Retinoic acid

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
IUPAC name (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid
Other names vitamin A acid; RA
Identifiers
CAS number	302-79-4 Y
PubChem	444795
ChEMBL	CHEMBL38 N
Jmol-3D images	Image 1
SMILES CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C
Properties
Molecular formula	C20H28O2
Molar mass	300.43512 g/mol
Appearance	yellow to light orange crystalline powder with characteristic floral odor [1]
Melting point	180-182 °C, crystals from ethanol [1]
Solubility in water	nearly insoluble
Solubility in fat	soluble
N acid (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans. During early embryonic development, 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.^[2] It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. ^[3]

The key role of retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin used for treatment of cancer and acne. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and retinoic acid itself, also have teratogenic potential by this same mechanism.

Mechanism of biological action

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 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). Retinoic acid receptors 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. 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.^[4] Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid.^[2][3]

The molecular basis for the interaction between retinoic acid and the Hox genes has been studied by using deletion analysis in transgenic mice carrying constructs of lacZ 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.^[5]

Biosynthesis

Retinoic acid can be produced in the body by two sequential oxidation steps which convert retinol to retinaldehyde to retinoic acid, but once produced it cannot be reduced again to retinol. The enzymes that generate retinoic acid for control of gene expression include retinol dehydrogenases (i.e. Rdh10) that metabolize retinol to retinaldehyde, and retinaldehyde dehydrogenases (Raldh1, Raldh2, and Raldh3) that metabolize retinaldehyde to retinoic acid.^[2] Enzymes that metabolize excess retinol to prevent toxicity include alcohol dehydrogenase and cytochrome P450(cyp26).

Retinoic acid function in the absence of precursors retinol or retinaldehyde

Retinoic acid is responsible for most of the activity of vitamin A, save visual pigment effects which require retinal (retinaldehyde), and cell metabolism effects that may require retinol itself. Also, some biochemical functions necessary for fertility in vitamin A deficient male and female mammals originally appeared to require retinol for rescue, but this is due to a requirement for local conversion of retinol to retinoic acid, as administered retinoic acid does not reach some critical tissues unless given in high amounts. Thus, if animals are fed only retinoic acid but no vitamin A (retinol or retinal), they suffer none of the growth-stunting or epithelial-damaging effects of lack of vitamin A (including no xerophthalmia-- dryness of the cornea). They do suffer retina degeneration and blindness, due to retinal (retinaldehyde) deficiency. They also suffer defects in reproduction: vitamin A-deprived but retinoic acid-supplemented male rats exhibit hypogonadism and infertility due to lack of local retinoic acid synthesis in the testis; similar treatment of female rats causes infertility due to fetal resorption caused by a lack of local retinoic acid synthesis in the embryo.^[6][7]

Related pharmaceuticals

• Tretinoin (Tradename: Retin-A)
• Isotretinoin (Tradename: Accutane(US), Roaccutane)

References

1. ^ ^{a b} Merck Index, 13th Edition, 8251.
2. ^ ^{a b c} Duester, G (September 2008). "Retinoic Acid Synthesis and Signaling during Early Organogenesis". Cell 134 (6): 921–31. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2632951. 
3. ^ ^{a b} Holland, Linda Z. (2007). "Developmental biology: A chordate with a difference". Nature 447 (7141): 153–155. doi:10.1038/447153a. PMID 17495912. 
4. ^ Edgar Wingender (1993). "Steroid/Thyroid Hormone Receptors". Gene Regulation in Eukaryotes. New York: VCH. pp. 316. ISBN 1-56081-706-2. 
5. ^ Marshall, H. et al. (1996.). "Retinoids and Hox genes". The FASEB Journal 10 (9): 969–978. http://www.fasebj.org/cgi/reprint/10/9/969.pdf. Retrieved 2009-02-19. 
6. ^ http://la.rsmjournals.com/cgi/content/abstract/5/2/239 Lab Anim 1971;5:239-250. The production of experimental vitamin A deficiency in rats and mice. T. Moore and P. D. Holmes. doi:10.1258/002367771781006492.
7. ^ VanPelt, H.M.M.; DeRooij, D.G. (1991). "Spermatogenesis in retinol-deficient rats maintained on retinoic acid". Endocrinology 128 (2): 697–704. doi:10.1530/jrf.0.0940327. PMID 1593535.