The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis
The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis
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DOI：
10.1124/mol.58.3.515
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发表时间：
2000-09-01
影响因子：
3.6
通讯作者：
Sherr, DH
中科院分区：
文献类型：
--
作者：
Quadri, SA;Qadri, AN;Sherr, DH
生物类黄酮是一种植物化合物，因其具有治疗或预防多种疾病的潜力，包括由常见环境化学物质诱发的癌症。此类污染物多环芳烃 (PAH) 的大部分生物活性是由芳基烃受体/转录因子 (AhR) 介导的。例如，AhR 调节 PAH 免疫毒性，在 B 细胞发育模型中表现为前 B 细胞凋亡。由于生物类黄酮能阻断 PAH 诱导的细胞转化，并且在结构上与 AhR 配体相似，因此推测其中一些可能通过直接阻断 AhR 来抑制 PAH 诱导的 AhR 依赖性免疫毒性。使用 B 细胞发育模型测试了这一假设，其中前 B 细胞与骨髓基质或肝实质细胞单层一起培养并依赖于骨髓基质或肝实质细胞单层。在筛选的七种生物类黄酮中，高良姜素（3,5,7-三羟基黄酮）可阻断 PAH 诱导的细胞凋亡，但不能阻断 C-2-神经酰胺或 H2O2 诱导的前 B 细胞凋亡。由于高良姜素阻断 AhR 依赖性报告基因表达、AhR 复合物-DNA 结合和 AhR 核转位，因此涉及对 AhR 信号转导相对早期步骤的抑制。这一假设得到了高良姜素在 AhR 激动剂存在下结合 AhR 并稳定 AhR-90-kDa 热休克蛋白复合物的能力的支持。这些研究证明了前 B 细胞培养系统在识别能够阻断 PAH 免疫毒性的化合物、定义至少一种高良姜素活性机制（即抑制 AhR 激活）方面的效用，并推动使用这种和类似的膳食生物类黄酮作为 AhR 激动剂活性的相对无毒的抑制剂和作为剖析 AhR 信号通路的药理制剂。
Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancers induced by common environmental chemicals. Much of the biologic activity of one such class of pollutants, polycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon receptor/transcription factor (AhR). For example, the AhR regulates PAH immunotoxicity that manifests as pre-B cell apoptosis in models of B cell development. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them would suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell development in which pre-B cells are cultured with and are dependent on bone marrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoids screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C-2-ceramide- or H2O2-induced pre-B cell apoptosis. Because galangin blocked AhR-dependent reporter gene expression, AhR complex-DNA binding, and AhR nuclear translocation, inhibition of a relatively early step in AhR signaling was implicated. This hypothesis was supported by the ability of galangin to bind the AhR and stabilize AhR-90-kDa heat shock protein complexes in the presence of AhR agonists. These studies demonstrate the utility of pre-B cell culture systems in identifying compounds capable of blocking PAH immunotoxicity, define at least one mechanism of galangin activity (i.e., repression of AhR activation), and motivate the use of this and similar dietary bioflavonoids as relatively nontoxic inhibitors of AhR agonist activity and as pharmacologic agents with which to dissect AhR signaling pathways.