Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway
Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway
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DOI：
10.1016/j.taap.2010.04.020
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Honscha, Walther
中科院分区：
文献类型：
--
作者：
Halwachs, Sandra;Lakoma, Cathleen;Honscha, Walther
二恶英，如2，3，7，8-四氯二苯并-对-二恶英（TCDD）是常见的环境污染物，已知通过激活转录因子芳烃受体（AhR）调节几种基因，与许多不良生物效应的发展相关。然而，对于二恶英在脊椎动物中显示其毒性作用的分子机制知之甚少。肝细胞还原型叶酸载体（Rfc 1; Slc 19 a1）的5'非翻译区显示出被称为二恶英反应元件（ORE）的AhR结合位点，其迄今仅在原型TCDD靶基因的启动子区中发现。Rfc 1介导的还原叶酸和抗叶酸药物如甲氨蝶呤（MTX）的转运在生理叶酸稳态和MIX癌症化疗中起着重要作用。为了确定该载体是否代表二恶英的靶基因，我们研究了TCDD对大鼠肝脏中功能性Rfc 1活性的影响。用TCDD预处理大鼠显著降低肝细胞Rfc 1摄取活性，并呈时间和剂量依赖性。在进一步的机制研究中，我们证明，这种减少是由于TCDD依赖性激活的AhR信号通路。我们还表明，激活的受体结合到Rfc 1启动子中的DRE基序导致Rfc 1基因表达下调和载体蛋白水平降低。由于下调关键Rfc 1活性导致功能性叶酸缺乏与心血管疾病或致癌风险升高相关，我们的研究结果表明，这一重要的运输途径的失调代表了一种新的监管机制，二恶英如何通过Ah受体显示其毒性作用。(C)2010年爱思唯尔公司All rights reserved.
Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (ORE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MIX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression and reduced carrier protein levels. As downregulation of pivotal Rfc1 activity results in functional folate deficiency associated with an elevated risk of cardiovascular diseases or carcinogenesis, our results indicate that deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptor. (C) 2010 Elsevier Inc. All rights reserved.