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Retinoid
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<h2 id="types">Types</h2> <p>Retinoids are divided into four generations based on their molecular structure and receptor selectivity.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <table><tbody><tr><th>Generation</th><th>Description</th><th>Compounds</th></tr><tr><td>First generation</td><td>Isomers and naturally occurring compounds</td><td><a href="/facts/Retinol/pUwofb2S">retinol</a>, <a href="/facts/Retinal/h20jN8FC">retinal</a>, <a href="/facts/Tretinoin/DjthvC01">tretinoin</a> (<a href="/facts/Retinoic_acid/tlyLyvCT">retinoic acid</a>), <a href="/facts/Isotretinoin/XBKv4fQJ">isotretinoin</a>, and <a href="/facts/Alitretinoin/fG4d0IlJ">alitretinoin</a></td></tr><tr><td>Second generation</td><td>Synthetic analogs formulated for oral dosing. There are no topically available second generation formulations of retinoids.</td><td><a href="/facts/Etretinate/VjVrtWff">etretinate</a> and its metabolite <a href="/facts/Acitretin/G2fYnt1S">acitretin</a></td></tr><tr><td>Third generation</td><td>Retinoidal benzoic acid derivatives</td><td><a href="/facts/Adapalene/nyFc9zDC">adapalene</a>, <a href="/facts/Oleyl_adapalenate/EUz2Nltc">oleyl adapalenate</a>, <a href="/facts/Bexarotene/MUw5fUJQ">bexarotene</a>, and <a href="/facts/Tazarotene/Q3PUkYPN">tazarotene</a></td></tr><tr><td>Fourth generation</td><td>Topical retinoid with selectivity towards the RAR receptor located in the epidermis</td><td><a href="/facts/Trifarotene/tyKRPUsu">Trifarotene</a>, seletinoid G</td></tr></tbody></table> <h2 id="structure">Structure</h2> <p>The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, a <a href="/facts/Polyene/gnf4zsEs">polyene</a> side chain and a polar end group. The <a href="/facts/Conjugated_system/Ddx9qzox">conjugated system</a> 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 <a href="/facts/Chromophore/9RykVkek">chromophores</a>. Alternation of side chains and end groups creates the various classes of retinoids. </p><p>First generation retinoids are produced naturally in the body and interact with their normal biological counterparts, such as <a href="/facts/Retinol_binding_protein_4/jlwhkLqD">retinol binding protein 4</a> for retinol, <a href="/facts/Retinoic_acid_receptor/YCYeUb6t">retinoid receptors</a> for <a href="/facts/All-trans-retinoic_acid/DjthvC01">all-trans-retinoic acid</a> or <a href="/facts/9-cis-retinoic_acid/fG4d0IlJ">9-cis-retinoic acid</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> <a href="/facts/13-cis_retinoic_acid/XBKv4fQJ">13-cis retinoic acid</a> has an unknown biological pathway but appears to act as a growth factor.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of <a href="/facts/Isotretinoin/XBKv4fQJ">isotretinoin</a>,<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> <a href="/facts/Bexarotene/MUw5fUJQ">bexarotene</a> binding only the <a href="/facts/Retinoid_X_receptor/VhHIuyLy">Retinoid X receptors</a>, and <a href="/facts/Tazarotene/Q3PUkYPN">tazarotene</a> binding the <a href="/facts/Retinoic_acid_receptor_beta/xk1wmnl1">Retinoic acid receptor beta</a> and <a href="/facts/Retinoic_acid_receptor_gamma/qoRJacdT">Retinoic acid receptor gamma</a> forms.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="pharmacokinetics">Pharmacokinetics</h2> <p>The major source of retinoids in human diet are plant pigments such as <a href="/facts/Carotene/oStTcszR">carotenes</a> and retinyl esters derived from animal sources.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Retinyl esters are transported through the <a href="/facts/Chylomicron/YPkGLpI6">chylomicron</a> pathway to the liver or fat tissue while <a href="/facts/Retinol/pUwofb2S">retinol</a> or <a href="/facts/Carotene/oStTcszR">carotenes</a> are transported from the enterocytes to the liver and are processed into retinyl esters by <a href="/facts/Lecithin_retinol_acyltransferase/0c9Cks7Q">LRAT</a> for storage.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>All classes of retinoid bind to many proteins. Natural retinoids such as <a href="/facts/Retinol/pUwofb2S">retinol</a> and retinyl esters bind to carrier proteins such as <a href="/facts/Retinol_binding_protein_4/jlwhkLqD">RBP4</a>, <a href="/facts/Chylomicron/YPkGLpI6">chylomicrons</a> and <a href="/facts/VLDL/uoQTgwX4">VLDL</a> while synthetic retinoids likely bind to these and other proteins.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> First generation retinoids are rapidly metabolized by <a href="/facts/Cytochrome_P450/alxusFD0">Cytochrome p450</a> enzymes, typically of the <a href="/facts/CYP26_family/JRVEfysd">Cyp26 family</a>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h2 id="uses">Uses</h2> <p>Common skin conditions treated by topical retinoids include acne, <a href="/facts/Psoriasis/WW1k1LsH">psoriasis</a>,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> and effects of photoaging.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> In addition, retinoids are used to treat some rare skin disorders, including <a href="/facts/Discoid_lupus_erythematosus/TP0dup6r">discoid lupus</a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> and <a href="/facts/Mycosis_fungoides/c0qdfwDH">mycosis fungoides</a>.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> In Japan, isotretinoin may be used for <a href="/facts/Neuroblastoma/nzCww7nE">neuroblastoma</a> treatment,<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> but it is not approved in other countries due to a lack of consistency in studies of its effectiveness.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Oral retinoids are readily toxic, requiring consistent clinical oversight, and are approved in several diseases for which said toxicity is paradoxically useful, including <a href="/facts/Acute_promyelocytic_leukemia/dFxwxHoX">acute promyelocytic leukemia</a>, <a href="/facts/Cutaneous_T-cell_lymphoma/gVeNtJ9N">cutaneous T-cell lymphoma</a>, and <a href="/facts/Heterotopic_ossification/c6NpKhUM">heterotopic ossification</a>.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h2 id="toxicity">Toxicity</h2> <p>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 <a href="/facts/Medical_sign/BzP6MrTN">medical sign</a> of chronic or acute poisoning with <a href="/facts/Retinol/pUwofb2S">retinol</a> is <a href="/facts/Hypervitaminosis_A/awIhJJMC">hypervitaminosis A</a>, which includes the presence of painful tender swellings on the long bones. <a href="/facts/Anorexia_(symptom)/G7RsaXp9">Anorexia</a>, <a href="/facts/Cutaneous_condition/Vkr5XpeG">skin lesions</a>, <a href="/facts/Hair_loss/uEPKUafl">hair loss</a>, <a href="/facts/Hepatosplenomegaly/mpVCuqgk">hepatosplenomegaly</a>, <a href="/facts/Papilledema/WKK6AIsT">papilloedema</a>, <a href="/facts/Bleeding/CGyFMU0F">bleeding</a>, general <a href="/facts/Malaise/vdb5DxAU">malaise</a>, <a href="/facts/Idiopathic_intracranial_hypertension/dGYKYw19">pseudotumor cerebri</a>, and <a href="/facts/Death/VJmq29qm">death</a> may also occur.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>Retinoids provoke rapid elevation of circulating <a href="/facts/Triglyceride/BQmjv4A0">triglycerides</a> leading to <a href="/facts/Hypertriglyceridemia/ztlqAVgG">hypertriglyceridemia</a> as well as cholesterol, leading to <a href="/facts/Hypercholesterolemia/UlIDdQuT">hypercholesterolemia</a>.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> 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.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> In addition to the harmful effects shared by other retinoids, <a href="/facts/Bexarotene/MUw5fUJQ">bexarotene</a> causes severe <a href="/facts/Hypothyroidism/oqtQDu2F">hypothyroidism</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p><p>Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> 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.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Hypervitaminosis_A/awIhJJMC">Hypervitaminosis A</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=Retinoids">Retinoids</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Motamedi M, Chehade A, Sanghera R, Grewal P (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. PMC 8750127. PMID 34292058. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750127" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750127</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858459" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858459</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418663" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418663</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097449" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097449</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Nagai Y, Ambinder AJ (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. PMC 10377082. PMID 37509198. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377082" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377082</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318670" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318670</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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". 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