View source for Retinoid

{{Short description|Group of tetraterpenes}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
[[File:Retinoids skeletal formulae.svg|thumb|upright=1.8|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 utilized in cosmetic formulations, clinical [[dermatology]], and the treatment of some forms of cancer.<ref name="a355">{{cite journal | last1=Motamedi | first1=Melika | last2=Chehade | first2=Ahmad | last3=Sanghera | first3=Ravina | last4=Grewal | first4=Parbeer | title=A Clinician's Guide to Topical Retinoids | journal=Journal of Cutaneous Medicine and Surgery | volume=26 | issue=1 | date=2022 | issn=1203-4754 | pmid=34292058 | pmc=8750127 | doi=10.1177/12034754211035091 | doi-access=free | pages=71–78 }}</ref>

Retinoids have many important functions throughout the body, including in vision,<ref>{{cite journal | vauthors = Kiser PD, Golczak M, Palczewski K | title = Chemistry of the retinoid (visual) cycle | journal = Chemical Reviews | volume = 114 | issue = 1 | pages = 194–232 | date = January 2014 | pmid = 23905688 | pmc = 3858459 | doi = 10.1021/cr400107q}}{{open access}}</ref> regulation of skin proliferation and differentiation, growth of bone tissue, immune function,<ref>{{cite journal | vauthors = Hall JA, Grainger JR, Spencer SP, Belkaid Y | title = The role of retinoic acid in tolerance and immunity | journal = Immunity | volume = 35 | issue = 1 | pages = 13–22 | date = July 2011 | pmid = 21777796 | pmc = 3418663 | doi = 10.1016/j.immuni.2011.07.002 }}</ref> and male fertility.<ref>{{cite journal | vauthors = Topping T, Griswold MD | title = Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis | journal = Frontiers in Endocrinology | volume = 13 | pages = 871225 | date = 2022-04-28 | pmid = 35574006 | pmc = 9097449 | doi = 10.3389/fendo.2022.871225 | doi-access = free }}</ref>

The biology of retinoids is complex, having well-documented effectiveness in the management of conditions ranging from [[acute promyelocytic leukemia]] to [[acne]] to [[photoaging]].<ref>{{cite journal |last1=Nagai |first1=Yuya |last2=Ambinder |first2=Alexander J. |title=The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out nor Fading Away |journal=Cancers |volume=15 |issue=14 |date=Jul 8, 2023 |issn=2072-6694 |pmid=37509198 |pmc=10377082 |doi=10.3390/cancers15143535 |doi-access=free |page=3535 }}</ref> On the other hand, retinoids may be involved in metabolic dysfunction and, at least in some forms, [[carcinogenesis]].<ref>{{cite journal |vauthors=Esposito M, Amory JK, Kang Y |title=The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes |journal=The Journal of Experimental Medicine |volume=221 |issue=9 |page=e20240519 |date=September 2024 |pmid=39133222 |doi=10.1084/jem.20240519 |doi-access=free |pmc=11318670 }}</ref><ref>{{cite journal |vauthors=Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, Valanis B, Williams JH |title=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=Journal of the National Cancer Institute |volume=96 |issue=23 |pages=1743–1750 |date=December 2004 |pmid=15572756 |doi=10.1093/jnci/djh320 }}</ref>

==Types==
Retinoids are divided into four generations based on their molecular structure and receptor selectivity.<ref>{{cite journal | vauthors=Motamedi M, Chehade A, Sanghera R, Grewal P | title=A Clinician's Guide to Topical Retinoids | journal=Journal of Cutaneous Medicine and Surgery | volume=26 | issue=1 | pages=71–78 | date=2021-07-22 | pmid=34292058 | pmc=8750127 | doi=10.1177/12034754211035091 | publisher=SAGE Publications }}</ref>
{| class="wikitable"
|-
! 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 [[chromophore]]s. Alternation of side chains and end groups creates the various classes of retinoids.{{cn|date=January 2025}}

First generation retinoids are produced naturally in the body and interact with their normal biological counterparts, such as [[retinol binding protein 4]] for retinol, [[Retinoic acid receptor|retinoid receptors]] for [[all-trans-retinoic acid]] or [[9-cis-retinoic acid]].<ref>{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–931 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref> [[13-cis retinoic acid]] has an unknown biological pathway but appears to act as a growth factor.<ref>{{cite journal | vauthors = Brzezinski P, Borowska K, Chiriac A, Smigielski J | title = Adverse effects of isotretinoin: A large, retrospective review | journal = Dermatologic Therapy | volume = 30 | issue = 4 | pages = e12483 | date = July 2017 | pmid = 28295859 | doi = 10.1111/dth.12483 | doi-access = free }}</ref>

Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.<ref>{{Cite web |date=2013-12-02 |title=Soriatane (Acitretin): Side Effects, Uses, Dosage, Interactions, Warnings |website=RxList |url=http://www.rxlist.com/soriatane-drug.htm |url-status=live |access-date=2024-08-30 |archive-url=https://web.archive.org/web/20131202230458/http://www.rxlist.com/soriatane-drug.htm |archive-date=2013-12-02 }}</ref>{{verification failed|reason=Source doesn't use the words "interact" (except in relation to other drugs) or "signaling" and is about soriatane specifically, not second generation retinoids generally|date=August 2024}}

Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of [[isotretinoin]],<ref name = "Mukherjee_2006">{{cite journal | vauthors = Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G | title = Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety | journal = Clinical Interventions in Aging | volume = 1 | issue = 4 | pages = 327–348 | date = 2006 | pmid = 18046911 | pmc = 2699641 | doi = 10.2147/ciia.2006.1.4.327 | doi-access = free }}</ref> [[bexarotene]] binding only the [[Retinoid X receptor]]s, and [[tazarotene]] binding the [[Retinoic acid receptor beta]] and [[Retinoic acid receptor gamma]] forms.<ref>{{Cite journal | vauthors =  Duvic M, Nagpal S, Asano AT, Chandraratna RA |date=August 1997 |title=Molecular mechanisms of tazarotene action in psoriasis |url=https://linkinghub.elsevier.com/retrieve/pii/S0190962297803969 |journal=Journal of the American Academy of Dermatology |volume=37 |issue=2 |pages=S18–S24 |doi=10.1016/s0190-9622(97)80396-9 |issn=0190-9622|url-access=subscription }}</ref>

The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.<ref>{{cite web |title=Drug Approval Package: Aklief | website=US Food and Drug Administration |date=October 21, 2019 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191119042411/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211527Orig1s000TOC.cfm |archive-date=19 November 2019 |url-status=dead |access-date=31 December 2021}}</ref>

== Pharmacokinetics ==
The major source of retinoids in human diet are plant pigments such as [[carotene]]s and retinyl esters derived from animal sources.<ref>{{cite journal | vauthors = Hall JA, Grainger JR, Spencer SP, Belkaid Y | title = The role of retinoic acid in tolerance and immunity | journal = Immunity | volume = 35 | issue = 1 | pages = 13–22 | date = July 2011 | pmid = 21777796 | pmc = 3418663 | doi = 10.1016/j.immuni.2011.07.002 }}</ref> Retinyl esters are transported through the [[chylomicron]] pathway to the liver or fat tissue while [[retinol]] or [[carotene]]s are transported from the enterocytes to the liver and are processed into retinyl esters by [[Lecithin retinol acyltransferase|LRAT]] for storage.<ref>{{cite journal | vauthors = Burri BJ, Clifford AJ | title = Carotenoid and retinoid metabolism: insights from isotope studies | journal = Archives of Biochemistry and Biophysics | volume = 430 | issue = 1 | pages = 110–119 | date = October 2004 | pmid = 15325918 | doi = 10.1016/j.abb.2004.04.028 | series = Highlight issue on Carotenoids }}</ref> Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised.<ref name = "Mukherjee_2006" />

All classes of retinoid bind to many proteins. Natural retinoids such as [[retinol]] and retinyl esters bind to carrier proteins such as [[Retinol binding protein 4|RBP4]], [[chylomicron]]s and [[VLDL]] while synthetic retinoids likely bind to these and other proteins.<ref>{{cite journal | vauthors = Burri BJ, Clifford AJ | title = Carotenoid and retinoid metabolism: insights from isotope studies | journal = Archives of Biochemistry and Biophysics | volume = 430 | issue = 1 | pages = 110–119 | date = October 2004 | pmid = 15325918 | doi = 10.1016/j.abb.2004.04.028 | series = Highlight issue on Carotenoids }}</ref> First generation retinoids are rapidly metabolized by [[Cytochrome P450|Cytochrome p450]] enzymes, typically of the [[CYP26 family|Cyp26 family]].<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}</ref>

==Uses==
Common skin conditions treated by topical retinoids include acne, [[psoriasis]],<ref>{{cite web|url=http://www.psoriasis.org/netcommunity/sublearn03_severe_acitretin|title=Systemic medications: Soriatane (acitretin) |publisher=National Psoriasis Foundation|access-date=16 March 2018|url-status=dead|archive-url=https://web.archive.org/web/20100613052050/http://psoriasis.org/netcommunity/sublearn03_severe_acitretin|archive-date=13 June 2010}}</ref><ref>{{cite web |url=http://www.mayoclinic.org/diseases-conditions/psoriasis/basics/treatment/con-20030838 |title=Psoriasis - Diagnosis and treatment |publisher=Mayo Clinic |access-date=16 March 2018 |url-status=live |archive-url=https://web.archive.org/web/20170507231658/http://www.mayoclinic.org/diseases-conditions/psoriasis/basics/treatment/con-20030838 |archive-date=7 May 2017 }}</ref> and effects of photoaging.<ref>{{cite journal | vauthors = Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G | title = Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety | journal = Clinical Interventions in Aging | volume = 1 | issue = 4 | pages = 327–348 | date = 2006 | pmid = 18046911 | pmc = 2699641 | doi = 10.2147/ciia.2006.1.4.327 | doi-access = free}}</ref><ref>{{cite journal | vauthors = Kafi R, Kwak HS, Schumacher WE, Cho S, Hanft VN, Hamilton TA, King AL, Neal JD, Varani J, Fisher GJ, Voorhees JJ, Kang S  | title = Improvement of naturally aged skin with vitamin A (retinol) | journal = Archives of Dermatology | volume = 143 | issue = 5 | pages = 606–612 | date = May 2007 | pmid = 17515510 | doi = 10.1001/archderm.143.5.606 | doi-access = free }}</ref> In addition, retinoids are used to treat some rare skin disorders, including [[Discoid lupus erythematosus|discoid lupus]]<ref>{{cite journal | vauthors = Laosakul K, Chiewchanvit S, Chuamanochan M, Tovanabutra N | title = Acitretin treatment in antimalarial-refractory/intolerant discoid lupus erythematosus: A prospective, open-label, uncontrolled study | journal = Lupus | volume = 31 | issue = 5 | pages = 575–581 | date = April 2022 | pmid = 35306922 | doi = 10.1177/09612033221086878 }}</ref> and [[mycosis fungoides]].<ref>{{cite journal | vauthors = Panchal MR, Scarisbrick JJ | title = The utility of bexarotene in mycosis fungoides and Sézary syndrome | journal = OncoTargets and Therapy | volume = 8 | pages = 367–373 | date = 2015-02-03 | pmid = 25678803 | pmc = 4322887 | doi = 10.2147/OTT.S61308 | doi-access = free }}</ref> In Japan, isotretinoin may be used for [[neuroblastoma]] treatment,<ref>{{cite journal | vauthors = Makimoto A, Fujisaki H, Matsumoto K, Takahashi Y, Cho Y, Morikawa Y, Yuza Y, Tajiri T, Iehara T  | title = Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects | journal = Cancers | volume = 16 | issue = 3 | pages = 544 | date = January 2024 | pmid = 38339295 | pmc = 10854948 | doi = 10.3390/cancers16030544 | doi-access = free }}</ref> but it is not approved in other countries due to a lack of consistency in studies of its effectiveness.<ref>{{cite journal | vauthors = Makimoto A, Fujisaki H, Matsumoto K, Takahashi Y, Cho Y, Morikawa Y, Yuza Y, Tajiri T, Iehara T  | title = Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects | journal = Cancers | volume = 16 | issue = 3 | pages = 544 | date = January 2024 | pmid = 38339295 | pmc = 10854948 | doi = 10.3390/cancers16030544 | doi-access = free }}</ref> 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]].<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}</ref>

==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 (symptom)|Anorexia]], [[Cutaneous condition|skin lesions]], [[hair loss]], [[hepatosplenomegaly]], [[Papilledema|papilloedema]], [[bleeding]], general [[malaise]], [[Idiopathic intracranial hypertension|pseudotumor cerebri]], and [[death]] may also occur.<ref>{{cite book |vauthors=Olson JM, Ameer MA, Goyal A |chapter=Vitamin A Toxicity |date=2024 |title=StatPearls |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK532916/ |access-date=2024-08-15 |place=Treasure Island (FL) |publisher=StatPearls |pmid=30422511 }}</ref>

Retinoids provoke rapid elevation of circulating [[triglyceride]]s leading to [[hypertriglyceridemia]] as well as cholesterol, leading to [[hypercholesterolemia]].<ref>{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}</ref> 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.<ref>{{cite journal | vauthors = Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL, Omenn GS, Valanis B, Williams JH  | title = 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 = Journal of the National Cancer Institute | volume = 96 | issue = 23 | pages = 1743–1750 | date = December 2004 | pmid = 15572756 | doi = 10.1093/jnci/djh320 }}</ref><ref>{{cite journal | title = The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers | journal = The New England Journal of Medicine | volume = 330 | issue = 15 | pages = 1029–1035 | date = April 1994 | pmid = 8127329 | doi = 10.1056/NEJM199404143301501 | vauthors = Alpha-Tocopherol BC }}</ref> In addition to the harmful effects shared by other retinoids, [[bexarotene]] causes severe [[hypothyroidism]].<ref>{{cite journal | vauthors = Sherman SI | title = Etiology, diagnosis, and treatment recommendations for central hypothyroidism associated with bexarotene therapy for cutaneous T-cell lymphoma | journal = Clinical Lymphoma | volume = 3 | issue = 4 | pages = 249–252 | date = March 2003 | pmid = 12672276 | doi = 10.3816/CLM.2003.n.006 }}</ref>

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.<ref>{{Cite web|title=PRAC recommends updating measures for pregnancy prevention during retinoid use|url=https://www.ema.europa.eu/en/documents/referral/retinoid-article-31-referral-prac-recommends-updating-measures-pregnancy-prevention-during-retinoid_en.pdf|access-date=2023-10-10|publisher=European Medicines Agency}}</ref><ref>{{Cite web |title=PRAC Seeks New Pregnancy Prevention Measures For Retinoids |url=https://www.medscape.com/viewarticle/892514 |access-date=2023-10-10 |work=Medscape }}</ref> The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy.<ref>{{Cite web |title=Oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women |author=[[Medicines and Healthcare products Regulatory Agency]] |url=https://www.gov.uk/drug-safety-update/oral-retinoid-medicines-revised-and-simplified-pregnancy-prevention-educational-materials-for-healthcare-professionals-and-women |access-date=2023-10-10 |website=GOV.uk }}</ref>

Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women.<ref>{{Cite web|title=Skincare Ingredients To Avoid During Pregnancy (+ List Of Harmful Chemicals In Beauty Products)|url=https://www.littlebabygear.com/skincare-ingredients-avoid-pregnancy/|access-date=2023-10-10|work=Little Baby Gear|date=20 December 2022 }}</ref><ref>{{Cite web|title=Is Vitamin A, Retinyl Palmitate and Retinol Safe for Pregnant Women?|url=https://www.metrin.com/blog-is-vitamin-a-retinyl-palmitate-and-retinol-safe-for-pregnant-women/|access-date=2023-10-10|publisher=Metrin Skincare|date=26 May 2022 }}</ref> 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.<ref>{{Cite web|title=Pregnancy-Safe Skin Care Guide: Ingredients to Avoid|url=https://www.whattoexpect.com/pregnancy/looking-good/everything-need-know-pregnancy-proof-beauty-routine/|access-date=2023-10-10|work=What To Expect}}</ref>

== See also ==
* [[Hypervitaminosis A]]

== References ==
{{Reflist}}

== External links ==
* {{MeshName|Retinoids}}

{{Carotenoids}}
{{Acne agents}}
{{Antipsoriatics}}
{{Retinoid receptor modulators}}
{{Prostanoid signaling modulators}}
{{Authority control}}

[[Category:Retinoids|*]]