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Retinoic acid

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For all-trans-retinoic acid as a drug, see Tretinoin. For 9-cis-retinoic acid as a drug, see Alitretinoin. For 13-cis-retinoic acid as a drug, see Isotretinoin.

All-trans-retinoic acid
Skeletal formula of retinoic acid
Ball-and-stick model of the retinoic acid molecule
Names
IUPAC name
Retinoic acid
Systematic IUPAC name
(2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid
Other names
vitamin A acid; RA
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • InChI=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+
    Key: SHGAZHPCJJPHSC-YCNIQYBTSA-N
  • CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C
Properties
C20H28O2
Molar mass 300.442 g·mol−1
Appearance Yellow to light orange crystalline powder with a characteristic of a floral scent[1]
Melting point 180 to 182 °C (356 to 360 °F; 453 to 455 K) Crystals from ethanol[1]
Nearly insoluble
Solubility in fat Soluble
Related compounds
Related compounds
 retinol; retinal; beta-carotene
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Retinoic acid (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function.[2] 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.[3] It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.[4] In adult tissues, the activity of endogenous retinoic acid appears limited to immune function.[2] and male fertility.[5] Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.[6]

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.[7]

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.[8]

Mechanism of biological action

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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 elements (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 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.[9] 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.[10] Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid.[3][4] The concentration of retinoic acid is tightly controlled and governs activation of the retinoid nuclear receptor pathway.[11] In adults, retinoic acid is only detected at physiologically relevant levels in the testes, pancreas and immune tissues.[12]

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 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.[13]

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.[14] This pathway is used by cancer cells to suppress the immune system.[15] In the testes, retinoic acid is necessary for the process of spermatogenesis.[16] Experiments in healthy male subjects suggests that retinoic acid is only necessary for fertility in adult humans.[17]

Biosynthesis and metabolism

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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)[18] that metabolize retinaldehyde to retinoic acid.[3] Enzymes that metabolize retinoic acid to turn off biological signaling include the cytochrome P450 members (CYP26).[19] Oxidized metabolites such as 4-oxoretinoic acid are eliminated by glucuronidation in the liver.

Function in embryonic development

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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.[20]

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 bud initiation, and formation of the atria in the heart.[21] 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 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.[22] 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.[21]

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References

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  1. ^ a b Merck Index, 13th Edition, 8251.
  2. ^ a b Hall JA, Grainger JR, Spencer SP, Belkaid Y (July 2011). "The role of retinoic acid in tolerance and immunity". Immunity. 35 (1): 13–22. doi:10.1016/j.immuni.2011.07.002. PMC 3418663. PMID 21777796.
  3. ^ a b c Duester G (September 2008). "Retinoic acid synthesis and signaling during early organogenesis". Cell. 134 (6): 921–931. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086.
  4. ^ a b Holland LZ (May 2007). "Developmental biology: a chordate with a difference". Nature. 447 (7141): 153–155. Bibcode:2007Natur.447..153H. doi:10.1038/447153a. PMID 17495912. S2CID 5549210.
  5. ^ Topping T, Griswold MD (2022-04-28). "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology. 13: 871225. doi:10.3389/fendo.2022.871225. PMC 9097449. PMID 35574006.
  6. ^ Esposito M, Amory JK, Kang Y (September 2024). "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine. 221 (9). doi:10.1084/jem.20240519. PMC 11318670. PMID 39133222.
  7. ^ Rühl R, Krezel W, de Lera AR (December 2018). "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". Nutrition Reviews. 76 (12): 929–941. doi:10.1093/nutrit/nuy057. PMID 30358857.
  8. ^ "PRAC Seeks New Pregnancy Prevention Measures For Retinoids". Medscape. Retrieved 2024-08-15.
  9. ^ Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, et al. (2013). "In vitro differentiation of cultured human CD34+ cells into astrocytes". Neurology India. 61 (4): 383–388. doi:10.4103/0028-3886.117615. PMID 24005729.
  10. ^ Wingender E (1993). "Steroid/Thyroid Hormone Receptors". Gene Regulation in Eukaryotes. New York: VCH. p. 316. ISBN 1-56081-706-2.
  11. ^ Feng R, Fang L, Cheng Y, He X, Jiang W, Dong R, et al. (May 2015). "Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus)". Scientific Reports. 5 (1): 10131. Bibcode:2015NatSR...510131F. doi:10.1038/srep10131. PMC 4432375. PMID 25976364.
  12. ^ Kane MA, Chen N, Sparks S, Napoli JL (May 2005). "Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS". The Biochemical Journal. 388 (Pt 1): 363–369. doi:10.1042/BJ20041867. PMC 1186726. PMID 15628969.
  13. ^ Marshall H, Morrison A, Studer M, Pöpperl H, Krumlauf R (July 1996). "Retinoids and Hox genes". FASEB Journal. 10 (9): 969–978. doi:10.1096/fasebj.10.9.8801179. PMID 8801179. S2CID 16062049.
  14. ^ Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. (July 2007). "Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid". Science. 317 (5835): 256–260. doi:10.1126/science.1145697. PMID 17569825.
  15. ^ Devalaraja S, To TK, Folkert IW, Natesan R, Alam MZ, Li M, et al. (March 2020). "Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression". Cell. 180 (6): 1098–1114.e16. doi:10.1016/j.cell.2020.02.042. PMC 7194250. PMID 32169218.
  16. ^ Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, et al. (2011-01-01). "Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis". Journal of Andrology. 32 (1): 111–119. doi:10.2164/jandrol.110.010751. PMC 3370679. PMID 20705791.
  17. ^ Heller CG, Moore DJ, Paulsen CA (January 1961). "Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 3 (1): 1–11. Bibcode:1961ToxAP...3....1H. doi:10.1016/0041-008X(61)90002-3. PMID 13713106.
  18. ^ "ALDH 1 Family". Dr. Vasilis Vasiliou's laboratory at the University of Colorado's Health Sciences Center. Archived from the original on 13 January 2013. Retrieved 22 October 2012.
  19. ^ Molotkov A, Ghyselinck NB, Chambon P, Duester G (October 2004). "Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation". The Biochemical Journal. 383 (Pt 2): 295–302. doi:10.1042/BJ20040621. PMC 1134070. PMID 15193143.
  20. ^ Lee K, Skromne I (November 2014). "Retinoic acid regulates size, pattern and alignment of tissues at the head-trunk transition". Development. 141 (22): 4375–4384. doi:10.1242/dev.109603. PMID 25371368.
  21. ^ a b Cunningham TJ, Duester G (February 2015). "Mechanisms of retinoic acid signalling and its roles in organ and limb development". Nature Reviews. Molecular Cell Biology. 16 (2): 110–123. doi:10.1038/nrm3932. PMC 4636111. PMID 25560970.
  22. ^ Rhinn M, Dollé P (March 2012). "Retinoic acid signalling during development". Development. 139 (5): 843–858. doi:10.1242/dev.065938. PMID 22318625.
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