# Retinoid

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.
Retinoids have many important functions throughout the body, including in vision, regulation of skin proliferation and differentiation, growth of bone tissue, immune function, and male fertility.
The biology of retinoids is complex, having well-documented effectiveness in the management of conditions ranging from acute promyelocytic leukemia to acne to photoaging. On the other hand, retinoids may be involved in metabolic dysfunction and, at least in some forms, carcinogenesis.

## Types

Retinoids are divided into four generations based on their molecular structure and receptor selectivity.
| 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, 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.
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. 13-cis retinoic acid has an unknown biological pathway but appears to act as a growth factor.
Second generation retinoids have a mixed effect and interact mainly with signaling in the skin.
Third generation retinoids have narrow biological roles due to their constrained structure, with adapalene mimicking the effects of isotretinoin, bexarotene binding only the Retinoid X receptors, and tazarotene binding the Retinoic acid receptor beta and Retinoic acid receptor gamma forms.
The only fourth generation retinoid, Trifarotene, binds selectively to the RAR-y receptor. It was approved for use in the US in 2019.

## Pharmacokinetics

The major source of retinoids in human diet are plant pigments such as carotenes and retinyl esters derived from animal sources. 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. Most synthetic retinoids are absorbed when taken orally while topical retinoids cannot diffuse through the skin barrier unless it is compromised.
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. First generation retinoids are rapidly metabolized by Cytochrome p450 enzymes, typically of the Cyp26 family. Later generation retinoids are resistant to Cyp26 metabolism and remain in the body for much longer.

## Uses

Common skin conditions treated by topical retinoids include acne, psoriasis, and effects of photoaging. In addition, retinoids are used to treat some rare skin disorders, including discoid lupus and mycosis fungoides. In Japan, isotretinoin may be used for neuroblastoma treatment, but it is not approved in other countries due to a lack of consistency in studies of its effectiveness. 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.

## 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. Similar effects occur with other retinoids, except for 13-cis retinoic acid and its derivatives, such as adapalene.
Retinoids provoke rapid elevation of circulating triglycerides leading to hypertriglyceridemia as well as cholesterol, leading to hypercholesterolemia. 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 addition to the harmful effects shared by other retinoids, bexarotene causes severe hypothyroidism.
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. The use of acitretin, alitretinoin and isotretinoin should be prohibited in women of childbearing age unless they take measures to prevent pregnancy. The use of topical retinoids should also be excluded during pregnancy and in women planning pregnancy.
Many lotions that claim to prevent or treat stretch marks contain retinol, which is not an ingredient that is safe for pregnant women. 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.