Retinoic Acid and Its Derivatives in Skin

Abstract

The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.

Keywords: all-trans-retinoic acid; dermatology; retinoic acid receptors; vitamin A.

Figure 1

Mechanism of all-trans-retinoic acid (ATRA) action. (A) In the absence of a ligand, retinoid X (or rexinoid) receptors and retinoic acid receptors (RXR-RAR) heterodimers bind to retinoic acid response elements (RAREs) in the regulatory regions of target genes and repress transcription through recruiting histone deacetylases (HDAC)/co-repressor (negative co-regulator (N-CoR) or silencing mediator for retinoid and thyroid hormone receptors (SMRT)) complexes. HDACs remove acetyl groups from nucleosomal histones causing chromatin condensation that precludes binding of other factors and ultimately results in the silencing of gene expression. (B) Upon ligand binding, RAR undergoes structural change leading to dissociation of the co-repressor complex and association of co-activators with histone acetyltransferase (HAT) activities (e.g., P300 and NCOA1) that cause decondensation of chromatin by adding acetyl groups to nucleosomal histones. (C) Additional multiprotein complexes called vitamin D3 receptor-interacting proteins or thyroid hormone receptor-associated proteins (DRIP or TRAP) may also be recruited for activation of transcription through interaction with basal transcriptional.

Figure 2

Non-genomic effects of ATRA. ATRA can cause rapid activation of various cellular kinases: shown above is the convergence of genomic and nongenomic signaling. Additionally, by directly up-regulating the expression of components of various signaling cascades, ATRA provides a positive feedback loop mechanism. Possibilities also exist for antagonistic interactions, which are not highlighted in the figure.

Figure 3

(A) ATRA effect on skin layers and skin cells. (B) ATRA molecular effects. Arrows directed upwards represent either increase or upregulation. Arrows directed downwards represent either decrease or downregulation. The figure was created using SMART (Servier Medical ART) modified graphics, licensed under a Creative Commons Attribution 3.0. Generic License.