RETINOIDS AND THE ARYLHYDROCARBON RECEPTOR PATHWAY

类维生素A和芳基烃受体途径

• 批准号: 6094147
• 负责人: DIANNE R SOPRANO
• 金额: $ 22.91万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6094147
• 关键词: analog; aromatic hydrocarbon receptor; benzopyrenes; bioassay; carbopolycyclic compound; chemical models; cytochrome P450; dioxins; drug design /synthesis /production; enzyme activity; gene induction /repression; halogens; heat shock proteins; intracellular transport; laboratory mouse; messenger RNA; protein transport; receptor binding; retinoids; transcription factor; unspecific monooxygenase

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.

视黄酸 (RA) 的作用由一组配体依赖性转录因子（核受体）介导，称为视黄酸受体 (RAR) 和类视黄酸 X 受体 (RXR)。自从 RAR 和 RXR 被发现以来，已经开发出数千种合成类视黄醇，其中许多在结构上是非类异戊二烯，以针对特定的 RAR/RXR 亚型或功能。初步数据表明，一种非类异戊二烯类视黄醇 AGN193109 可以提高小鼠胚胎和 Hepa-1c1c7 细胞中 CYP1A1 mRNA 的水平。 所提供的数据表明 CYP1A1 mRNA 的这种调节是由芳基烃受体 (AhR)/Ah 核转位子 (Arnt) 途径介导的。 AhR/Arnt 途径已被证明分别受到多环芳烃 (PAH) 和卤代芳烃 (HAH) 的调节，例如苯并[a]芘和 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 。 我们假设 AGN193109 和潜在的其他非类异戊二烯和类视黄醇可以模拟 PAH 和 HAH 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 RAR 和 RXR。 这是两个截然不同的转录调控途径（AhR/Arnt 和 RAR/RXR）的第一个例子，它们可能被同一个类维生素A同时调控。 由于 PAHs 和 HAHs 激活 AhR 可导致人类产生严重的适应性、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) 检查导致 CYP1A1 mRNA 水平升高的合成类视黄醇的结构特征； (3) 评估 AGN193109 和潜在的其他非类异戊二烯类视黄醇升高 CYP1A1 mRNA 水平的生理后果。 这些研究的结果将对合成类视黄醇的药理学应用的设计和使用产生重要影响，因为沿着 RAR/RXR 途径的所需调节激活 AhR/Arnt 途径是不可取的。