Pharmacology and molecular action of retinoids and vitamin D in skin.

All-trans retinoic acid and 1,25-dihydroxyvitamin D3 are biologically active hormones derived from metabolism of vitamins A and D, respectively. Their cellular effects in physiology and pharmacology are mediated mainly through their nuclear receptors, retinoic acid receptors (RARs), and vitamin D receptor (VDR), which are members of the steroid/thyroid hormone receptor superfamily. The nuclear receptor superfamily is a group of hormone (ligand)-dependent transcription factors that bind to specific DNA recognition sequences located in the promotor region of target genes and modulate the gene transcription. Both RARs and VDR bind to DNA in the form of heterodimers with retinoid X receptor (RXR) as the key partner. In human skin epidermis, endogenous RAR and VDR bind to their respective enhancer elements as heterodimers (RAR-RXR, VDR-RXR) and not as homodimers. 9-cis retinoic acid is the natural ligand for RXRs. Because RXR heterodimerizes with either RARs or VDR, it functions as a key protein in the overall retinoid or vitamin D response of a given biological system. The contribution of RXRs in coregulating these signaling pathways is likely to depend on the abundance of the RXRs within target cells, the relative amounts of other receptors with which they can dimerize, and the availability of their ligands (hormones). Understanding each of these components in human skin in vivo will lead to practical applications in dermatologic therapeutics.