Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ.
Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ.
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DOI：
10.1021/acs.chemrestox.5b00416
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发表时间：
2016-01
影响因子：
4.1
通讯作者：
A. Smirnova;E. Wincent;Linda Vikström Bergander;T. Alsberg;J. Bergman;A. Rannug;U. Rannug
中科院分区：
文献类型：
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作者：
A. Smirnova;E. Wincent;Linda Vikström Bergander;T. Alsberg;J. Bergman;A. Rannug;U. Rannug
芳烃受体（AhR）是一种保守的转录因子，是高毒性卤化物质（如二恶英）的靶标，在正常的无外源条件下，芳烃受体（AhR）的激活具有相当大的科学意义。我们之前已经证明，色氨酸的光产物6-甲酰基林多洛[3,2-b]咔唑（FICZ）满足该受体内源性配体的标准，并提出该化合物是AhR生理功能的神秘介质。在这里，我们描述了一种新的不依赖光的途径，通过这种途径可以形成FICZ。在没有光线的情况下，氧化剂H2O2可以自行将色氨酸转化为FICZ。酶对色胺的脱胺反应产生吲哚-3-乙醛（I3A），然后重新排列为FICZ及其氧化产物吲哚[3,2-b]咔唑-6-羧酸（CICZ）。吲哚-3-丙酮酸酯（I3P）也产生I3A、FICZ和CICZ。马拉色菌属酵母菌是正常皮肤微生物群的一部分，从色氨酸中产生许多AhR活化剂。我们在这些产品中确定了FICZ和CICZ。由色氨酸或I3P形成的FICZ会产生吲哚衍生物的复杂混合物，其中一些是CYP1A1抑制剂。这些可以阻碍FICZ的细胞清除，从而增加其作为AhR激动剂的能力。我们提出了一个一般的分子机制，包括脱氢和氧化偶联的形成，其中I3A是重要的前体。综上所述，我们的结果表明，FICZ可能是系统性形成的。
Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.