Retinoids at a Glance
- Definition: any molecule that by itself or through metabolic conversion binds to and activates retinoic acid receptors.
- Retinoid receptors: ligand-dependent transcription factors.
- Predominant retinoid receptors in human skin: retinoic acid receptor-g (RAR-g) and retinoid X receptor-α (RXR-α).
- RAR-γ/RXR-α heterodimers bind to retinoic acid-responsive elements and are responsible for retinoid signaling.
- Clinical use of topical retinoids:
- Approved indications—acne, psoriasis, cutaneous T-cell lymphoma, Kaposi sarcoma, melasma, and photoaged skin.
- Unapproved indications with clinical studies supporting benefit—postinflammatory hyperpigmentations early stretch marks and natural aging.
- Local skin irritation: mainly due to retinoid-induced epidermal hyperplasia. Clinical use should be titrated based on the severity of local reactions.
In topical preparations, retinoids are widely used as prescription drugs as well as cosmeceuticals. In some of these products, retinoids are naturally occurring compounds while others are synthetic molecules. All retinoids, however, share predictable pharmacology in eliciting human skin responses due to the fact that retinoid effects are primarily mediated through their intranuclear retinoid receptors acting as transcription factors. Indeed, the discovery and characterization of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) have been pivotal to our understanding of the retinoid action mechanism and gave rise to the idea that retinoids act similarly to hormones.1,2 In 1976, Michael Sporn and his colleagues originally defined retinoids as both the naturally occurring compounds with vitamin A activity and the synthetic analogs of retinol. This concept is no longer adequate. Now, retinoid is defined as any molecule that, by itself or through metabolic conversion, binds to and activates the RARs, thereby eliciting transcriptional activation of retinoic acid-responsive genes that results in specific biologic responses.
The discovery and characterization of RARs as having molecular features that are similar to steroid/thyroid hormone receptors were landmark findings.1,2 A characteristic common to these receptors is that they bind to regulatory regions in DNA called hormone response elements, or target sequences, and activate gene transcription in a ligand-dependent manner. Therefore, they are referred to as ligand (hormone)-dependent transcription factors. These receptors bind to specific DNA sequences as dimers. Unlike receptors for the steroid hormones, which form homodimers (two identical monomers); RAR, vitamin D receptor (VDR), and thyroid hormone receptors (TR) bind to their elements with greater affinity as heterodimers (two different monomers). The critical partner for heterodimerization and ultimate functioning of RAR, VDR, and TR is the RXR,3 whose physiologic ligand is 9-cis-retinoic acid.4 The ability of RXRs to interact with many receptors suggests their importance as regulatory proteins. There are three different members of RAR (α, β, and γ) and RXR (α, β, and γ), each encoded by different genes. Furthermore, each of the receptors has isoforms, adding to the diversity of retinoid receptors.
The identification and functional characterization of retinoid receptor families cleared the way for drug discovery. ...