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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">Template:Cite journal</ref>
Retinoids have many important functions throughout the body, including in vision,<ref>Template:Cite journalTemplate:Open access</ref> regulation of skin proliferation and differentiation, growth of bone tissue, immune function,<ref>Template:Cite journal</ref> and male fertility.<ref>Template:Cite journal</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>Template:Cite journal</ref> On the other hand, retinoids may be involved in metabolic dysfunction and, at least in some forms, carcinogenesis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
TypesEdit
Retinoids are divided into four generations based on their molecular structure and receptor selectivity.<ref>Template:Cite journal</ref>
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 |
StructureEdit
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.Template:Cn
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.<ref>Template:Cite journal</ref> 13-cis retinoic acid has an unknown biological pathway but appears to act as a growth factor.<ref>Template:Cite journal</ref>
Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Verification failed
Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of isotretinoin,<ref name = "Mukherjee_2006">Template:Cite journal</ref> bexarotene binding only the Retinoid X receptors, and tazarotene binding the Retinoic acid receptor beta and Retinoic acid receptor gamma forms.<ref>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
PharmacokineticsEdit
The major source of retinoids in human diet are plant pigments such as carotenes and retinyl esters derived from animal sources.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</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 RBP4, chylomicrons and VLDL while synthetic retinoids likely bind to these and other proteins.<ref>Template:Cite journal</ref> First generation retinoids are rapidly metabolized by Cytochrome p450 enzymes, typically of the Cyp26 family.<ref>Template:Cite journal</ref>
UsesEdit
Common skin conditions treated by topical retinoids include acne, psoriasis,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and effects of photoaging.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In addition, retinoids are used to treat some rare skin disorders, including discoid lupus<ref>Template:Cite journal</ref> and mycosis fungoides.<ref>Template:Cite journal</ref> In Japan, isotretinoin may be used for neuroblastoma treatment,<ref>Template:Cite journal</ref> but it is not approved in other countries due to a lack of consistency in studies of its effectiveness.<ref>Template:Cite journal</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>Template:Cite journal</ref>
ToxicityEdit
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.<ref>Template:Cite book</ref>
Retinoids provoke rapid elevation of circulating triglycerides leading to hypertriglyceridemia as well as cholesterol, leading to hypercholesterolemia.<ref>Template:Cite journal</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>Template:Cite journal</ref><ref>Template:Cite journal</ref> In addition to the harmful effects shared by other retinoids, bexarotene causes severe hypothyroidism.<ref>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
See alsoEdit
ReferencesEdit
External linksEdit
Template:Carotenoids Template:Acne agents Template:Antipsoriatics Template:Retinoid receptor modulators Template:Prostanoid signaling modulators Template:Authority control