RETINOIDS AND THE ARYLHYDROCARBON RECEPTOR PATHWAY

维甲酸(RA)的作用是由一组称为维甲酸受体(RARs)和维甲酸X受体(RXRs)的配体依赖的转录因子(核受体)介导的。自从RARs和RXRs被发现以来，数以千计的合成维甲酸被开发出来，其中许多在结构上是非异戊二烯的，以针对特定的RAR/RXR亚型或功能。初步研究表明，一种非异戊二烯类维甲酸AGN193109可以提高小鼠胚胎和HEPA-1c1c7细胞中细胞色素P1A1基因的表达水平。有数据表明，这种对CYP1A1 mRNA的调节是通过芳香烃受体(AhR)/Ah核转运体(ArnT)途径介导的。已证实AhR/Arnt途径分别受多环芳烃(PAHs)和卤代芳香烃(HAHS)的调控，如苯并[a]芘和2，3，7，8-四氯二苯并对二恶英(TCDD)。我们假设AGN193109和其他潜在的非异戊二烯和维甲酸类化合物可以模拟PAHs和HAHS并激活AhR，导致诱导细胞色素P1A1 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。这是两条完全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的维甲酸的调节。由于PAHs和HAHS激活AhR可导致严重的适应性、致癌和潜在的毒性反应，因此很重要的一点是：(1)确定AhR/Arnt通路在AGN193109调节CYP1A1 mRNA水平中的作用；(2)检测合成维甲酸的结构特征，这些结构特征是导致CYP1A1 mRNA水平上调的原因；(3)评估AGN193109和其他潜在的非异戊二烯类维A酸上调CYP1A1 mRNA水平的生理后果。这些研究的结果将对设计和使用合成维甲酸用于药理学应用具有重要意义，因为不希望沿着RAR/RXR途径的所需调制来激活AhR/Arnt途径。

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.