Introduction:
Retinoic acid belongs to retinoids, and the term retinoid refers to the synthetic and natural analogs of vitamin A. Retinoids are derived from vitamin A or structure, and function similarly to vitamin A. Retinoids are compounds that bind to and activate the relevant nuclear receptors and generate a transcription of appropriate genes either directly or after metabolic transformation. Retinoids are used in cosmetics being a concentrated dermatological agent used in psoriasis, acne, as well as other skin diseases. These are the compounds of both natural and biologically active forms of vitamin A (retinol, retinal and retinoic acid) as well as synthetic analogs of retinol. Retinoic acid has the same biological characteristics as vitamin A.
Retinol does not put out a considerable biological effect on tissues but evolves after modification into more active metabolites. The most significant one is retinoic acid, depicted by its multilateral action. Retinoic acid is present in the form of two isomers, the fully-trans form, and the 9-cis form. This affects the multiplication and differentiation of cells by controlling the respective genes. Retinoids are implicated in various biological actions, including cellular cohesion, cellular growth, immunomodulatory effects, and antitumor functions.
How Does Retinoic Acid Work?
Retinoids such as vitamin A and its derivatives are involved in embryogenesis. They play a role in the development of the liver, nervous system, heart, kidneys, eyes, intestine, and limbs. The conversion of retinol to its active form, retinoic acid, happens in the target organ through the two-step oxidation process. Retinol dehydrogenase (RDH) or alcohol dehydrogenase (ADH), after entering the cell, catalyze the oxidation of retinol to the retinal. The reaction can be reversed by the same enzyme as the oxidation of retinol to retinoic aldehyde is a reversible process.
Moreover, many enzymes can catalyze the reverse reaction, that is, the conversion from retinamide to retinol. This suggests the presence of a different mechanism that controls the local retinol concentration in the tissues. Thereafter, retinol is oxidized to retinoid acid by retinaldehyde dehydrogenase (RALDH) or some enzymes of the cytochrome P450 family. This reaction is irreversible. The outcome formed is a natural ligand of nuclear receptors and it reflects the activity of vitamin A. Also, the oxidation of the retinoic acid by the CYP26 enzyme results in receiving of inactive vitamin A metabolites.
How Is Retinoic Acid Formed?
Vitamin A is derived from food and cannot be made in the body. It is specified and stored in the liver. Retinoic acid is synthesized from retinol by two enzymatic reactions. The first of them is a reversible oxidation of retinol to the retinal. The next is followed by a second and irreversible oxidation reaction to retinoic acid.
Retinoic acid is a light-sensitive compound due to the alternating double bonds between the carbon atoms in its hydrophobic tail, which is attached to a 6-carbon ring. The low molecular weight of the compound also makes it highly fat-soluble, which means it readily diffuses across cell membranes.
What Are the Functions of Retinoic Acid?
The functions of retinoic acid are:
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Reduces Sebum and Inflammation - Retinoic acid (all-trans retinoic acid, tretinoin)- accelerates the elimination of sebum remaining in ducts, stimulates the process of epidermal cell proliferation, thus reducing inflammation in sebaceous glands; loosens connections among cells in stratum corneum and inhibits keratosis. It can be used for psoriasis, acne, and chronic inflammation of hair follicles and sebaceous glands.
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Anti- Acne Therapy - Tretinoin (all-trans-retinoic acid) is a considerably bioactive form among retinoids used topically on the skin. It causes the dispersion of melanin granules and increases epidermal cellular turnover. Generally used tretinoin concentration in anti-acne therapy varies from 0.01 to 0.4 percent. It is available in the form of gel or cream and is applied topically. Retinoic acid can be present in different formulas- cream (0.025, 0.05, and 0.1 percent), gel (0.01 and 0.25 percent), new technology microspheres (0.04 and 0.1 percent), emollient (0.05 percent), and solution (0.05 percent). Retinoic acid firmly affects epithelial differentiation and proliferation. In vitro cultivated keratinocytes in media with retinoic acid deficiency have reduced motility. They do not form distinct patterns and have increased adhesiveness.
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Regulation of Keratin Production - The production of keratins is controlled by the concentration of retinoids. In cells cultured without retinoic acid, the production of keratin 1 (67 kiloDalton), which is characteristic of terminally differentiating keratinocytes, is increased whereas the synthesis of keratin 8/18 (52 kiloDalton) and keratin 19 (40 kiloDalton) is decreased. Supplementation of retinoids in cultured human epidermal keratinocytes results in increased expression of keratin 7, keratin 13, keratin 15, and keratin 19 and the reduced expression of keratin 1, keratin 5, keratin 6, keratin 10, and keratin 14. Most of the affected genes are involved in the regulation of the cell cycle, DNA synthesis and repair, translation, transcription factors, adhesion, RNA metabolism, receptor expression, apoptosis, membrane proteins, and protein kinase. Retinoic acid controls its own bioavailability. Retinoic acid also proved to be essential in preadipocyte differentiation in adipose tissues.
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Treatment of Basal Cell Carcinoma - Regression of basaliomatous cells associated with reduced proliferation and increased apoptosis occurs in basal cell carcinoma. Unresponsive tumors after administration of retinoic acid show keratotic differentiation. Keratotic BBCs display overexpression of retinol-binding protein-1 (RBP-1) and p53 compared to undifferentiated tumors.
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Regulating Cell Growth and Differentiation - Retinoic acid helps to control the growth and differentiation of cells, particularly in developing embryos. It is involved in the formation of organs, limbs, and the central nervous system.
Conclusion
Treatment with retinoic acid derivatives is very effective in basal cell carcinomas. Tazarotene is effective in treating basal cell carcinoma. Retinoic acid is an active form of retinoids and vitamin A. It can be used in the treatment of various skin diseases such as acne and psoriasis. However, retinoid acid therapy cannot be used in pregnancy as it can have negative effects on the fittest development. Also, usage of retinoic acid leads to a buildup of tolerance and the development of adverse effects such as rash, erythema, scaling, dryness, and desquamation which in turn leads to epidermal barrier dysfunction.
