Differential effects of the organochlorine pesticide DDT and its metabolite p,p′-DDE on p-glycoprotein activity and expression
Differential effects of the organochlorine pesticide DDT and its metabolite p,p′-DDE on p-glycoprotein activity and expression
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DOI：
10.1016/j.taap.2004.07.011
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发表时间：
2005-03-01
影响因子：
3.8
通讯作者：
Caplan, AJ
中科院分区：
文献类型：
--
作者：
Shabbir, A;DiStasio, S;Caplan, AJ
1，1-二(4-氯苯基)-2，2，2-三氯乙烷(DDT)是一种有机氯农药。其代谢产物1，1-二氯-2，2-二(对氯苯基)-乙烯(pp‘-DDE)是一种持久性的环境污染物，两者都在动物体内积累。由于多药耐药转运蛋白，如p-糖蛋白，起到防御异种生物暴露的作用，我们分析了DDT和p，p‘-DDE作为外排调节剂的能力。使用基于荧光染料罗丹明123外流的完整细胞竞争实验，我们发现DDT而不是p，p‘-DDE促进了染料保留率。随后使用维拉帕米作为竞争对手的研究表明，DDT是一种弱的P-糖蛋白抑制剂。进一步研究了DDT和p，p‘-DDE诱导编码p-糖蛋白基因mdr1的能力。在HepG2细胞中，我们发现这两种化合物都能诱导两倍到三倍的MDR1。在单剂量p，p‘-DDE的小鼠肝脏中也观察到了类似的结果，尽管注意到了一些性别特异性的诱导差异。相比之下，pp‘-DDE不能在HeLa细胞中诱导多药耐药，这表明诱导具有细胞特异性。进一步的表达研究表明，内质网分子伴侣Bip的水平增加是对DDT的反应，但不是pp‘-DDE的反应。这些结果表明，DDT而不是pp‘-DDE诱导了内质网应激反应。(C)2004 Elsevier Inc.保留所有权利。
1,1-Bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) is an organochlorine pesticide. Its metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethene (pp'-DDE) is a persistent environmental contaminant and both compounds accumulate in animals. Because multidrug resistance transporters, such as p-glycoprotein, function as a defense against xenobiotic exposure, we analyzed the ability of DDT and p,p'-DDE to act as efflux modulators. Using a competitive intact cell assay based on the efflux of the fluorescent dye rhodamine 123, we found that DDT, but not p,p'-DDE, stimulated dye retention. Subsequent studies using verapamil as competitor suggested that DDT is a weak p-glycoprotein inhibitor. Further studies addressed the ability of DDT and p,p'-DDE to induce MDR1, the gene encoding p-glycoprotein. In HepG2 cells, we found that both compounds induced MDR1 by twofold to threefold. Similar results were observed in mouse liver after a single dose of p,p'-DDE, although some gender-specific induction differences were noted. By contrast, pp'-DDE failed to induce MDR1 in HeLa cells, indicating some cell-specific effects for induction. Further expression studies demonstrated increased levels of the endoplasmic reticulum molecular chaperone, Bip, in response to DDT, but not pp'-DDE. These results suggest that DDT, but not pp'-DDE, induces an endoplasmic reticulum stress response. (C) 2004 Elsevier Inc. All rights reserved.