The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor.
The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor.
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DOI：
10.1021/bi901786x
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发表时间：
2010-01-19
期刊：
影响因子：
2.9
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
--
作者：
Schroeder, Jennifer C.;DiNatale, Brett C.;Murray, Iain A.;Flaveny, Colin A.;Liu, Qiang;Laurenzana, Elizabeth M.;Lin, Jyh Ming;Strom, Stephen C.;Omiecinski, Curtis J.;Amin, Shantu;Perdew, Gary H.
芳香烃受体（aryl hydrocarbon receptor，AHR）是一种配体激活的转录因子，参与多种细胞途径的调控，如外源性物质代谢和Th 17细胞分化。调节AHR功能的关键生理相关配体的鉴定仍有待完成。吲哚代谢物的筛选已确定吲哚酚-3-硫酸盐（I3 S）是一种有效的内源性配体，在原代人肝细胞中以纳摩尔浓度选择性激活人AHR，调节多个基因的转录，包括：CYP 1A 1、CYP 1A 2、CYP 1B 1、UGT 1A 1、UGT 1A 6、IL 6和SAA 1。此外，在细胞系中，I3 S在人AHR的转录激活方面表现出比小鼠AHR高约500倍的效力。结构-功能研究表明，硫酸基团是有效激活AHR的重要决定因素。这是鉴定的第一个可以显著激活AHR的II相酶产物，并且配体竞争结合测定表明I3 S是直接的AHR配体。I3 S无法激活CAR或PXR。I3 S的生理重要性在于它是一种关键的尿毒症毒素，在肾透析患者中积累至高微摩尔浓度，但其作用机制尚不清楚。I3 S代表了第一个鉴定的相对高效力的内源性AHR配体，其在人类疾病进展中起关键作用。这些研究提供的证据表明，I3 S的产生可以导致AHR激活和药物代谢的改变。我们的研究结果还表明，I3 S对AHR的长期激活可能导致在肾透析患者中观察到的毒性，因此代表了一个可能的治疗靶点。
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in the regulation of multiple cellular pathways, such as xenobiotic metabolism and Th17 cell differentiation. Identification of key physiologically relevant ligand(s) that regulate AHR function remains to be accomplished. Screening of indole metabolites has identified indoxyl-3-sulfate (I3S) as a potent endogenous ligand that selectively activates the human AHR at nanomolar concentrations in primary human hepatocytes, regulating transcription of multiple genes, including: CYP1A1, CYP1A2, CYP1B1, UGT1A1, UGT1A6, IL6, and SAA1. Furthermore, I3S exhibits an ~ 500-fold greater potency in terms of transcriptional activation of the human AHR relative to the mouse AHR in cell lines. Structure-function studies reveal that the sulfate group is important determinant for efficient AHR activation. This is the first phase II enzymatic product identified that can significantly activate the AHR and ligand competition binding assays indicate that I3S is a direct AHR ligand. I3S failed to activate either CAR or PXR. The physiological importance of I3S lies in the fact that it is a key uremic toxin that accumulates to high micromolar concentrations in kidney dialysis patients, but its mechanism of action is unknown. I3S represents the first identified relatively high potency endogenous AHR ligand that plays a key role in human disease progression. These studies provide evidence that the production of I3S can lead to AHR activation and altered drug metabolism. Our results also suggest that prolonged activation of the AHR by I3S may contribute to toxicity observed in kidney dialysis patients and thus represent a possible therapeutic target.
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影响因子：
3.6
作者：
Harstad, EB;Guite, CA;Bradfield, CA
通讯作者：
Bradfield, CA
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作者：
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作者：
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作者：
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通讯作者：
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