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HomeProduct name listRetinoic acid

Retinoic acid

Synonym(s):Tretinoin;Retinoic acid;ATRA;Vitamin A acid;Tretinoin, ATRA, Vitamin A Acid

  • CAS NO.:302-79-4
  • Empirical Formula: C20H28O2
  • Molecular Weight: 300.44
  • MDL number: MFCD00001551
  • EINECS: 206-129-0
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-19 15:53:33
Retinoic acid Structural

What is Retinoic acid?

Absorption

Tretinoin applied topically is expected to remain on the stratum corneum and undergo minimal systemic absorption. In one study, the topical application of radiolabelled tretinoin for 28 days was associated with a total percutaneous absorption of 2%.
The extent of absorption was examined after a once-daily application of 1.9 g of the combination product with benzoyl peroxide for 14 days. On Day 14, at steady-state, the mean Cmax was 0.15-0.19 ng/mL for tretinoin, 0.27-0.34 ng/mL for the metabolite 4-keto 13-cis retinoic acid, and 0.13-0.28 ng/mL for 13-cis retinoic acid, respectively. The Cmax varied across different age groups (children, adolescents, and adults). The corresponding ranges for the mean AUC0-24 were 0.63-2.06, 2.39-2.89, and 0.96-1.99 ng*h/mL.
Following oral administration, the absolute bioavailability of tretinoin was approximately 50%. While the effect of food on tretinoin is unclear, food increases the oral absorption of retinoids, as a class. When the oral dose of 22.5 mg/m2 tretinoin was administered twice daily, the mean ± SD Cmax was 394 ± 89 ng/mL after the first dose and 138 ± 139 ng/mL after one week of continuous treatment. The area under the curve (AUC) was 537 ± 191 ng·h/mL after the first dose and 249 ± 185 ng·h/mL after one week of continuous treatment. The Tmax was between one and two hours.

Toxicity

The oral LD50 in rats is 2000 mg/kg. The dermal LD50 in rabbits is >2500 mg/kg.
Reversible signs of hypervitaminosis A, such as headache, nausea, vomiting, and mucocutaneous symptoms, are expected to appear in tretinoin overdose. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia: these symptoms have quickly resolved without apparent residual effects. here is no specific treatment in the case of an overdose and it is advised to treat patients experiencing tretinoin overdose in a special hematological unit.

Description

all-trans Retinoic acid is a metabolite of vitamin A and a ligand for retinoic acid receptors (RARs) with IC50 values of 9, 3, and 10 nM for RARα, RARβ, and RARγ, respectively, in radioligand binding assays. It induces expression of a luciferase reporter in COS-7 cells expressing RARα, RARβ, or RARγ (EC50s = 169, 9, and 2 nM, respectively). all-trans Retinoic acid (17 nmol) reduces papilloma formation induced by phorbol 12-myristate 13-acetate (TPA; ) in mice. It reduces bile duct proliferation, hydroxyproline levels, and liver inflammation in a rat model of α-naphthylisothiocyanate-induced chronic cholestasis and reduces plasma levels of alkaline phosphatase and bile salts in the Mdr2-/- mouse model of cholestasis. all-trans Retinoic acid also reduces hepatic fat accumulation, triglycerides, body weight, and serum glucose levels in mice with Western diet-induced obesity.

Description

Vitamin A, or retinol, is produced from carotenoids in the livers of animals. It is also broadly defined as a series of compounds that have structures similar to retinol. It is essential for growth and development, and for strong vision. Retinoic acid is a metabolite of vitamin A that mediates the vitamin’s functions.
Recently, H. Veiga-Fernandes and co-workers at the Institute of Molecular Medicine (Lisbon) discovered that vitamin A is not only necessary for animals’ health, but?it also may be essential for setting up the immune system before birth, when fetuses are in utero. They found that pregnant mice with vitamin A–poor diets produce babies with small lymph nodes and consequently weak immune systems. Retinoic acid produced from the mother’s vitamin A activates a gene that produces a hormone receptor that mediates the growth of lymphoid cells.

Chemical properties

Yellow-Orange Powder

Originator

Aberel,McNeil,US,1973

The Uses of Retinoic acid

Physiological metabolite of vitamin A. Effects gene expression via nuclear retinoic acid receptors (RAR); mediates cellular growth and differentiation

The Uses of Retinoic acid

retinoic acid (tretinoin) is a vitamin A derivative. It has demonstrated an ability to alter collagen synthesis, increase dermal hyaluronic acid levels, and stimulate fibroblast growth and the extracellular matrix. It is used for keratinization disorders and for treating acne. Retinoic acid’s anti-aging effect has been convincingly documented and it is often used for treating the visible signs of aging, though these results can take approximately 6 months to be visible. It is associated with a number of adverse effects, including irritation, photosensitivity, skin dryness, redness, and peeling. It should also not be used while pregnant.

What are the applications of Application

Retinoic Acid, all trans is an oxidized carboxylic acid form of Vitamin A, and an activator of RAR and RXR and used in stem cells

Background

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A (retinol). It is an oxidation product in the physiological pathway of vitamin A metabolism. In human circulation, tretinoin is normally found at very low concentrations, approximately 4 to 14 nmol/L. Tretinoin exhibits anti-inflammatory, antineoplastic, antioxidant, and free radical-scavenging activities. It has been used in dermatology for many years to treat various skin conditions ranging from acne to wrinkles and activates nuclear receptors to regulate epithelial cell growth and differentiation. Tretinoin is given orally to treat acute promyelocytic leukemia and topically to treat skin conditions such as acne.

Indications

Oral tretinoin is indicated for induction of remission in adults and pediatric patients one year of age and older with acute promyelocytic leukemia (APL), characterized by the presence of t(15;17) translocation or presence of PML/RARα gene expression and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.
Topical tretinoin is also indicated alone or in combination with benzoyl peroxide or clindamycin for the treatment of acne vulgaris. It is also used in prescription and over-the-counter for treating various skin conditions such as melasma, hyperpigmentation, and photoaging alone or in combination with other drugs.

Definition

ChEBI: Retinoic acid is a retinoid in which all four exocyclic double bonds have E- (trans-) geometry. It is a naturally occurring derivative of vitamin A (retinol). Retinoids such as tretinoin are important regulators of cell reproduction, proliferation, and differentiation and are used to treat acne and photodamaged skin and to manage keratinization disorders such as ichthyosis and keratosis follicularis.

Indications

Topical tretinoin (Retin-A, Renova, Avita), like isotretinoin, alters keratinization in the acroinfundibulum. In addition, it reverses certain premalignant and other histological changes associated with the photoaging changes that accompany chronic exposure to ultraviolet radiation. Topically applied tretinoin is indicated in comedogenic and papulopustular acne vulgaris, and its mild exfoliative effects make it sometimes useful in molluscum contagiosum, flat warts, and some ichthyotic disorders. It is often prescribed to lessen the clinical signs of photoaging (wrinkling and hyperpigmented macules).

Manufacturing Process

100 parts of beta-ionol are dissolved in 200 parts of dimethylforrnamide and after the addition of 165 parts of triphenylphosphine hydrobromide, stirred for 7 hours at room temperature. Then 70 parts of 4-methyl-1-al-hexadiene- (2,4)-acid-(6) (melting point 177°C, white needles from water) are added to the now clear solution. 150 parts of isopropanol are added and the whole cooled to -30°C. Into this solution, while stirring vigorously, 190 parts by volume of a 30% solution of sodium methylate in methanol are allowed to flow in. A vigorous exothermic reaction takes place and the temperature in the interior of the flask rises to +5°C. It is stirred for another 5 minutes and neutralized with 10% of sulfuric acid (until acid to Congo).
After stirring for 2 hours at room temperature, the mass of vitamin A acid has crystallized out. It is sharply filtered off by suction and washed with a little ice-cold isopropanol. From the filtrate, a further small amount of mainly all trans vitamin A acid crystallizes out upon the addition of water. The filter cake is suspended in 600 parts of water and stirred for 4 hours at room temperature; it is filtered by suction and the product washed with water. It is dried in vacuo at 40° to 50°C and 115 parts of vitamin A acid are obtained. The melting point lies between 146° and 159°C.
The mixture of the all trans and mainly 9,10-cis vitamin A acid may be separated by fractional crystallization from ethanol. All trans vitamin A acid has a melting point of 180° to 182°C and 9,10-cis vitamin A acid, which crystallized in the form of pale yellow fine needles collected into clusters, has a melting point of 189° to 190°C.

brand name

A-acido;Acid a vit;Acnavit;Acnavyse;Acretin;Airoderm;Aknebon;Aknefug;Anition;Antibio-aberel;Apsor;A-vitamisyre;Avitoin;Cordes vas;Dermoclar;Dermojuventas;Derugin;Locacid;Pigmanorm;R0 22-6595;Reiderma;Retin a;Ro 1-5488;Sebo-psor;Stie vaa;Stievaa;Tretin m;Vas dexa;Verra-med;Vitacid a.

Therapeutic Function

Keratolytic

World Health Organization (WHO)

Tretinoin, a retinol derivative, was introduced in 1973 exclusively for the topical treatment of severe acne. Preparations of tretinoin are indicated for topical use only since oral administration has been associated with risk of toxicity from hypervitaminosis-A and subsequently of teratogenicity.

General Description

Yellow to light-orange crystalline powder.

General Description

Tretinoin is available in 10-mg capsules for oral administrationin the treatment of APL. The mechanism of action involvespassive diffusion through the cell membrane andthen movement to the nucleus where it interacts with theretinoic acid receptor (RAR) portion of the PML-RAR fusionprotein. Binding of tretinoin allows the cell to differentiateand has also been shown to result in the destruction ofthe PML-RAR fusion protein. Resistance to tretinoin isproblematic and associated with an increase in cellularretinoic acid–binding proteins (CRAPBs) located in the cytosol.The complexation with tretinoin prevents movementinto the nucleus and may present the drug to metabolizingenzymes that inactivate it. Amino acid mutation of thePML-RAR protein has also been established as a mechanismof resistance. The agent is well absorbed upon oral administrationand highly (95%) protein bound. Metabolismoccurs in the liver and several inactive metabolites havebeen identified including 13-cis-retinoic acid, 4-oxo cisretinoic,4-oxo trans-retinoic acid and 4-oxo trans-retinoicacid glucuronide. Elimination occurs in the urine (63%) andfeces (31%) with an elimination half-life of 40 to 120 minutes.Vitamin A toxicity is seen in nearly all patients andpresents as headache, fever, dryness of the skin, skin rash,mucositis, and peripheral edema. APL differentiation syndromesuch as that seen for arsenic trioxide also occurs.Cardiovascular effects include flushing, hypotension, CHF,stroke, and myocardial infarction have been reported butoccur only rarely. There are also several CNS and GI effectsthat have been associated with the agent as well.

Air & Water Reactions

Tretinoin may be sensitive to prolonged exposure to air. Insoluble in water.

Reactivity Profile

Tretinoin may discolor on exposure to light. Tretinoin is extremely sensitive to exposure to light and, therefore, Tretinoin should be fully protected from light during all handling. Solutions are unstable in the presence of strong oxidizers. Tretinoin is incompatible with strong oxidizing agents. .

Fire Hazard

Flash point data for Tretinoin are not available; however, Tretinoin is probably combustible.

Biological Activity

Endogenous agonist for retinoic acid receptors. Also positively modulates PPAR δ receptors (K d = 17 nM). Promotes differentiation of embryonic stem cells (ESCs) into adipocytes, neurons and glia in vitro .

Biochem/physiol Actions

all?trans?Retinoic acid (ATRA) is a ligand for both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). The bound RAR and RXR act as transcription factors that regulate the growth and differentiation of both normal and malignant cells. Cytochromes P450 (CYPs) catalyze the 4-hydroxylation of ATRA. Retinoic acid primes embryonic stem cells to become neurons.

Pharmacokinetics

Tretinoin is a vitamin A derivative that promotes cell production, proliferation, and differentiation. When used topically, tretinoin regulates epidermal cell turnover and collagen production. It also prevents collagen loss, reduces inflammation, and blocks the induction of matrix metalloproteinase (MMP), which are enzymes that disrupt collagen and elastic fibres. In short-term and long-term studies, topical application of tretinoin at doses ranging from 0.001% to 0.1% was associated with improvements in clinical signs of photoaging and fine wrinkles, increased epidermal thickness, compaction of the stratum corneum, and decreased melanin content. It also improved melanocyte differentiation and distribution, promotion of epidermal hyperplasia, and angiogenesis.
Tretinoin exhibits antineoplastic activities when given orally. Tretinoin was shown to induce differentiation in tumour cells. It induced cytodifferentiation and decreased acute promyelocytic leukemia (APL) cell proliferation in culture and in vivo. In patients with APL, tretinoin promoted the initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission.

Clinical Use

The major toxic effect of tretinoin is erythema and irritation of the skin to which it is applied, especially if the skin is moist.This toxicity often decreases with continued therapy.

Safety Profile

Poison by ingestion, intraperitoneal, subcutaneous, and intravenous routes. Experimental reproductive effects. Questionable carcinogen with experimental neoplastigenic and teratogenic data. Human mutation data reported. A human skin irritant. When heated to decomposition it emits acrid smoke and irritating fumes. Used to treat acne and other skin problems.

Toxicology

Oral retinoic acid has strong teratogenic effects on experimental animals (including mice, rats, hamsters, rabbits, monkeys, etc.) and humans[2]. Topical application of retinoic acid on the skin has clear embryotoxicity and teratogenicity to the mothers of mice, rats, hamsters and rabbits in the embryo sensitive period, and can cause maternal systemic toxicity. However, retrospective data so far have not found teratogenicity after topical administration of human skin. Retinoids are irritating to the skin. The skin reaction of the above-mentioned experimental animals is significantly heavier than the human reaction, which can cause different degrees of skin irritation, inflammation, redness, erosion, weakening of the stratum corneum barrier, increased drug absorption, and systemic toxicity depending on the drug concentration and the number of times of administration. Although external use on human skin is irritating, it does not have the above-mentioned serious reactions. It may be due to differences in skin structure and sensitivity to retinoic acid stimulation between animals and humans. Therefore, the safety data of local administration of retinoic acid in animals and its predictive significance for clinical drug safety should be carefully evaluated.

Veterinary Drugs and Treatments

Topical tretinoin may be useful in treating localized follicular or hyperkeratotic disorders such as acanthosis nigrans, idiopathic nasal and footpad hyperkeratosis, callous pyodermas, or chin acne. Tretinoin’s exact mechanism of action is not well understood, but it stimulates cellular mitotic activity, increases cell turnover, and decreases the cohesiveness of follicular epithelial cells.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: possibly increased risk of benign intracranial hypertension with tetracyclines - avoid.
Antifungals: possible increased risk of tretinoin toxicity with fluconazole, ketoconazole and voriconazole.
Vitamin A: risk of hypervitaminosis - avoid.

Metabolism

Tretinoin is rapidly metabolized to form various oxidized and conjugated metabolites. It forms several metabolites stereoisomerization derivatives (9-cis-retinoic acid or alitretinoin and 13-cis-retinoic acid or isotretinoin), oxidation derivatives (4-hydroxy-retinoic acid, 4-oxo-retinoic acid, 18-hydroxy-retinoic acid, 5,6-epoxy-retinoic acid, 3,4-didehydro-retinoic acid and retinotaurine), stereoisomerization and oxidation derivatives (13-cis-4-oxo-retinoic acid), glucuronidation derivatives (retinoyl beta-glucuronide, 13-cis-retinoyl beta-glucuronide, 4-oxo-retinoyl beta-glucuronide, 5,6-epoxyretinoyl beta-glucuronide and 13-cis-4-oxo-retinoyl beta-glucuronide), nonpolar metabolites of retinoic acid, and retinoic acid esters.
Tretinoin is metabolized by several CYP enzymes, including CYP3A4, CYP2C8, and CYP2E. It also undergoes glucuronidation by UGT2B7. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. When the plasma concentrations decreased to one-third of their day-one concentrations after one week of continuous therapy, tretinoin induced its own metabolism.

Metabolism

Metabolised in the liver by the cytochrome P450 isoenzyme system to form isotretinoin, 4-oxo-transretinoic acid, and 4-oxo-cis-retinoic acid.
Tretinoin is excreted in the bile and the urine.

storage

Store at -20°C

Purification Methods

Purify the acid by chromatography on silicic acid columns, and eluting it with a small amount of EtOH in hexane. Also dissolve it in Et2O, wash it with H2O, dry (Na2SO4), evaporate and the solid residue is recrystallised from MeOH (0.53g /3.5mL MeOH to give 0.14g) or EtOH. It also recrystallises from i-PrOH, or as the methyl ester from MeOH. UV in MeOH has max at 351nm ( 45,000). 9-Cis-acid forms yellow needles from EtOH, with m 189-190o, and its UV in MeOH has max at 343nm ( 36,500); the 13-cis-acid forms red-orange plates from i-PrOH with m 174-175o, and UV has max at 345nm ( 39,800). Store it in the dark, in an inert atmosphere, at 0o [Robeson et al. J Am Chem Soc 77 4111 1955]. [Beilstein 9 IV 2387.]

References

1) Allenby (1993), Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acid; Proc. Natl. Acad. Sci. USA, 90 30 2) Dani et . (1997) Differentiation of embryonic stem cells into adipocytes in vitro; J. Cell Sci. 110 1279 3) Hu (2009) Differentiation Of Spinal Motor Neurons From Pluripotent Human Stem Cells; Nat. Protoc., 4 1295 4) Sasai (2002) Generation of dopaminergic neurons from embryonic stem cells J. Neurol., 249 II 41

Properties of Retinoic acid

Melting point: 180-181 °C (lit.)
Boiling point: 381.66°C (rough estimate)
Density  1.0597 (rough estimate)
refractive index  1.4800 (estimate)
storage temp.  -20°C
solubility  Practically insoluble in water, soluble in methylene chloride, slightly soluble in ethanol (96 per cent).
form  powder
pka 4.73±0.33(Predicted)
color  yellow
Water Solubility  insoluble
Sensitive  Light Sensitive
Merck  14,8165
BRN  2057223
Stability: Store Dry in Freezer at -20°C for up to 1 year; in Solution at -20°C for up to 3 Months.
CAS DataBase Reference 302-79-4(CAS DataBase Reference)
EPA Substance Registry System Retinoic acid (302-79-4)

Safety information for Retinoic acid

Signal word Danger
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
ghs
Health Hazard
GHS08
ghs
Environment
GHS09
GHS Hazard Statements H302:Acute toxicity,oral
H315:Skin corrosion/irritation
H410:Hazardous to the aquatic environment, long-term hazard
Precautionary Statement Codes P202:Do not handle until all safety precautions have been read and understood.
P264:Wash hands thoroughly after handling.
P264:Wash skin thouroughly after handling.
P273:Avoid release to the environment.
P301+P312:IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P302+P352:IF ON SKIN: wash with plenty of soap and water.
P308+P313:IF exposed or concerned: Get medical advice/attention.

Computed Descriptors for Retinoic acid

InChIKey SHGAZHPCJJPHSC-ZVCIMWCZSA-N

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