Berbis P
Service de Dermatologie, Hôpital Nord, Chemin des Bourrellys 13015 Marseille, France.
Ann Dermatol Venereol. 2010 Nov;137 Suppl 3:S97-103. doi: 10.1016/S0151-9638(10)70036-3.
Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, β, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450.
类视黄醇是维生素A的衍生物，是具有多效性的天然或合成分子，可调节细胞分化、增殖和凋亡。在靶细胞中，活性天然代谢产物视黄酸（RA）和9-顺式视黄酸通过两步过程由视黄醇与中间代谢产物视黄醛合成。1987年，属于核受体超家族的核视黄酸受体的鉴定在理解类视黄醇的作用机制方面取得了重大进展。有两类类视黄醇核受体（RNR），即视黄酸受体（RAR），其天然配体是RA；以及视黄醇X受体（RXR），其天然配体是9-顺式视黄酸。在合成类视黄醇中，异维A酸、阿维A、他扎罗汀和阿达帕林是RAR的配体，贝沙罗汀是首个视黄酸X受体激动剂（RXR的配体），alitretinoin是首个全激动剂（RAR + RXR）。对于每个家族，有3种同种型（α、β、γ），对于每种同种型有几种亚型。每个NRR由6个区域（A - F）组成。3个区域很重要：A/B区域具有不依赖配体的转录激活功能，C区域包含DNA结合域，E区域包含配体结合域。为了调节靶基因的表达，NRR必须二聚化。RXR在二聚体中是必需的（异二聚体RAR - RXR、同二聚体RXR - RXR）。二聚体结合存在于靶基因启动子中的特定DNA序列。当天然或合成配体与RNR结合时，共激活因子被募集，转录因子被激活。在靶细胞中，未被利用的类视黄醇被细胞色素P450酶降解为极性代谢产物。
