Chemistry:Retinoid

From HandWiki

The retinoids are a class of chemical compounds consisting of vitamin A and related derivatives.[1][2] Synthetic retinoids are utilized in cosmetic formulations, clinical dermatology, and the treatment of some forms of cancer.[3]

Retinoids have many important functions throughout the body, including in vision,[4] regulation of skin proliferation and differentiation, growth of bone tissue, immune function,[5] and male fertility.[6]

The biology of retinoids is complex, having well-documented effectiveness in the management of conditions ranging from acute promyelocytic leukemia to acne to photoaging.[7] On the other hand, retinoids may be involved in metabolic dysfunction and, at least in some forms, carcinogenesis.[8][9]

Types

Retinoids are divided into four generations based on their molecular structure and receptor selectivity.[10]

Generation Description Compounds
First generation Isomers and naturally occurring compounds retinol, retinal, tretinoin (retinoic acid), isotretinoin, and alitretinoin
Second generation Synthetic analogs formulated for oral dosing. There are no topically available second generation formulations of retinoids. etretinate and its metabolite acitretin
Third generation Retinoidal benzoic acid derivatives adapalene, oleyl adapalenate, bexarotene, and tazarotene
Fourth generation Topical 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.[citation needed]

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.[11] 13-cis retinoic acid has an unknown biological pathway but appears to act as a growth factor.[12]

Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.[13][failed verification]

Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of isotretinoin,[14] bexarotene binding only the retinoid X receptors, and tazarotene binding the retinoic acid receptor beta and retinoic acid receptor gamma forms.[15]

The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.[16]

Pharmacokinetics

The major source of retinoids in human diet are plant pigments such as carotenes and retinyl esters derived from animal sources.[17] 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.[18] Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised.[14]

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.[19] First generation retinoids are rapidly metabolized by Cytochrome p450 enzymes, typically of the Cyp26 family.[20]

Uses

Common skin conditions treated by topical retinoids include acne, psoriasis,[21][22] and effects of photoaging.[23][24] In addition, retinoids are used to treat some rare skin disorders, including discoid lupus[25] and mycosis fungoides.[26] In Japan, isotretinoin may be used for neuroblastoma treatment,[27] but it is not approved in other countries due to a lack of consistency in studies of its effectiveness.[28] Oral retinoids are readily toxic, requiring consistent clinical oversight, and are approved in several diseases for which said toxicity is paradoxically useful, including acute promyelocytic leukemia, cutaneous T-cell lymphoma, and heterotopic ossification.[29]

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.[30]

Retinoids provoke rapid elevation of circulating triglycerides leading to hypertriglyceridemia as well as cholesterol, leading to hypercholesterolemia.[31] 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 in smokers and asbestos workers.[32][33] In addition to the harmful effects shared by other retinoids, bexarotene causes severe hypothyroidism.[34]

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.[35][36] The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy.[37]

Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women.[38][39] 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.[40]

See also

References

  1. ↑ "Neurological Complications of Chemotherapy and Radiation Therapy" (in en-US), Neurology and General Medicine (Churchill Livingstone): pp. 523–545, 2008-01-01, https://www.sciencedirect.com/science/chapter/edited-volume/abs/pii/B9780443067075500316, retrieved 2026-03-02 
  2. ↑ Zasada, Malwina; Budzisz, Elżbieta (2019-08-30). "Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments". Postepy Dermatologii I Alergologii 36 (4): 392–397. doi:10.5114/ada.2019.87443. ISSN 1642-395X. PMID 31616211. PMC 6791161. https://pmc.ncbi.nlm.nih.gov/articles/PMC6791161/. 
  3. ↑ Motamedi, Melika; Chehade, Ahmad; Sanghera, Ravina; Grewal, Parbeer (2022). "A Clinician's Guide to Topical Retinoids". Journal of Cutaneous Medicine and Surgery 26 (1): 71–78. doi:10.1177/12034754211035091. ISSN 1203-4754. PMID 34292058. 
  4. ↑ "Chemistry of the retinoid (visual) cycle". Chemical Reviews 114 (1): 194–232. January 2014. doi:10.1021/cr400107q. PMID 23905688. open access
  5. ↑ "The role of retinoic acid in tolerance and immunity". Immunity 35 (1): 13–22. July 2011. doi:10.1016/j.immuni.2011.07.002. PMID 21777796. 
  6. ↑ "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology 13. 2022-04-28. doi:10.3389/fendo.2022.871225. PMID 35574006. 
  7. ↑ Nagai, Yuya; Ambinder, Alexander J. (Jul 8, 2023). "The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out nor Fading Away". Cancers 15 (14): 3535. doi:10.3390/cancers15143535. ISSN 2072-6694. PMID 37509198. 
  8. ↑ "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine 221 (9). September 2024. doi:10.1084/jem.20240519. PMID 39133222. 
  9. ↑ "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. December 2004. doi:10.1093/jnci/djh320. PMID 15572756. 
  10. ↑ "A Clinician's Guide to Topical Retinoids". Journal of Cutaneous Medicine and Surgery (SAGE Publications) 26 (1): 71–78. 2021-07-22. doi:10.1177/12034754211035091. PMID 34292058. 
  11. ↑ "Retinoic acid synthesis and signaling during early organogenesis". Cell 134 (6): 921–931. September 2008. doi:10.1016/j.cell.2008.09.002. PMID 18805086. 
  12. ↑ "Adverse effects of isotretinoin: A large, retrospective review". Dermatologic Therapy 30 (4). July 2017. doi:10.1111/dth.12483. PMID 28295859. 
  13. ↑ "Soriatane (Acitretin): Side Effects, Uses, Dosage, Interactions, Warnings". 2013-12-02. http://www.rxlist.com/soriatane-drug.htm. 
  14. ↑ 14.0 14.1 "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging 1 (4): 327–348. 2006. doi:10.2147/ciia.2006.1.4.327. PMID 18046911. 
  15. ↑ "Molecular mechanisms of tazarotene action in psoriasis". Journal of the American Academy of Dermatology 37 (2): S18–S24. August 1997. doi:10.1016/s0190-9622(97)80396-9. ISSN 0190-9622. https://linkinghub.elsevier.com/retrieve/pii/S0190962297803969. 
  16. ↑ "Drug Approval Package: Aklief". October 21, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000TOC.cfm. 
  17. ↑ "The role of retinoic acid in tolerance and immunity". Immunity 35 (1): 13–22. July 2011. doi:10.1016/j.immuni.2011.07.002. PMID 21777796. 
  18. ↑ "Carotenoid and retinoid metabolism: insights from isotope studies". Archives of Biochemistry and Biophysics. Highlight issue on Carotenoids 430 (1): 110–119. October 2004. doi:10.1016/j.abb.2004.04.028. PMID 15325918. 
  19. ↑ "Carotenoid and retinoid metabolism: insights from isotope studies". Archives of Biochemistry and Biophysics. Highlight issue on Carotenoids 430 (1): 110–119. October 2004. doi:10.1016/j.abb.2004.04.028. PMID 15325918. 
  20. ↑ "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine 221 (9). September 2024. doi:10.1084/jem.20240519. PMID 39133222. 
  21. ↑ "Systemic medications: Soriatane (acitretin)". National Psoriasis Foundation. http://www.psoriasis.org/netcommunity/sublearn03_severe_acitretin. 
  22. ↑ "Psoriasis - Diagnosis and treatment". Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/psoriasis/basics/treatment/con-20030838. 
  23. ↑ "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging 1 (4): 327–348. 2006. doi:10.2147/ciia.2006.1.4.327. PMID 18046911. 
  24. ↑ "Improvement of naturally aged skin with vitamin A (retinol)". Archives of Dermatology 143 (5): 606–612. May 2007. doi:10.1001/archderm.143.5.606. PMID 17515510. 
  25. ↑ "Acitretin treatment in antimalarial-refractory/intolerant discoid lupus erythematosus: A prospective, open-label, uncontrolled study". Lupus 31 (5): 575–581. April 2022. doi:10.1177/09612033221086878. PMID 35306922. 
  26. ↑ "The utility of bexarotene in mycosis fungoides and Sézary syndrome". OncoTargets and Therapy 8: 367–373. 2015-02-03. doi:10.2147/OTT.S61308. PMID 25678803. 
  27. ↑ "Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects". Cancers 16 (3): 544. January 2024. doi:10.3390/cancers16030544. PMID 38339295. 
  28. ↑ "Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects". Cancers 16 (3): 544. January 2024. doi:10.3390/cancers16030544. PMID 38339295. 
  29. ↑ "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine 221 (9). September 2024. doi:10.1084/jem.20240519. PMID 39133222. 
  30. ↑ "Vitamin A Toxicity". StatPearls. Treasure Island (FL): StatPearls. 2024. https://www.ncbi.nlm.nih.gov/books/NBK532916/. Retrieved 2024-08-15. 
  31. ↑ "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine 221 (9). September 2024. doi:10.1084/jem.20240519. PMID 39133222. 
  32. ↑ "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. December 2004. doi:10.1093/jnci/djh320. PMID 15572756. 
  33. ↑ "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. April 1994. doi:10.1056/NEJM199404143301501. PMID 8127329. 
  34. ↑ "Etiology, diagnosis, and treatment recommendations for central hypothyroidism associated with bexarotene therapy for cutaneous T-cell lymphoma". Clinical Lymphoma 3 (4): 249–252. March 2003. doi:10.3816/CLM.2003.n.006. PMID 12672276. 
  35. ↑ "PRAC recommends updating measures for pregnancy prevention during retinoid use". European Medicines Agency. https://www.ema.europa.eu/en/documents/referral/retinoid-article-31-referral-prac-recommends-updating-measures-pregnancy-prevention-during-retinoid_en.pdf. 
  36. ↑ "PRAC Seeks New Pregnancy Prevention Measures For Retinoids". Medscape. https://www.medscape.com/viewarticle/892514. 
  37. ↑ Medicines and Healthcare products Regulatory Agency. "Oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women". https://www.gov.uk/drug-safety-update/oral-retinoid-medicines-revised-and-simplified-pregnancy-prevention-educational-materials-for-healthcare-professionals-and-women. 
  38. ↑ "Skincare Ingredients To Avoid During Pregnancy (+ List Of Harmful Chemicals In Beauty Products)". Little Baby Gear. 20 December 2022. https://www.littlebabygear.com/skincare-ingredients-avoid-pregnancy/. 
  39. ↑ "Is Vitamin A, Retinyl Palmitate and Retinol Safe for Pregnant Women?". Metrin Skincare. 26 May 2022. https://www.metrin.com/blog-is-vitamin-a-retinyl-palmitate-and-retinol-safe-for-pregnant-women/. 
  40. ↑ "Pregnancy-Safe Skin Care Guide: Ingredients to Avoid". What To Expect. https://www.whattoexpect.com/pregnancy/looking-good/everything-need-know-pregnancy-proof-beauty-routine/. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Retinoid&oldid=4358312"