Investigating the role of the aryl hydrocarbon receptor in benzene-initiated toxicity in vitro
Investigating the role of the aryl hydrocarbon receptor in benzene-initiated toxicity in vitro
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DOI：
10.1016/j.tox.2006.10.021
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发表时间：
2007-01-18
期刊：
影响因子：
4.5
通讯作者：
Winn, Louise M.
中科院分区：
文献类型：
--
作者：
Badham, Helen J.;Winn, Louise M.
慢性职业性苯暴露与再生障碍性贫血和急性髓性白血病有关，但苯毒性的机制尚不清楚。有趣的是，在缺乏芳烃受体（AhR）的小鼠中不存在苯引发的血液毒性，这表明该受体在苯毒性中的重要作用。本研究调查了两个潜在的作用，AhR在苯毒性使用hepa 1c1c7野生型和AhR缺陷细胞。考虑到AhR配体的许多毒性作用依赖于AhR活化，我们的第一个目标是确定苯、氢醌（HQ）或苯醌（BQ）是否可以活化AhR。其次，由于AhR调节参与氧化应激途径的许多酶，我们试图确定AhR是否在HQ和BQ诱导的活性氧（ROS）产生中起作用。双荧光素酶法检测二恶英反应元件（DRE）的活化，结果表明，在暴露于苯，HQ或BQ 24 h后，DRE活性无显著变化。免疫荧光染色显示AhR在与苯、HQ或BQ孵育2小时后的胞质定位。细胞暴露于苯，HQ或BQ 1，12和24小时的蛋白质印迹分析没有表现出诱导CYP1A1蛋白质表达。二氯二氢荧光素染色的细胞暴露于苯，HQ或BQ显示，AhR的存在并不影响BQ和HQ诱导的ROS的产生。这些结果表明，苯毒性中的AhR的参与似乎不是通过经典的激活该受体或通过氧化应激途径的干扰。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Chronic occupational exposure to benzene has been correlated with aplastic aneamia and acute myelogenous leukemia, however mechanisms behind benzene toxicity remain unknown. Interestingly, benzene-initiated hematotoxicity is absent in mice lacking the aryl hydrocarbon receptor (AhR) suggesting an imperative role for this receptor in benzene toxicities. This study investigated two potential roles for the AhR in benzene toxicity using hepa 1c1c7 wild type and AhR deficient cells. Considering that many toxic effects of AhR ligands are dependent on AhR activation, our first objective was to determine if benzene, hydroquinone (HQ) or benzoquinone (BQ) could activate the AhR. Secondly, because the AhR regulates a number of enzymes involved in oxidative stress pathways, we sought to determine if the AhR had a role in HQ and BQ induced production of reactive oxygen species (ROS). Dual luciferase assays measuring dioxin response element (DRE) activation showed no significant change in DRE activity after exposure to benzene, HQ or BQ for 24 h. Immunofluorescence, staining showed cytosolic localization of the AhR after 2 h incubations with benzene, HQ or BQ. Western blot analysis of cells exposed to benzene, HQ or BQ for 1, 12 and 24 h did not demonstrate induction of CYP1A1 protein expression. Dichlorodihydrofluorescein staining of cells exposed to benzene, HQ or BQ revealed that the presence of the AhR did not affect BQ and HQ induced ROS production. These results indicate that the involvement of the AhR in benzene toxicity does not seem to be through classical activation of this receptor or through interference of oxidative stress pathways. (c) 2006 Elsevier Ireland Ltd. All rights reserved.