Retinoic acid: Difference between revisions

{{short description|Metabolite of vitamin A}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

| Watchedfields = changed

| verifiedrevid = 459436793

| Name = All-''trans''-retinoic acid

| ImageFile = ActivevitaminAwithstereochemistryEisomer.png

| ImageSize = 260

| ImageAlt = Skeletal formula of retinoic acid

| ImageFile1 = Retinoic acid 3D ball.png

| ImageSize1 = 260

| ImageAlt1 = Ball-and-stick model of the retinoic acid molecule

| IUPACName = Retinoic acid

| SystematicName = (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-tetraenoic acid

| OtherNames = vitamin A acid; RA

| Section1 = {{Chembox Identifiers

| IUPHAR_ligand = 2644

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 5688UTC01R

| ChEMBL = 38

| ChemSpiderID = 392618

| ChEBI = 15367

| StdInChI = 1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+

| StdInChIKey = SHGAZHPCJJPHSC-YCNIQYBTSA-N

| Section2 = {{Chembox Properties

| C=20|H=28|O=2

| Appearance = Yellow to light orange crystalline powder with a characteristic of a floral scent<ref name="Merck">''Merck Index'', 13th Edition, '''8251'''.</ref>

| Density =

| MeltingPtC = 180 to 182

| MeltingPt_notes = Crystals from ethanol<ref name="Merck"/>

| Solubility = Nearly insoluble

| SolubleOther = Soluble

| Section7 = {{Chembox Hazards

| AutoignitionPt =

}}

| Section8 = {{Chembox Related

| OtherFunction =

| OtherFunction_label =

| OtherCompounds = [[retinol]]; [[retinal]]; [[beta-carotene]]

}}

'''Retinoic acid''' (simplified nomenclature for all-''trans''-retinoic acid) is a [[metabolite]] of [[vitamin A]]₁ (all-''trans''-[[retinol]]) that is required for embryonic development, male fertility, regulation of bone growth and immune function.<ref name=jah>{{cite journal | vauthors = Hall JA, Grainger JR, Spencer SP, Belkaid Y | title = The role of retinoic acid in tolerance and immunity | journal = Immunity | volume = 35 | issue = 1 | pages = 13–22 | date = July 2011 | pmid = 21777796 | pmc = 3418663 | doi = 10.1016/j.immuni.2011.07.002 }}</ref> All-''trans''-retinoic acid is required for [[chordate]] animal development, which includes all higher animals from fish to humans. During early [[embryonic development]], all-''trans''-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an [[intercellular signaling]] molecule that guides development of the posterior portion of the embryo.<ref name="Duester">{{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> It acts through [[Hox gene]]s, which ultimately control anterior/posterior patterning in early developmental stages.<ref name="Holland">{{cite journal | vauthors = Holland LZ | title = Developmental biology: a chordate with a difference | journal = Nature | volume = 447 | issue = 7141 | pages = 153–155 | date = May 2007 | pmid = 17495912 | doi = 10.1038/447153a | s2cid = 5549210 | doi-access = free | bibcode = 2007Natur.447..153H }}</ref> In adult tissues, the activity of endogenous retinoic acid appears limited to immune function.<ref name=jah/> and male fertility.<ref>{{cite journal | vauthors = Topping T, Griswold MD | title = Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis | language = English | journal = Frontiers in Endocrinology | volume = 13 | pages = 871225 | date = 2022-04-28 | pmid = 35574006 | pmc = 9097449 | doi = 10.3389/fendo.2022.871225 | doi-access = free }}</ref> Retinoic acid administered as a drug (see [[tretinoin]] and [[alitretinoin]]) causes significant toxicity that is distinct from normal retinoid biology.<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>

All-''trans''-retinoic acid is the major occurring retinoic acid, while isomers like 13-''cis''- and 9-''cis''-retinoic acid are also present in much lower levels.<ref name="Rühl_2018">{{cite journal | vauthors = Rühl R, Krezel W, de Lera AR | title = 9-Cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5 | journal = Nutrition Reviews | volume = 76 | issue = 12 | pages = 929–941 | date = December 2018 | pmid = 30358857 | doi = 10.1093/nutrit/nuy057 | doi-access = free }}</ref>

The key role of all-''trans''-retinoic acid in embryonic development mediates the high [[teratogenicity]] of retinoid pharmaceuticals, such as [[isotretinoin]] (13-''cis''-retinoic acid) used for treatment of [[acne]] or [[retinol]] used for skin disorders. High oral doses of preformed vitamin A ([[retinyl palmitate]]), and all-''trans''-retinoic acid itself, also have teratogenic potential by this same mechanism.<ref>{{Cite web |title=PRAC Seeks New Pregnancy Prevention Measures For Retinoids |url=https://www.medscape.com/viewarticle/892514?form=fpf |access-date=2024-08-15 |website=Medscape |language=en}}</ref>

All-''trans''-retinoic acid acts by binding to the [[retinoic acid receptor]] (RAR), which is bound to DNA as a heterodimer with the [[retinoid X receptor]] (RXR) in regions called retinoic acid [[response element]]s (RAREs). Binding of the all-''trans''-retinoic acid ligand to RAR alters the conformation of the RAR, which affects the binding of other proteins that either induce or repress [[Transcription (biology)|transcription]] of a nearby gene (including Hox genes and several other target genes). RARs mediate transcription of different sets of genes controlling differentiation of a variety of cell types, thus the target genes regulated depend upon the target cells.<ref name="pmid24005729">{{cite journal | vauthors = Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV | title = In vitro differentiation of cultured human CD34+ cells into astrocytes | journal = Neurology India | volume = 61 | issue = 4 | pages = 383–388 | date = 2013 | pmid = 24005729 | doi = 10.4103/0028-3886.117615 | doi-access = free }}</ref> In some cells, one of the target genes is the gene for the retinoic acid receptor itself ([[RAR-beta]] in mammals), which amplifies the response.<ref>{{cite book | vauthors = Wingender E | title = Gene Regulation in Eukaryotes| publisher = VCH| location = New York | year = 1993 | chapter = Steroid/Thyroid Hormone Receptors | pages = 316 | isbn = 1-56081-706-2 }}</ref> Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid.<ref name="Duester"/><ref name="Holland"/> The concentration of retinoic acid is tightly controlled and governs activation of the [[Retinoic acid receptor|retinoid nuclear receptor]] pathway.<ref>{{cite journal | vauthors = Feng R, Fang L, Cheng Y, He X, Jiang W, Dong R, Shi H, Jiang D, Sun L, Wang D | title = Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus) | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 10131 | date = May 2015 | pmid = 25976364 | pmc = 4432375 | doi = 10.1038/srep10131 | bibcode = 2015NatSR...510131F }}</ref> In adults, retinoic acid is only detected at physiologically relevant levels in the testes, pancreas and immune tissues.<ref>{{cite journal | vauthors = Kane MA, Chen N, Sparks S, Napoli JL | title = Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS | journal = The Biochemical Journal | volume = 388 | issue = Pt 1 | pages = 363–369 | date = May 2005 | pmid = 15628969 | pmc = 1186726 | doi = 10.1042/BJ20041867 }}</ref>

The molecular basis for the interaction between all-''trans''-retinoic acid and the Hox genes has been studied by using deletion analysis in [[transgenic mice]] carrying constructs of GFP [[Reporter gene|reporter genes]]. Such studies have identified functional RAREs within flanking sequences of some of the most 3′ Hox genes (including ''[[HOXA1]]'', ''[[HOXB1]]'', ''[[HOXB4]]'', ''[[HOXD4]]''), suggesting a direct interaction between the genes and retinoic acid. These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.<ref>

{{cite journal | vauthors = Marshall H, Morrison A, Studer M, Pöpperl H, Krumlauf R | title = Retinoids and Hox genes | journal = FASEB Journal | volume = 10 | issue = 9 | pages = 969–978 | date = July 1996 | pmid = 8801179 | doi = 10.1096/fasebj.10.9.8801179 | s2cid = 16062049 | doi-access = free }}</ref>

In adults, retinoic acid has a key role in preventing autoimmunity in mucosal tissues. Retinoic acid produced by dendritic cells promotes [[regulatory T cell]] formation to promote tolerance within the colon.<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> This pathway is used by cancer cells to suppress the immune system.<ref>{{cite journal | vauthors = Devalaraja S, To TK, Folkert IW, Natesan R, Alam MZ, Li M, Tada Y, Budagyan K, Dang MT, Zhai L, Lobel GP, Ciotti GE, Eisinger-Mathason TS, Asangani IA, Weber K, Simon MC, Haldar M | title = Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression | journal = Cell | volume = 180 | issue = 6 | pages = 1098–1114.e16 | date = March 2020 | pmid = 32169218 | pmc = 7194250 | doi = 10.1016/j.cell.2020.02.042 }}</ref> In the testes, retinoic acid is necessary for the process of spermatogenesis.<ref>{{cite journal | vauthors = Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, Amory DW, Evanoff R, Goldstein AS, Griswold MD | title = Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis | journal = Journal of Andrology | volume = 32 | issue = 1 | pages = 111–119 | date = 2011-01-01 | pmid = 20705791 | pmc = 3370679 | doi = 10.2164/jandrol.110.010751 }}</ref> Experiments in healthy male subjects suggests that retinoic acid is only necessary for fertility in adult humans.<ref>{{cite journal | vauthors = Heller CG, Moore DJ, Paulsen CA | title = Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines | journal = Toxicology and Applied Pharmacology | volume = 3 | issue = 1 | pages = 1–11 | date = January 1961 | pmid = 13713106 | doi = 10.1016/0041-008X(61)90002-3 | bibcode = 1961ToxAP...3....1H }}</ref>

== Biosynthesis and metabolism ==

All''-trans''-retinoic acid can be produced in the body by two sequential oxidation steps that convert all-''trans''-retinol to [[retinaldehyde]] to all-''trans''-retinoic acid, but once produced it cannot be reduced again to all-''trans''-retinal. The enzymes that generate retinoic acid for [[regulation of gene expression]] include [[retinol dehydrogenase]] (Rdh10) that metabolizes retinol to retinaldehyde, and three types of [[retinaldehyde dehydrogenase]], i.e. [[ALDH1A1]] (RALDH1), [[ALDH1A2]] (RALDH2), and [[ALDH1A3]] (RALDH3)<ref name="ALDH">{{cite web|url=http://www.aldh.org/superfamily.php|title=ALDH 1 Family|access-date=22 October 2012|publisher=Dr. Vasilis Vasiliou's laboratory at the University of Colorado's Health Sciences Center|url-status=dead|archive-url=https://web.archive.org/web/20130113102740/http://www.aldh.org/superfamily.php|archive-date=13 January 2013}}</ref> that metabolize retinaldehyde to retinoic acid.<ref name="Duester" /> Enzymes that metabolize retinoic acid to turn off biological signaling include the [[cytochrome P450|cytochrome P450 members]] ([[CYP26]]).<ref name="Molotkov et al.">{{cite journal | vauthors = Molotkov A, Ghyselinck NB, Chambon P, Duester G | title = Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation | journal = The Biochemical Journal | volume = 383 | issue = Pt 2 | pages = 295–302 | date = October 2004 | pmid = 15193143 | pmc = 1134070 | doi = 10.1042/BJ20040621 }}</ref> Oxidized metabolites such as 4-oxoretinoic acid are eliminated by glucuronidation in the liver.

== Function in embryonic development ==

All-''trans''-retinoic acid is a [[morphogen]] signaling molecule, which means it is concentration dependent; malformations can arise when the concentration of retinoic acid is in excess or deficient. Other signaling pathways that interact with the retinoic acid pathway are [[fibroblast growth factor 8]], [[Cdx]] and Hox genes, all participating in the development of various structures within the embryo. For example, retinoic acid plays an important role in activating Hox genes required for [[hindbrain]] development. The hindbrain, which later differentiates into the [[brain stem]], serves as a major signaling center defining the border of the head and trunk.<ref>{{cite journal | vauthors = Lee K, Skromne I | title = Retinoic acid regulates size, pattern and alignment of tissues at the head-trunk transition | journal = Development | volume = 141 | issue = 22 | pages = 4375–4384 | date = November 2014 | pmid = 25371368 | doi = 10.1242/dev.109603 | doi-access = free }}</ref>

A double-sided retinoic acid gradient that is high in the trunk and low at the junction with the head and tail represses fibroblast growth factor 8 in the developing trunk to allow normal [[somitogenesis]], [[forelimb]] [[limb bud|bud]] initiation, and formation of the [[Atrium (heart)|atria in the heart]].<ref name="Cunningham and Duester">{{cite journal | vauthors = Cunningham TJ, Duester G | title = Mechanisms of retinoic acid signalling and its roles in organ and limb development | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 2 | pages = 110–123 | date = February 2015 | pmid = 25560970 | pmc = 4636111 | doi = 10.1038/nrm3932 }}</ref> During exposure to excess retinoic acid, the hindbrain becomes enlarged, hindering the growth of other parts of the brain; other developmental abnormalities that can occur during excess retinoic acid are missing or fused [[Somite|somites]], and problems with the aorta and large vessels within the heart. With an accumulation of these malformations, an individual can be diagnosed with [[DiGeorge syndrome]].<ref name=":0">{{cite journal | vauthors = Rhinn M, Dollé P | title = Retinoic acid signalling during development | journal = Development | volume = 139 | issue = 5 | pages = 843–858 | date = March 2012 | pmid = 22318625 | doi = 10.1242/dev.065938 | doi-access = free }}</ref> However, since retinoic acid acts in various developmental processes, abnormalities associated with loss of retinoic acid are not only limited to sites associated with DiGeorge syndrome. Genetic loss-of-function studies in mouse and zebrafish embryos that eliminate retinoic acid synthesis or retinoic acid receptors (RARs) have revealed abnormal development of the somites, forelimb buds, heart, hindbrain, spinal cord, eye, [[forebrain]] [[basal ganglia]], kidney, foregut [[endoderm]], etc.<ref name="Cunningham and Duester" />

*[[Talarozole]]

*[[Tretinoin]] / all-''trans'' retinoic acid (Tradename: Retin-A)

*[[Isotretinoin]] / 13-''cis'' retinoic acid (Tradename: Accutane(US), Roaccutane)

*[[Alitretinoin]] / 9-cis retinoic acid

*[[Tamibarotene]] / RAR-alpha agonist

*[[Trifarotene]]

*[[Adapalene]]

*[[Acitretin|Aciretin]]

== References ==

{{Reflist|2}}

== External links ==

* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=REA Retinoic acid bound to proteins] in the [[Protein Data Bank|PDB]]

{{Carotenoids}}

{{Retinoid receptor modulators}}

[[Category:Cyclohexenes]]