RETINOIDS AND THE ARYLHYDROCARBON RECEPTOR PATHWAY

视黄酸（RA）的作用是由一组称为视黄酸受体（RARs）和类视黄X受体（RXRs）的配体依赖性转录因子（核受体）介导的。自从RAR和RXR被发现以来，成千上万的合成类维生素a被开发出来，其中许多在结构上是非类异戊二烯，用于特定的RAR/RXR亚型或功能。初步研究表明，一种非类异戊二烯类维甲酸AGN193109可以提高小鼠胚胎和Hepa-1c1c7细胞中CYP1A1 mRNA的表达水平。数据表明，CYP1A1 mRNA的这种调节是由芳烃受体(AhR)/Ah核转运器（Arnt）途径介导的。AhR/Arnt通路已被证明分别受到多芳烃（PAHs）和卤代芳烃（HAHs）如苯并[a]芘和2,3,7,8-四氯二苯并-对二恶英（TCDD）的调控。我们假设AGN193109和潜在的其他非类异戊二烯和类维甲酸可以模拟PAHs和HAHs并激活AhR，从而诱导CYP1A1 mRNA水平和潜在的其他[Ah]电池基因，同时结合和激活/拮抗RARs和RXRs。这是两种完全不同的转录调控途径（AhR/Arnt和RAR/RXR）可能同时被同一类维甲酸调节的第一个例子。由于PAHs和HAHs激活AhR可导致人类严重的适应性、致癌性和潜在毒性反应，因此重要的是：(1)确定AhR/Arnt通路在AGN193109调节CYP1A1 mRNA水平中的作用；(2)研究导致CYP1A1 mRNA水平升高的合成类维生素a的结构特征；(3)评估AGN193109和其他可能的非类异戊二烯类维甲酸对CYP1A1 mRNA水平升高的生理影响。这些研究的发现将对合成类维生素a的药理应用的设计和使用具有重要意义，因为不希望在激活RAR/RXR通路的同时激活AhR/Arnt通路。

The actions of retinoic acid (RA) are mediated by a group of ligand-dependent transcription factors (nuclear receptors) called retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Since the discovery of the RARs and RXRs, thousands of synthetic retinoids, many of which are non-isoprenoid in structure, have been developed to target a specific RAR/RXR subtype or function. Preliminary data demonstrate that one non-isoprenoid retinoid, AGN193109, can elevate the level of CYP1A1 mRNA in mouse embryos and Hepa-1c1c7 cells. Data are presented which suggest that this regulation of CYP1A1 mRNA is mediated by the aryl hydrocarbon receptor (AhR)/Ah nuclear translocator (Arnt) pathway. The AhR/Arnt pathway has been demonstrated to be regulated by polyaromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. We hypothesize that AGN193109 and potentially other non-isoprenoid and retinoids can mimic PAHs and HAHs and activate AhR causing an induction in CYP1A1 mRNA levels and potentially other [Ah] battery genes along with binding and activating/antagonizing RARs and RXRs. This is the first example of two quite distinct transcriptional regulatory pathways (AhR/Arnt and RAR/RXR) which could potentially be regulated simultaneously by the same retinoid. Since the activation of AhR by PAHs and HAHs can result in severe adaptive, carcinogenic and potentially toxic responses in humans, it is important: (1) to determine the role of the AhR/Arnt pathway in the regulation of CYP1A1 mRNA levels by AGN193109; (2) to examine the structural features of synthetic retinoids which are responsible for the eleveation of CYP1A1 mRNA levels and; (3) to assess the physiological consequences of the elevation of CYP1A1 mRNA levels by AGN193109 and potentially other non-isoprenoid retinoids. The findings from these studies will have important implications in the design and use of synthetic retinoids for pharmacological application since it would be undesirable to activate the AhR/Arnt pathway along the desired modulation of the RAR/RXR pathway.