Retinoic acid
Encyclopedia
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. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.
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.
(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. Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid.
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.
and cytochrome P450(cyp26).
(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.
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
(retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
) that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate
Chordate
Chordates are animals which are either vertebrates or one of several closely related invertebrates. They are united by having, for at least some period of their life cycle, a notochord, a hollow dorsal nerve cord, pharyngeal slits, an endostyle, and a post-anal tail...
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. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.
The key role of retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
used for treatment of cancer and acne
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
. 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 receptorRetinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
(RAR) which is bound to DNA as a heterodimer with the retinoid X receptor
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
(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. Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid.
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.
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. Enzymes that metabolize excess retinol to prevent toxicity include alcohol dehydrogenaseAlcohol dehydrogenase
Alcohol dehydrogenases are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide...
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 retinalRetinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
(retinaldehyde), and cell metabolism effects that may require retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
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
Xerophthalmia
Xerophthalmia is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes....
-- dryness of the cornea). They do suffer retina degeneration and blindness, due to retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
(retinaldehyde) deficiency. They also suffer defects in reproduction: vitamin A-deprived but retinoic acid-supplemented male rats exhibit hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
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.
Related pharmaceuticals
- TretinoinTretinoinTretinoin is the acid form of vitamin A and is also known as all-trans retinoic acid or ATRA. It is a drug commonly used to treat acne vulgaris and keratosis pilaris. It is available as a cream or gel...
(Tradename: Retin-A) - IsotretinoinIsotretinoinIsotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
(Tradename: Accutane(US), Roaccutane)