Retinoid

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1st, 2nd, 3rd-generation retinoid compounds. Retinoids skeletal formulae.svg
1st, 2nd, 3rd-generation retinoid compounds.

The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are used in medicine where they regulate skin health, immunity and bone disorders.

Contents

Retinoids have many important functions throughout the body, including roles in vision, [1] regulation of skin proliferation and differentiation, growth of bone tissue, immune function, [2] and male fertility. [3]

The biology of retinoids is complex and their use in medicine has well-known benefits in diseases like acute promyelocytic leukemia (APL) or acne. On the other hand, retinoids are known to have many harmful effects on metabolism [4] and cancer. [5]

Types

Retinoids are divided into four generations based on their molecular structure and receptor selectivity. [6]

GenerationDescriptionCompounds
First generationIsomers and naturally occurring compounds retinol, retinal, tretinoin (retinoic acid), isotretinoin, and alitretinoin
Second generationSynthetic analogs formulated for oral dosing. There are no topically available second generation formulations of retinoids. etretinate and its metabolite acitretin
Third generationRetinoidal benzoic acid derivatives adapalene, bexarotene, and tazarotene
Fourth generationTopical retinoid with selectivity towards the RAR receptor located in the epidermis. Trifarotene, seletinoid G

Structure

The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, a polyene side chain and a polar end group. The conjugated system formed by alternating C=C double bonds in the polyene side chain are responsible for the color of retinoids (typically yellow, orange, or red). Hence, many retinoids are chromophores. Alternation of side chains and end groups creates the various classes of retinoids.

First generation retinoids are produced naturally in the body and interact with their normal biological counterparts, such as retinol binding protein 4 for retinol, retinoid receptors for all-trans-retinoic acid or 9-cis-retinoic acid. [7] 13-cis retinoic acid has an unknown biological pathway but appears to act as a growth factor. [8]

Second generation retinoids have a mixed effect and interact mainly with signaling in the skin. [9] [ failed verification ]

Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of isotretinoin, [10] bexarotene binding only the Retinoid X receptors, and tazarotene binding the Retinoic acid receptor beta and Retinoic acid receptor gamma forms. [11]

The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019. [12]

Pharmacokinetics

The major source of retinoids in human diet are plant pigments such as carotenes and retinyl esters derived from animal sources. [13] Retinyl esters are transported through the chylomicron pathway to the liver or fat tissue while retinol or carotenes are transported from the enterocytes to the liver and are processed into retinyl esters by LRAT for storage. [14] Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised. [10]

All classes of retinoid bind to many proteins. Natural retinoids such as retinol and retinyl esters bind to carrier proteins such as RBP4, chylomicrons and VLDL while synthetic retinoids likely bind to these and other proteins. [15] First generation retinoids are rapidly metabolized by Cytochrome p450 enzymes, typically of the Cyp26 family. [16] Later generation retinoids are resistant to Cyp26 metabolism and remain in the body for much longer.

Uses

Common skin conditions treated by topical retinoids include acne and psoriasis. [17] [18] photoaging, [19] and skin wrinkles. [20] In addition, retinoids are used to treat rare skin disorders including discoid lupus [21] and mycosis fungoides. [22] In Japan, isotretinoin may be used for neuroblastoma treatment [23] although it is not approved in other countries due to a lack of consistency in the demonstrated effects. [24] Oral retinoids show considerable toxicity if they interact with retinoid receptors and thus are only approved in several severe diseases including acute promyelocytic leukemia, cutaneous T-cell lymphoma and heterotopic ossification. [25]

Toxicity

Toxic effects of retinoids occur with both acute or prolonged intake, depending on which retinoid is considered. The specific toxicity is related to the mechanism of action as well as exposure. A medical sign of chronic or acute poisoning with retinol is hypervitaminosis A, which includes the presence of painful tender swellings on the long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding, general malaise, pseudotumor cerebri, and death may also occur. [26] Similar effects occur with other retinoids, except for 13-cis retinoic acid and its derivatives, such as adapalene.

Retinoids provoke rapid elevation of circulating triglycerides leading to hypertriglyceridemia as well as cholesterol, leading to hypercholesterolemia. [27] Retinoids are further shown to worsen many metabolic diseases, such as diabetes and congestive heart failure. Large-scale randomized, controlled clinical trials have conclusively shown that vitamin A, retinol and other retinoids increase mortality and cancer rates. [28] [29] In addition to the harmful effects shared by other retinoids, bexarotene causes severe hypothyroidism. [30]

The Pharmacovigilance Risk Assessment Committee (PRAC), based on its review, confirmed that taking oral retinoids during pregnancy can have harmful effects on the baby as they may cause CNS, cranio-facial, cardiovascular and other defects. [31] [32] The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy. [33] The use of topical retinoids should also be excluded during pregnancy and in women planning pregnancy.

Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women. [34] [35] The Association of the American Academy of Dermatology (AAD) recommends that pregnant women consult a health care provider before trying any lotions or oils for stretch mark prevention. [36]

See also

Related Research Articles

<span class="mw-page-title-main">Carotene</span> Class of compounds

The term carotene (also carotin, from the Latin carota, "carrot") is used for many related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but in general cannot be made by animals (with the exception of some aphids and spider mites which acquired the synthesizing genes from fungi). Carotenes are photosynthetic pigments important for photosynthesis.

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most notably β-carotene (beta-carotene). Vitamin A has multiple functions: growth during embryo development, maintaining the immune system, and healthy vision. For aiding vision specifically, it combines with the protein opsin to form rhodopsin, the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Retinol</span> Chemical compound

Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.

<span class="mw-page-title-main">Isotretinoin</span> Medication primarily used to treat severe acne

Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderate acne that is unresponsive to antibiotics. Isotretinoin is used off-label to treat basal cell carcinoma and squamous cell carcinoma, although clinical evidence suggests it is not effective in this setting. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.

β-Carotene Red-orange pigment of the terpenoids class

β-Carotene (beta-carotene) is an organic, strongly colored red-orange pigment abundant in fungi, plants, and fruits. It is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 carbons.

<span class="mw-page-title-main">Tretinoin</span> Medication

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present and is taken by mouth for up to three months. Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.

<span class="mw-page-title-main">Retinal</span> Vitamin A aldehyde, a polyene chromophore

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Retinyl palmitate</span> Vitamin A chemical compound

Retinyl palmitate, or vitamin A palmitate, is the ester of retinol (vitamin A) and palmitic acid, with formula C36H60O2. It is the most abundant form of vitamin A storage in animals.

<span class="mw-page-title-main">Hypervitaminosis A</span> Toxic effects of ingesting too much vitamin A

Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A. Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans, and the problem has persisted throughout human history. Toxicity results from ingesting too much preformed vitamin A from foods, supplements, or prescription medications and can be prevented by ingesting no more than the recommended daily amount.

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

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. 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. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function. and male fertility. Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist. Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.

<span class="mw-page-title-main">Alitretinoin</span> Chemical compound

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

<span class="mw-page-title-main">Vitamin A deficiency</span> Disease resulting from low Vitamin A concentrations in the body

Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries. Nyctalopia is one of the first signs of VAD, as the vitamin has a major role in phototransduction; but it is also the first symptom that is reversed when vitamin A is consumed again. Xerophthalmia, keratomalacia, and complete blindness can follow if the deficiency is more severe.

<span class="mw-page-title-main">Lipocalin</span>

The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids, and most lipocalins are also able to bind to complexed iron as well as heme. They share limited regions of sequence homology and a common tertiary structure architecture. This is an eight stranded antiparallel beta barrel with a repeated + 1 topology enclosing an internal ligand binding site.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">CRABP2</span> Protein-coding gene in the species Homo sapiens

Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene.

Vitamins occur in a variety of related forms known as vitamers. A vitamer of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.

<span class="mw-page-title-main">ALDH1A2</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.

<span class="mw-page-title-main">RARRES1</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor responder protein 1 is a protein that in humans is encoded by the RARRES1 gene.

<span class="mw-page-title-main">Retinol-binding protein</span> Family of proteins that bind retinol

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.

References

  1. ↑ Kiser PD, Golczak M, Palczewski K (January 2014). "Chemistry of the retinoid (visual) cycle". Chemical Reviews. 114 (1): 194–232. doi:10.1021/cr400107q. PMC   3858459 . PMID   23905688. Open Access logo PLoS transparent.svg
  2. ↑ 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. ↑ 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.
  4. ↑ 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): e20240519. doi: 10.1084/jem.20240519 . PMC   11318670 . PMID   39133222.
  5. ↑ Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, et al. (December 2004). "The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements". Journal of the National Cancer Institute. 96 (23): 1743–1750. doi:10.1093/jnci/djh320. PMID   15572756.
  6. ↑ Motamedi M, Chehade A, Sanghera R, Grewal P (2021-07-22). "A Clinician's Guide to Topical Retinoids". Journal of Cutaneous Medicine and Surgery. 26 (1). SAGE Publications: 71–78. doi:10.1177/12034754211035091. PMC   8750127 . PMID   34292058.
  7. ↑ 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.
  8. ↑ Brzezinski P, Borowska K, Chiriac A, Smigielski J (July 2017). "Adverse effects of isotretinoin: A large, retrospective review". Dermatologic Therapy. 30 (4): e12483. doi: 10.1111/dth.12483 . PMID   28295859.
  9. ↑ "Soriatane (Acitretin): Side Effects, Uses, Dosage, Interactions, Warnings". RxList. 2013-12-02. Archived from the original on 2013-12-02. Retrieved 2024-08-30.
  10. 1 2 Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (2006). "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging. 1 (4): 327–348. doi: 10.2147/ciia.2006.1.4.327 . PMC   2699641 . PMID   18046911.
  11. ↑ Duvic M, Nagpal S, Asano AT, Chandraratna RA (August 1997). "Molecular mechanisms of tazarotene action in psoriasis". Journal of the American Academy of Dermatology. 37 (2): S18–S24. doi:10.1016/s0190-9622(97)80396-9. ISSN   0190-9622.
  12. ↑ "Drug Approval Package: Aklief". US Food and Drug Administration. October 21, 2019. Archived from the original on 19 November 2019. Retrieved 31 December 2021.
  13. ↑ 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.
  14. ↑ Burri BJ, Clifford AJ (October 2004). "Carotenoid and retinoid metabolism: insights from isotope studies". Archives of Biochemistry and Biophysics. Highlight issue on Carotenoids. 430 (1): 110–119. doi:10.1016/j.abb.2004.04.028. PMID   15325918.
  15. ↑ Burri BJ, Clifford AJ (October 2004). "Carotenoid and retinoid metabolism: insights from isotope studies". Archives of Biochemistry and Biophysics. Highlight issue on Carotenoids. 430 (1): 110–119. doi:10.1016/j.abb.2004.04.028. PMID   15325918.
  16. ↑ 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.
  17. ↑ "Systemic medications: Soriatane (acitretin)". National Psoriasis Foundation. Archived from the original on 13 June 2010. Retrieved 16 March 2018.
  18. ↑ "Psoriasis - Diagnosis and treatment". Mayo Clinic. Archived from the original on 7 May 2017. Retrieved 16 March 2018.
  19. ↑ Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (2006). "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging. 1 (4): 327–348. doi: 10.2147/ciia.2006.1.4.327 . PMC   2699641 . PMID   18046911.
  20. ↑ Kafi R, Kwak HS, Schumacher WE, Cho S, Hanft VN, Hamilton TA, et al. (May 2007). "Improvement of naturally aged skin with vitamin A (retinol)". Archives of Dermatology. 143 (5): 606–612. doi: 10.1001/archderm.143.5.606 . PMID   17515510.
  21. ↑ Laosakul K, Chiewchanvit S, Chuamanochan M, Tovanabutra N (April 2022). "Acitretin treatment in antimalarial-refractory/intolerant discoid lupus erythematosus: A prospective, open-label, uncontrolled study". Lupus. 31 (5): 575–581. doi:10.1177/09612033221086878. PMID   35306922.
  22. ↑ Panchal MR, Scarisbrick JJ (2015-02-03). "The utility of bexarotene in mycosis fungoides and Sézary syndrome". OncoTargets and Therapy. 8: 367–373. doi: 10.2147/OTT.S61308 . PMC   4322887 . PMID   25678803.
  23. ↑ Makimoto A, Fujisaki H, Matsumoto K, Takahashi Y, Cho Y, Morikawa Y, et al. (January 2024). "Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects". Cancers. 16 (3): 544. doi: 10.3390/cancers16030544 . PMC   10854948 . PMID   38339295.
  24. ↑ Makimoto A, Fujisaki H, Matsumoto K, Takahashi Y, Cho Y, Morikawa Y, et al. (January 2024). "Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects". Cancers. 16 (3): 544. doi: 10.3390/cancers16030544 . PMC   10854948 . PMID   38339295.
  25. ↑ 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.
  26. ↑ Olson JM, Ameer MA, Goyal A (2024). "Vitamin A Toxicity". StatPearls. Treasure Island (FL): StatPearls. PMID   30422511 . Retrieved 2024-08-15.
  27. ↑ 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.
  28. ↑ Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, et al. (December 2004). "The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements". Journal of the National Cancer Institute. 96 (23): 1743–1750. doi:10.1093/jnci/djh320. PMID   15572756.
  29. ↑ Alpha-Tocopherol BC (April 1994). "The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers". The New England Journal of Medicine. 330 (15): 1029–1035. doi:10.1056/NEJM199404143301501. PMID   8127329.
  30. ↑ Sherman SI (March 2003). "Etiology, diagnosis, and treatment recommendations for central hypothyroidism associated with bexarotene therapy for cutaneous T-cell lymphoma". Clinical Lymphoma. 3 (4): 249–252. doi:10.3816/CLM.2003.n.006. PMID   12672276.
  31. ↑ "PRAC recommends updating measures for pregnancy prevention during retinoid use" (PDF). European Medicines Agency. Retrieved 2023-10-10.
  32. ↑ "PRAC Seeks New Pregnancy Prevention Measures For Retinoids". Medscape. Retrieved 2023-10-10.
  33. ↑ Medicines and Healthcare products Regulatory Agency. "Oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women". GOV.UK. Retrieved 2023-10-10.
  34. ↑ "Skincare Ingredients To Avoid During Pregnancy (+ List Of Harmful Chemicals In Beauty Products)". Little Baby Gear. 20 December 2022. Retrieved 2023-10-10.
  35. ↑ "Is Vitamin A, Retinyl Palmitate and Retinol Safe for Pregnant Women?". Metrin Skincare. 26 May 2022. Retrieved 2023-10-10.
  36. ↑ "Pregnancy-Safe Skin Care Guide: Ingredients to Avoid". What To Expect. Retrieved 2023-10-10.
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