Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts
Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts
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DOI：
10.1016/j.bbrc.2003.09.086
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发表时间：
2003-10-24
影响因子：
3.1
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Hayashi, A;Suzuki, H;Sugiyama, Y
核因子-E2P45相关因子(NRF)2是一种转录因子，用于抗氧化剂反应元件介导的结合酶的诱导。由于多药耐药相关蛋白1(MRp1/Abcc1)是一种三磷酸腺苷结合盒转运体，在结合代谢产物的细胞排泄中起重要作用，因此与结合酶协同作用对外源物质的细胞解毒作用，我们探讨了Nrf2在小鼠胚胎成纤维细胞中也参与MRp1表达的可能性。与野生型细胞相比，Nrf2(-/-)细胞中MRP1mRNA和蛋白的组成性表达水平显著降低。此外，在野生型细胞中观察到马来酸二乙酯的显著诱导作用，但在Nrf2(-/-)细胞中没有观察到明显的诱导作用，这表明Nrf2参与了MRp1的结构性和诱导性mRNA和蛋白的表达。此外，MRP1的典型底物[H-3]2，4-二硝基苯基-S-谷胱甘肽被分离的膜泡摄取也表明NRF2调节谷胱甘肽结合物在小鼠成纤维细胞中的转运活性。这是第一次证明Nrf2是MRP家族蛋白的组成性和诱导性表达所必需的。(C)2003 Elsevier Inc.保留所有权利。
The nuclear factor-E2 p45-related factor (Nrf) 2 is a transcription factor for the antioxidant responsive element-mediated induction of enzymes responsible for conjugation. Since multidrug resistance-associated protein1 (Mrp1/Abcc1) is an ATP-binding cassette transporter which plays an important role in the cellular extrusion of conjugated metabolites and, therefore, acts synergistically with conjugating enzymes for the cellular detoxification of xenobiotics, we examined the possibility that Nrf2 is also involved in the expression of Mrp1 in mouse embryo fibroblasts. The constitutive expression levels of Mrp1 mRNA and protein were significantly lower in Nrf2 (-/-) cells compared with those in wild type cells. In addition, significant induction by diethyl maleate was observed in wild type, but not in Nrf2 (-/-), cells, suggesting the involvement of Nrf2 in both the constitutive and inducible mRNA and protein expression of Mrp1. In addition, the uptake of [H-3]2,4-dinitrophenyl-S-glutathione, a typical substrate of Mrp1, into isolated membrane vesicles also demonstrated that Nrf2 regulates the transport activity of glutathione conjugates in mouse fibroblasts. This is the first demonstration that Nrf2 is required for the constitutive and inducible expression of Mrp family proteins. (C) 2003 Elsevier Inc. All rights reserved.