RETINOIDS AND THE ARYLHYDROCARBON RECEPTOR PATHWAY

视黄酸（RA）的作用由一组称为视黄酸受体（RAR）和类维生素A X受体（RXR）的配体依赖性转录因子（核受体）介导。自从发现RAR和RXR以来，已经开发了数千种合成类视色素，其中许多在结构上是非类异戊二烯的，以靶向特定的RAR/RXR亚型或功能。初步数据表明，一种非异戊二烯类维甲酸，AGN 193109，可以提高小鼠胚胎和Hepa-1c 1c 7细胞中CYP 1A 1 mRNA的水平。 数据表明，这种调节CYP 1A 1 mRNA介导的芳香烃受体（AhR）/Ah核转位（Arnt）途径。AhR/Arnt途径被证明分别受到多环芳烃（PAH）和卤代芳烃（HAH）如苯并[a]芘和2，3，7，8-四氯二苯并-对-二恶英（TCDD）的调节。 我们假设AGN 193109和潜在的其他非类异戊二烯和类维生素A可以模拟PAH和HAH并激活AhR，导致CYP 1A 1 mRNA水平的诱导和潜在的其他[Ah]电池基因沿着结合和激活/拮抗RAR和RXR。 这是两个非常不同的转录调控途径（AhR/Arnt和RAR/RXR）的第一个例子，它们可能同时受到相同维甲酸的调控。 由于多环芳烃和多环芳烃激活AhR可导致严重的适应性、致癌性和潜在毒性反应，因此，（1）确定AhR/Arnt通路在AGN 193109调节CYP 1A 1 mRNA水平中的作用，（2）研究与CYP 1A 1 mRNA水平升高有关的合成类维生素A的结构特征，（3）研究AGN 193109对细胞色素P450的影响，（4）研究AGN 193109对细胞色素P450的影响，（5）研究AGN 193109对细胞色素P450的影响。（3）评估AGN 193109和潜在的其他非异戊二烯类维生素A升高CYP 1A 1 mRNA水平的生理后果。 这些研究的发现将对合成类维生素A的药理学应用的设计和使用具有重要意义，因为沿着RAR/RXR途径的期望调节激活AhR/Arnt途径是不期望的。

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.