Cheng Yating, Jin Un-Ho, Allred Clint D, Jayaraman Arul, Chapkin Robert S, Safe Stephen
Department of Veterinary Physiology and Pharmacology (Y.C., U.-H.J., S.S.), Department of Nutrition and Food Science (C.D.A., R.S.C.), Department of Chemical Engineering (A.J.), Texas A&M University, College Station, Texas.
Department of Veterinary Physiology and Pharmacology (Y.C., U.-H.J., S.S.), Department of Nutrition and Food Science (C.D.A., R.S.C.), Department of Chemical Engineering (A.J.), Texas A&M University, College Station, Texas
Drug Metab Dispos. 2015 Oct;43(10):1536-43. doi: 10.1124/dmd.115.063677. Epub 2015 Apr 14.
The tryptophan microbiota metabolites indole-3-acetate, indole-3-aldehyde, indole, and tryptamine are aryl hydrocarbon receptor (AhR) ligands, and in this study we investigated their AhR agonist and antagonist activities in nontransformed young adult mouse colonocyte (YAMC) cells. Using Cyp1a1 mRNA as an Ah-responsive end point, we observed that the tryptophan metabolites were weak AhR agonists and partial antagonists in YAMC cells, and the pattern of activity was different from that previously observed in CaCo2 colon cancer cells. However, expansion of the end points to other Ah-responsive genes including the Cyp1b1, the AhR repressor (Ahrr), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiParp) revealed a highly complex pattern of AhR agonist/antagonist activities that were both ligand- and gene-dependent. For example, the magnitude of induction of Cyp1b1 mRNA was similar for TCDD, tryptamine, and indole-3-acetate, whereas lower induction was observed for indole and indole-3-aldehyde was inactive. These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators.
色氨酸微生物群代谢产物吲哚 - 3 - 乙酸、吲哚 - 3 - 醛、吲哚和色胺是芳烃受体（AhR）的配体，在本研究中，我们研究了它们在未转化的成年小鼠结肠细胞（YAMC）中的AhR激动剂和拮抗剂活性。以Cyp1a1 mRNA作为Ah反应终点，我们观察到色氨酸代谢产物在YAMC细胞中是弱AhR激动剂和部分拮抗剂，其活性模式与先前在CaCo2结肠癌细胞中观察到的不同。然而，将终点扩展到其他Ah反应基因，包括Cyp1b1、AhR阻遏物（Ahrr）和2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）诱导的聚（ADP - 核糖）聚合酶（TiParp），揭示了一种高度复杂的AhR激动剂/拮抗剂活性模式，该模式既依赖配体也依赖基因。例如，TCDD、色胺和吲哚 - 3 - 乙酸对Cyp1b1 mRNA的诱导程度相似，而吲哚的诱导程度较低，吲哚 - 3 - 醛则无活性。这些结果表明，微生物群中鉴定出的色氨酸代谢产物是选择性AhR调节剂。
