Dietary and microbial indoles can act as ligands and activators of pregnane X receptor (PXR), with implications in human intestinal health. In the current study, we examined the effects of simple mono-methylated indoles (MMIs) on the activity and function of PXR, using a series of human hepatic and intestinal cell models. Indoles 1-MMI and 2-MMI strongly induced CYP3A4 and MDR1 mRNAs in human intestinal adenocarcinoma cells LS180, but not in primary human hepatocytes. The levels of CYP3A4 mRNA were increased by 1-MMI and 2-MMI in wild type, but not in PXR-knock-out human hepatic progenitor HepaRG cells, implying the involvement of PXR in CYP3A4 induction by MMIs. Utilizing reporter gene assay, we observed dose-dependent activation of PXR by all MMIs, and their efficacies and potencies were comparable. Tested MMIs also displayed moderate antagonist effects on PXR, revealing about partial agonist effects of these compounds. As demonstrated using the Chromatin immunoprecipitation assay (ChIP),1-MMI increased PXR occupancy of the CYP3A4 promoter. Time-Resolved Fluorescence Resonance Energy Transfer revealed that MMIs are weak ligands of human PXR. Collectively, we show that MMIs are ligands and partial agonists of human PXR, which induce PXR-regulated genes in human intestinal cells.

中文翻译：

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在肠道和肝脏体外模型中异构单甲基化吲哚对人孕烷 X 受体 PXR 的差异激活

膳食和微生物吲哚可作为孕烷 X 受体 (PXR) 的配体和激活剂，对人类肠道健康产生影响。在当前的研究中，我们使用一系列人肝和肠细胞模型检查了简单单甲基化吲哚 (MMI) 对 PXR 活性和功能的影响。吲哚 1-MMI 和 2-MMI 在人肠腺癌细胞 LS180 中强烈诱导 CYP3A4 和 MDR1 mRNA，但在原代人肝细胞中没有。野生型中 CYP3A4 mRNA 的水平通过 1-MMI 和 2-MMI 增加，但在敲除 PXR 的人肝祖 HepaRG 细胞中没有增加，这意味着 PXR 参与了 MMI 对 CYP3A4 的诱导。利用报告基因分析，我们观察到所有 MMI 对 PXR 的剂量依赖性激活，并且它们的功效和效力相当。经测试的 MMI 还显示出对 PXR 的中等拮抗作用，揭示了这些化合物的部分激动作用。正如使用染色质免疫沉淀试验 (ChIP) 所证明的那样，1-MMI 增加了 CYP3A4 启动子的 PXR 占有率。时间分辨荧光共振能量转移表明 MMI 是人类 PXR 的弱配体。总的来说，我们表明 MMI 是人类 PXR 的配体和部分激动剂，可在人类肠道细胞中诱导 PXR 调节基因。