Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene.
Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene.
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DOI：
10.1016/j.toxlet.2012.04.006
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发表时间：
2012-06-20
影响因子：
3.5
通讯作者：
Blanco, Javier G.
中科院分区：
文献类型：
--
作者：
Kalabus, James L.;Cheng, Qiuying;Jamil, Raqeeb G.;Schuetz, Erin G.;Blanco, Javier G.
羰基还原酶1(CBR1)可将各种外来的羰基底物还原为相应的乙醇代谢物。在这里，我们证明了苯并[a]芘(B[a]P)是一种强烈的致癌物质，也是香烟烟雾和空气污染物中的主要多环芳烃化合物，在体外和体内都能上调CBR1基因的表达，并且近端的异种反应元件(XRE)基序(−122XRE)介导了苯并[a]P的诱导作用。首先，我们观察到吸烟者与不吸烟者相比，人肺组织中CBR1mRNA和CBR1蛋白水平分别增加了46%和50%。第二，我们检测到在2.5uM B[a]P孵育24小时的人肺癌细胞株A549中，CBR1mRNA和蛋白水平分别增加了3倍和1.5倍(P<；0.0001)。第三，CBR1启动子结构的实验结果表明，近端的XRE基序(−122XRE)介导了对B[a]P的报告活性的诱导。此外，我们在A549细胞中检测到B[a]P暴露后芳香烃受体(AhR)的核转位增加。最后，我们证明了在B[a]P处理的细胞核提取物中，特定的蛋白质复合体与−122XRE的结合增加，并且在特定的核蛋白−122XRE复合体中存在AhR/ArnT复合体。
Carbonyl reductase 1 (CBR1) reduces various xenobiotic carbonyl substrates to corresponding alcohol metabolites. Here we demonstrated that benzo[a]pyrene (B[a]P), a potent pro-carcinogen and predominant polycyclic aromatic hydrocarbon (PAH) compound in cigarette smoke and air pollutants, upregulates CBR1 gene expression in vitro and in vivo, and that a proximal xenobiotic response elements (XRE) motif (−122XRE) mediates the induction effect of B[a]P. First, we observed 46% and 50% increases in CBR1 mRNA and CBR1 protein levels, respectively, in human lung tissue samples from smokers compared to never-smokers. Second, we detected 3.0-fold (p < 0.0001) induction of CBR1 mRNA and 1.5-fold (p < 0.01) induction of CBR1 protein levels in cells of the human lung cancer cell line A549 incubated with 2.5µM B[a]P for 24 hours. Third, results from experiments with CBR1 promoter constructs indicated that a proximal XRE motif (−122XRE) mediates induction of reporter activity in response to B[a]P. Furthermore, we detected enhanced nuclear translocation of aryl hydrocarbon receptor (AhR) following B[a]P exposure in A549 cells. Finally, we demonstrated increased binding of specific protein complexes to −122XRE in nuclear extracts from B[a]P-treated cells and the presence of the AhR/Arnt complex in the specific nuclear protein−122XRE complexes.
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