarily in the pigment epithelial cells.<ref name=bs>{{cite journal | vauthors = Sahu B, Maeda A | title = Retinol Dehydrogenases Regulate Vitamin A Metabolism for Visual Function | journal = Nutrients | volume = 8 | issue = 11 | pages = 746 | date = November 2016 | pmid = 27879662 | pmc = 5133129 | doi = 10.3390/nu8110746 | doi-access = free }}</ref>

Without adequate amounts of retinol, regeneration of rhodopsin is incomplete and [[night blindness]] occurs. Night blindness, the inability to see well in dim light, is associated with a deficiency of [[vitamin A]], a class of compounds that includes retinol and retinal. In the early stages of [[vitamin A]] deficiency, the more light-sensitive and abundant [[rod cell|rod]]s, which have [[rhodopsin]], have impaired sensitivity, and the [[cone cell]]s are less affected. The cones are less abundant than rods and come in three types, each contains its own type of [[iodopsin]], the opsins of the cones. The cones mediate [[color vision]], and vision in bright light (day vision).

===Glycoprotein synthesis===
[[Glycoprotein]] synthesis requires adequate vitamin A status. In severe vitamin A deficiency, lack of glycoproteins may lead to [[corneal ulcer]]s or liquefaction.<ref>{{cite book | vauthors = Starck T |title=Advances in Corneal Research |chapter=Severe Corneal Ulcerations and Vitamin A Deficiency |publisher=Springer, Boston, MA |year=1997 |page=558 |isbn=978-1-4613-7460-2 |doi=10.1007/978-1-4615-5389-2_46 }}</ref>

===Immune system===
Vitamin A is involved in maintaining a number of immune cell types from both the innate and acquired immune systems.<ref>{{cite web|url=https://www.sciencedaily.com/releases/2015/07/150709132634.htm|title=Vitamin A directs immune cells to intestines|website=ScienceDaily|language=en|access-date=17 March 2020}}</ref> These include the [[lymphocytes]] ([[B-cells]], [[T-cells]], and [[natural killer cells]]), as well as many myelocytes ([[neutrophils]], [[macrophages]], and myeloid [[dendritic cells]]). Vitamin A maintains immune barriers in the gut through its activity as retinoic acid.<ref>{{cite journal | vauthors = Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H | title = Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid | journal = Science | volume = 317 | issue = 5835 | pages = 256–260 | date = July 2007 | pmid = 17569825 | doi = 10.1126/science.1145697 }}</ref>

===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 | page = 302 | date = January 2021 | pmid = 33494277 | pmc = 7909803 | doi = 10.3390/nu13020302 | 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 [[antimicrobial peptides]] (AMPs). Production of AMPs [[resistin]] and [[cathelicidin]], are promoted by RA.<ref name="Roche2021"/> Another way that vitamin A helps maintain a healthy skin and hair follicle [[microbiome]], especially on the face, is by reduction of [[sebum]] secretion, which is a nutrient source for bacteria.<ref name="Roche2021"/> Retinol has been the subject of clinical studies related to its ability to reduce the appearance of fine lines on the face and neck.<ref name="Kong 2015" /><ref>{{cite web |date=7 November 2016 |title=Vitamin A and Skin Health |url=https://lpi.oregonstate.edu/mic/health-disease/skin-health/vitamin-A |access-date=10 August 2023 |website=Linus Pauling Institute |language=en}}</ref>

===Red blood cells===
Vitamin A may be needed for normal [[haematopoiesis|red blood cell formation]];<ref>{{cite journal | vauthors = Oren T, Sher JA, Evans T | title = Hematopoiesis and retinoids: development and disease | journal = Leukemia & Lymphoma | volume = 44 | issue = 11 | pages = 1881–1891 | date = November 2003 | pmid = 14738139 | doi = 10.1080/1042819031000116661 | s2cid = 11348076 }}</ref><ref>{{cite journal | vauthors = Evans T | title = Regulation of hematopoiesis by retinoid signaling | journal = Experimental Hematology | volume = 33 | issue = 9 | pages = 1055–1061 | date = September 2005 | pmid = 16140154 | doi = 10.1016/j.exphem.2005.06.007 | doi-access = free }}</ref> deficiency causes abnormalities in [[iron metabolism]].<ref>{{cite journal | vauthors = García-Casal MN, Layrisse M, Solano L, Barón MA, Arguello F, Llovera D, Ramírez J, Leets I, Tropper E | title = Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans | journal = The Journal of Nutrition | volume = 128 | issue = 3 | pages = 646–650 | date = March 1998 | pmid = 9482776 | doi = 10.1093/jn/128.3.646 | doi-access = free }}</ref> Vitamin A is needed to produce the red blood cells from stem cells through retinoid differentiation.<ref>{{cite web|url=https://www.ebi.ac.uk/interpro/potm/2005_6/Page2.htm|title=Carotenoid Oxygenase |website=InterPro|access-date=7 November 2018}}</ref>

==Units of measurement==
When referring to dietary allowances or [[nutrition]]al science, retinol is usually measured in [[international unit]]s (IU). IU refers to biological activity and therefore is unique to each individual compound, however, 1 IU of retinol is equivalent to approximately 0.3 micrograms (300 nanograms).

==Nutrition==
{| class="wikitable" style="width:300px; float:right; margin:0 0 0 0.5em; background:#fff; border-collapse:collapse;"
|-
! style="background:#fda;" colspan="2"| Vitamin properties
|-
| style="background:#fed;"| [[Solubility]]
| Fat
|-
| style="background:#fed;"| [[Recommended Dietary Allowance|RDA]] (adult male)
| 900 [[microgram|μg]]/day
|-
| style="background:#fed;"| RDA (adult female)
| 700 [[microgram|μg]]/day
|-
| style="background:#fed;"| RDA upper limit (adult male)
| 3,000 [[microgram|μg]]/day
|-
| style="background:#fed;"| RDA upper limit (adult female)
| 3,000 [[microgram|μg]]/day
|-
! style="background:#fed;" colspan="2"| Deficiency symptoms
|-
| colspan="2" |
* [[Night blindness]]
* [[Keratomalacia]]
* Pale, dry skin
|-
! style="background:#fed;" colspan="2"| Excess symptoms
|-
| colspan="2" |
* Liver toxicity
* Dry skin
* Hair loss
* [[Teratogenesis|Teratological]] effects
* [[Osteoporosis]] (suspected, long-term)
|-
! style="background:#fda;" colspan="2"| Common sources
|-
| colspan="2" |
* [[Liver]] and other organs
* fortified [[Dairy products]]
|}
This vitamin plays an essential role in vision, particularly night vision, normal bone and tooth development, reproduction, and the health of skin and mucous membranes (the mucus-secreting layer that lines body regions such as the respiratory tract). While Vitamin A is often considered to be an antioxidant that prevents cancers, it does not have antioxidant activity<ref>{{cite journal | vauthors = Blaner WS, Shmarakov IO, Traber MG | title = Vitamin A and Vitamin E: Will the Real Antioxidant Please Stand Up? | journal = Annual Review of Nutrition | volume = 41 | pages = 105–131 | date = October 2021 | pmid = 34115520 | doi = 10.1146/annurev-nutr-082018-124228 }}</ref> and is shown to promote the development of many cancers.<ref>{{cite journal | title = The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers | journal = The New England Journal of Medicine | volume = 330 | issue = 15 | pages = 1029–1035 | date = April 1994 | pmid = 8127329 | doi = 10.1056/NEJM199404143301501 | vauthors = Alpha-Tocopherol BC }}</ref><ref>{{cite journal | vauthors = Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, Valanis B, Williams JH | title = The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements | journal = Journal of the National Cancer Institute | volume = 96 | issue = 23 | pages = 1743–1750 | date = December 2004 | pmid = 15572756 | doi = 10.1093/jnci/djh320 }}</ref>

There are two sources of dietary vitamin A. Retinyl ester or retinol forms, which are immediately available to the body or [[carotene]] precursors, also known as provitamins, which must be converted to active forms by the body. These are obtained from fruits and vegetables containing yellow, orange and dark green pigments, known as [[carotenoid]]s, the most well-known being β-carotene.<ref>{{cite journal | vauthors = Burri BJ, Clifford AJ | title = Carotenoid and retinoid metabolism: insights from isotope studies | journal = Archives of Biochemistry and Biophysics | volume = 430 | issue = 1 | pages = 110–119 | date = October 2004 | pmid = 15325918 | doi = 10.1016/j.abb.2004.04.028 | series = Highlight issue on Carotenoids }}</ref> For this reason, amounts of vitamin A are measured in Retinol Equivalents (RE). One RE is equivalent to 0.001&nbsp;mg of retinol, or 0.006&nbsp;mg of β-carotene, or 3.3 International Units of vitamin A.

Vitamin A is fat-soluble and is stored in the liver and fat tissue.<ref>{{cite journal | vauthors = Steinhoff JS, Wagner C, Dähnhardt HE, Košić K, Meng Y, Taschler U, Pajed L, Yang N, Wulff S, Kiefer MF, Petricek KM, Flores RE, Li C, Dittrich S, Sommerfeld M, Guillou H, Henze A, Raila J, Wowro SJ, Schoiswohl G, Lass A, Schupp M | title = Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting | journal = EMBO Reports | volume = 25 | issue = 7 | pages = 2878–2895 | date = July 2024 | pmid = 38769419 | pmc = 11239848 | doi = 10.1038/s44319-024-00158-x }}</ref> When required by a particular part of the body, the liver releases some vitamin A, which is carried by the blood and delivered to the target cells and tissues.<ref>{{cite journal | vauthors = Amengual J, Zhang N, Kemerer M, Maeda T, Palczewski K, Von Lintig J | title = STRA6 is critical for cellular vitamin A uptake and homeostasis | journal = Human Molecular Genetics | volume = 23 | issue = 20 | pages = 5402–5417 | date = October 2014 | pmid = 24852372 | pmc = 4168826 | doi = 10.1093/hmg/ddu258 }}</ref>

===Dietary intake===
The [[Dietary Reference Intake]] (DRI) Recommended Daily Amount (RDA) for vitamin A for a 25-year-old male is 900 micrograms/day, or 3000 IU. [[National Health Service]] daily recommended values are slightly lower at 700 micrograms for men and 600 micrograms for women.<ref>{{cite web|date=23 October 2017|title=Vitamins and minerals - Vitamin A|url=https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-a/|access-date=18 February 2023|website=nhs.uk|language=en}}</ref>

During the absorption process in the [[intestine]]s, retinol is incorporated into [[chylomicron]]s as the ester form, and it is these particles that mediate transport to the [[liver]]. Liver cells store vitamin A as the ester, and when retinol is needed in other tissues, it is de-esterifed and released into the blood as the alcohol. Retinol then attaches to a serum carrier, [[retinol binding protein]], for transport to target tissues.<ref>{{cite journal | vauthors = Amengual J, Zhang N, Kemerer M, Maeda T, Palczewski K, Von Lintig J | title = STRA6 is critical for cellular vitamin A uptake and homeostasis | journal = Human Molecular Genetics | volume = 23 | issue = 20 | pages = 5402–5417 | date = October 2014 | pmid = 24852372 | pmc = 4168826 | doi = 10.1093/hmg/ddu258 }}</ref> A binding protein inside cells, cellular retinoic acid binding protein, serves to store and move retinoic acid [[intracellular]]ly.

===Deficiency===
{{main|Vitamin A deficiency}}
[[Image:Vitamin A deficiency.PNG|right|thumb|360px|Prevalence of vitamin A deficiency in 1995]]
Vitamin A deficiency is common in developing countries but rarely seen in developed countries. Approximately 250,000 to 500,000 malnourished children in the developing world go blind each year from a deficiency of vitamin A.<ref>{{cite web |url=https://www.who.int/nutrition/topics/vad/en/ |title=Micronutrient deficiencies - Vitamin A deficiency |author=<!--Not stated--> |date=18 April 2018 |website=World Health Organization |access-date=18 April 2018 }}</ref> Vitamin A deficiency in expecting mothers increases the mortality rate of children shortly after childbirth.<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> [[Night blindness]] is one of the first signs of vitamin A deficiency. Vitamin A deficiency contributes to blindness by depleting the necessary form needed for rhodopsin.<ref name=bs/>

===Sources===
{{See also|Vitamin_A#Sources}}

Retinoids are found naturally only in foods of animal origin. Each of the following contains at least 0.15&nbsp;mg of retinoids per {{convert|1.75|-|7|oz|g|abbr=on}}:
* [[Cod liver oil]]
* [[Butter]]
* [[Liver (food)|Liver]] (beef, pork, chicken, turkey, fish)
* [[Egg (food)|Eggs]]
* [[Cheese]], [[milk]]<ref>{{cite book | vauthors = Brown JE | date = 2002 | title = Vitamins and Your Health. Nutrition Now | edition = 3rd | pages = 1–20 }}</ref>

==Chemistry==
Many different geometric isomers of retinol, retinal and retinoic acid are possible as a result of either a ''[[trans isomer|trans]]'' or ''[[Cis-trans isomerism|cis]]'' configuration of four of the five [[double bond]]s found in the [[polyene]] chain. The ''cis'' isomers are less stable and can readily convert to the all-''trans'' configuration (as seen in the structure of all-''trans''-retinol shown at the top of this page). Nevertheless, some ''cis'' isomers are found naturally and carry out essential functions. For example, the 11-''cis''-retinal isomer is the [[chromophore]] of [[rhodopsin]], the [[vertebrate]] [[Photoreceptor protein|photoreceptor]] molecule. Rhodopsin is composed of the 11-cis-retinal covalently linked via a [[Schiff base]] to the [[opsin]] protein (either rod opsin or blue, red, or green cone opsins). The process of vision relies on the light-induced isomerisation of the chromophore from 11-''cis'' to all-''trans'' resulting in a change of the conformation and activation of the photoreceptor molecule.<ref name=bs/>

Many of the non-visual functions of vitamin A are mediated by retinoic acid, which regulates gene expression by activating nuclear [[retinoic acid receptor]]s.<ref name="Duester_2008">{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–931 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref> The non-visual functions of vitamin A are essential in the immunological function, reproduction, and embryonic development of vertebrates as evidenced by the impaired growth, susceptibility to infection, and birth defects observed in populations receiving suboptimal vitamin A in their diet.

==Synthesis==
===Biosynthesis===
[[File:Chem 157 vitamin a synthesis project.png|thumb|class=skin-invert-image|Vitamin A biosynthesis]]
Retinol is synthesized from the breakdown of [[β-carotene]]. First, the [[β-carotene 15,15'-monooxygenase]] cleaves β-carotene at the central double bond, creating an [[epoxide]]. This epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. The cleavage occurs when these alcohols are oxidized to the aldehydes using [[NADH]]. This compound is called retinal. Retinal is then reduced to retinol by the enzyme [[retinol dehydrogenase]]. Retinol dehydrogenase is an enzyme that is dependent on NADH.<ref>{{cite book | vauthors = Dewick PM | date = 2009 | title = Medicinal Natural Products | publisher = Wiley | isbn = 978-0470741672}}</ref>

===Industrial synthesis===
[[File:Ionone beta.svg|thumb|left|class=skin-invert-image|β-ionone ring]]
Retinol is made industrially via [[total synthesis]] using either a method developed by [[BASF]]<ref name="β-Carotin-1">{{cite patent | inventor = Wittig G, Pommer H | country = DE | number = 954247 | gdate =  13 December 1956 | title = Verfahren zur Herstellung von best-Carotin bzw. 15,15'-Dehydro-beta-carotin | postscript = . }}</ref><ref name="β-Carotin-2">{{cite patent | country = US | number = 2917524 | inventor = Wittig G, Pommer H | title = Compounds of the vitamin A series | gdate = 1959 | assign1 = Badische Anilin- & Soda-Fabrik Akt.-Ges. }}</ref> or a [[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 = 2 September 1952 |inventor = Herloff IH, Horst P | postscript = . }}</ref> The two major suppliers, DSM and BASF, are believed to use total synthesis.<ref name="Parker2016"/>

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"/> 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 [[ester]] derivatives [[retinyl acetate]] or [[retinyl palmitate]]. Before 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 Euros on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989. Roche sold its vitamin division to [[DSM (company)|DSM]] in 2003. DSM and BASF have the major share of industrial production.<ref name="Parker2016"/>

==History==
[[File:Frederick Gowland Hopkins nobel.jpg|thumb|left|Frederick Gowland Hopkins, 1929 Nobel Prize for Physiology or Medicine]]
[[File:George Wald nobel.jpg|thumb|right|George Wald, 1967 Nobel Prize for Physiology or Medicine]]
In 1912, [[Frederick Gowland Hopkins]] demonstrated that unknown accessory factors found in milk, other than [[carbohydrate]]s, [[protein]]s, and [[fat]]s were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.<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> One year later, [[Elmer McCollum]], a [[biochemist]] at the [[University of Wisconsin–Madison]], and colleague [[Marguerite Davis]] identified a fat-soluble nutrient in [[butterfat]] and [[cod liver oil]]. Their work confirmed that of [[Thomas Burr Osborne (chemist)|Thomas Burr Osborne]] and [[Lafayette Mendel]], at [[Yale University|Yale]], also in 1913, which suggested a fat-soluble nutrient in butterfat.<ref name=Semba2>{{cite journal | vauthors = Semba RD | title = Vitamin A as "anti-infective" therapy, 1920-1940 | journal = The Journal of Nutrition | volume = 129 | issue = 4 | pages = 783–791 | date = April 1999 | pmid = 10203551 | doi = 10.1093/jn/129.4.783 | doi-access = free }}</ref> The "accessory factors" were termed "fat-soluble" in 1918 and later "vitamin A" in 1920. In 1931, Swiss chemist [[Paul Karrer]] described the chemical structure of vitamin A.<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=|doi-access=free }}</ref>


In 1967, [[George Wald]] was a co-recipient of the Nobel Prize in Physiology and Medicine "..."for their discoveries concerning the primary physiological and 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> [[Photoreceptor cell]]s in the eye contain a [[chromophore]] composed of the protein [[opsin]] and [[11-cis retinal]]. When struck by light, 11-cis retinal undergoes photoisomerization to all-trans retinal and via signal transduction cascade sends a nerve signal to the brain. The all-trans retinal is reduced to all-trans retinol and travels back to the retinal pigment epithelium to be recycled to 11-cis retinal and conjugated to opsin.<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>

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

== References ==
{{reflist}}

== External links ==
* {{pauling|id=vitamins/vitaminA|title=Vitamin A|author=Jane Higdon}}
* [http://ods.od.nih.gov/factsheets/cc/vita.html NIH Office of Dietary Supplements – Vitamin A]
* [http://www.merck.com/mrkshared/mmanual/section1/chapter3/3b.jsp Vitamin A Deficiency] at the ''[[Merck Manual of Diagnosis and Therapy]]''

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