Theretinoids are a class ofchemical compounds that are natural derivatives ofvitamin A or are chemically related to it. Synthetic retinoids are utilized in cosmetic formulations, clinicaldermatology, and the treatment of some forms of cancer.^[1]

Retinoids have many important functions throughout the body, including in vision,^[2] regulation of skin proliferation and differentiation, growth of bone tissue, immune function,^[3] and male fertility.^[4]

The biology of retinoids is complex, having well-documented effectiveness in the management of conditions ranging fromacute promyelocytic leukemia toacne tophotoaging.^[5] On the other hand, retinoids may be involved in metabolic dysfunction and, at least in some forms,carcinogenesis.^[6][7]

Retinoids are divided into four generations based on their molecular structure and receptor selectivity.^[8]

The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, apolyene side chain and a polar end group. Theconjugated 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 arechromophores. 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 asretinol binding protein 4 for retinol,retinoid receptors forall-trans-retinoic acid or9-cis-retinoic acid.^[9]13-cis retinoic acid has an unknown biological pathway but appears to act as a growth factor.^[10]

Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.^{[11][failed verification]}

Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects ofisotretinoin,^[12]bexarotene binding only theRetinoid X receptors, andtazarotene binding theRetinoic acid receptor beta andRetinoic acid receptor gamma forms.^[13]

The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.^[14]

The major source of retinoids in human diet are plant pigments such ascarotenes and retinyl esters derived from animal sources.^[15] Retinyl esters are transported through thechylomicron pathway to the liver or fat tissue whileretinol orcarotenes are transported from the enterocytes to the liver and are processed into retinyl esters byLRAT for storage.^[16] Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised.^[12]

All classes of retinoid bind to many proteins. Natural retinoids such asretinol and retinyl esters bind to carrier proteins such asRBP4,chylomicrons andVLDL while synthetic retinoids likely bind to these and other proteins.^[17] First generation retinoids are rapidly metabolized byCytochrome p450 enzymes, typically of theCyp26 family.^[18] Later generation retinoids are resistant to Cyp26 metabolism and remain in the body for much longer.^{[citation needed]}

Common skin conditions treated by topical retinoids includeacne,psoriasis,^[19][20] and effects ofphotoaging.^[21][22] In addition, retinoids are used to treat some rare skin disorders, includingdiscoid lupus^[23] andmycosis fungoides.^[24] In Japan, isotretinoin may be used forneuroblastoma treatment,^[25] but it is not approved in other countries due to a lack of consistency in studies of its effectiveness.^[26] Oral retinoids are readily toxic, requiring consistent clinical oversight, and are approved in several diseases for which said toxicity is paradoxically useful, includingacute promyelocytic leukemia,cutaneous T-cell lymphoma, andheterotopic ossification.^[27]

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. Amedical sign of chronic or acute poisoning withretinol ishypervitaminosis A, which includes the presence of painful tender swellings on the long bones.Anorexia,skin lesions,hair loss,hepatosplenomegaly,papilloedema,bleeding, generalmalaise,pseudotumor cerebri, anddeath may also occur.^[28] Similar effects occur with other retinoids, except for13-cis retinoic acid and its derivatives, such asadapalene.^{[citation needed]}

Retinoids provoke rapid elevation of circulatingtriglycerides leading tohypertriglyceridemia as well as cholesterol, leading tohypercholesterolemia.^[29] 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.^[30][31] In addition to the harmful effects shared by other retinoids,bexarotene causes severehypothyroidism.^[32]

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.^[33][34] The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy.^[35] The use of topical retinoids should also be excluded during pregnancy and in women planning pregnancy.^{[citation needed]}

Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women.^[36][37] 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.^[38]

• Hypervitaminosis A

• Retinoids at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Retinoids

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