Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-Universität Düsseldorf gGmbH, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
Arch Toxicol. 2010 Aug;84(8):619-29. doi: 10.1007/s00204-010-0548-2. Epub 2010 May 7.
The dioxin receptor, also known as arylhydrocarbon receptor (AhR), is a ligand-activated transcription factor that mediates the toxicity of dioxins and related environmental contaminants. In addition, there is a growing list of natural compounds, mainly plant polyphenols that can modulate AhR function and downstream signaling with quite unknown consequences for cellular function. We investigate the potential of four different beta-carboline alkaloids to stimulate AhR signaling in human hepatoma cells and keratinocytes. Three test substances, namely rutaecarpine, annomontine and xestomanzamine A, increase AhR-driven reporter gene activity as well as expression of two AhR target genes in a dose-dependent and time-dependent manner. Additionally, the three test alkaloids stimulate cytochrome P450 (CYP) 1 enzyme activity without showing any antagonistic effects regarding benzo(a)pyrene-stimulated CYP1 activation. The AhR-activating property of the beta-carbolines is completely abrogated in AhR-deficient cells providing evidence that rutaecarpine, annomontine and xestomanzamine A are natural stimulators of the human AhR. The toxicological relevance of beta-carboline-mediated AhR activation is discussed.
二恶英受体，也称为芳香烃受体 (AhR)，是一种配体激活的转录因子，介导二恶英和相关环境污染物的毒性。此外，越来越多的天然化合物，主要是植物多酚，可以调节 AhR 功能和下游信号转导，对细胞功能的影响尚不清楚。我们研究了四种不同的β-咔啉生物碱在人肝癌细胞和角质形成细胞中刺激 AhR 信号转导的潜力。三种测试物质，即一叶萩碱、安诺默丁和色满曼碱 A，以剂量和时间依赖性方式增加 AhR 驱动的报告基因活性以及两种 AhR 靶基因的表达。此外，这三种测试生物碱刺激细胞色素 P450 (CYP)1 酶活性，而对苯并 (a) 芘刺激的 CYP1 激活没有表现出任何拮抗作用。β-咔啉对 AhR 的激活作用在 AhR 缺陷细胞中完全被阻断，这为一叶萩碱、安诺默丁和色满曼碱 A 是人类 AhR 的天然激动剂提供了证据。讨论了β-咔啉介导的 AhR 激活的毒理学相关性。
