Identification of endocrine disrupting chemicals activating SXR-mediated transactivation of CYP3A and CYP7A1.
Identification of endocrine disrupting chemicals activating SXR-mediated transactivation of CYP3A and CYP7A1.
复制标题
鉴定激活 SXR 介导的 CYP3A 和 CYP7A1 反式激活的内分泌干扰化学物质。
DOI：
10.1016/j.mce.2012.09.001
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发表时间：
2013
影响因子：
4.1
通讯作者：
Zhao Y.
中科院分区：
文献类型：
--
作者：
Zhou T.;Cong S.;Sun S.;Sun H.;Zou R.;Wang S.;Wang C.;Jiao J.;Goto K.;Nawata H.;Yanase T.;Zhao Y.
内分泌干扰物（EDCs）已成为一个主要的公共卫生问题，因为它们对生理激素的作用可能产生破坏性影响。SXR（类固醇异生素受体），也称为NR1I2，在与SXRE（SXR反应元件）结合后调节CYP3A表达以响应外源性化学物质，如EDCs。荧光素酶检测结果表明，55种内分泌干扰物中有14种能均匀地增强SXR介导的大鼠或人CYP3A基因的转录，并能通过SXR和LXRE（LXRα反应元件）的交叉作用激活大鼠CYP7A1基因的转录。SXR在无配体的情况下在核中扩散，而配体SXR的核内病灶产生。14种阳性EDCs均能促进CYP3A4基因的内源性mRNA表达。我们的研究结果表明，一个可能的机制，内分泌干扰物通过SXR破坏类固醇或外源性代谢稳态。
Endocrine disrupting chemicals (EDCs) have emerged as a major public health issue because of their potentially disruptive effects on physiological hormonal actions. SXR (steroid xenobiotic receptor), also known as NR1I2, regulates CYP3A expression in response to exogenous chemicals, such as EDCs, after binding to SXRE (SXR response element). In our study, luciferase assay showed that 14 out of 55 EDCs could enhance SXR-mediated rat or human CYP3A gene transcription nearly evenly, and could also activate rat CYP7A1 gene transcription by cross-interaction of SXR and LXRE (LXRα response element). SXR diffused in the nucleus without ligand, whereas intranuclear foci of liganded SXR were produced. Furthermore, endogenous mRNA expression of CYP3A4 gene was enhanced by the 14 positive EDCs. Our results suggested a probable mechanism of EDCs disrupting the steroid or xenobiotic metabolism homeostasis via SXR.