The ATP-Binding Cassette Transporter ABCB6 Is Induced by Arsenic and Protects against Arsenic Cytotoxicity
The ATP-Binding Cassette Transporter ABCB6 Is Induced by Arsenic and Protects against Arsenic Cytotoxicity
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DOI：
10.1093/toxsci/kfr008
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发表时间：
2011-04-01
影响因子：
3.8
通讯作者：
Krishnamurthy, Partha
中科院分区：
文献类型：
--
作者：
Chavan, Hemantkumar;Oruganti, Mahitha;Krishnamurthy, Partha
砷是一种环境致癌物，仍然是一个主要的公共卫生问题。砷通过多种机制损害生物系统，包括产生活性氧。 ABCB6 是一种 ATP 结合盒转运蛋白，在砷抗性细胞中高表达。我们最近证明 ABCB6 表达可以防止细胞应激源。在本研究中，我们评估了 ABCB6 表达对小鼠和细胞培养物中砷毒性的重要性。我们发现，在饮用水中喂食亚砷酸钠的小鼠和体外暴露于亚砷酸钠的细胞中，亚砷酸钠均以剂量依赖性方式诱导 ABCB6 表达。亚砷酸盐诱导的 ABCB6 表达受到转录调节，但这种诱导不是由氧化还原敏感转录因子核因子 - 红细胞 2 相关因子 2 (Nrf2) 介导的。我们证明，在 HepG2 和 Hep3B 细胞中，使用 ABCB6 特异性小干扰 RNA 敲低 ABCB6 表达可使细胞对亚砷酸盐毒性敏感。相比之下，ABCB6 的稳定过表达对亚砷酸盐诱导的氧化应激具有强大的生存优势。总的来说，通过功能丧失和功能获得分析获得的这些结果表明，亚砷酸钠响应的 ABCB6 表达可能是一种内源性保护机制，被激活以保护细胞免受亚砷酸盐诱导的氧化应激。
Arsenic, an environmental carcinogen, remains a major public health problem. Arsenic damages biological systems through multiple mechanisms, including the generation of reactive oxygen species. ABCB6 is an ATP-binding cassette transporter that is highly expressed in cells resistant to arsenic. We have recently demonstrated that ABCB6 expression protects against cellular stressors. In the present study, we evaluated the significance of ABCB6 expression to arsenic toxicity both in mice and in cell culture. We show that sodium arsenite induces ABCB6 expression in a dose-dependent manner both in mice fed sodium arsenite in drinking water and in cells exposed to sodium arsenite in vitro. Arsenite-induced ABCB6 expression was transcriptionally regulated, but this induction was not mediated by the redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2). We demonstrate that, in HepG2 and Hep3B cells, knockdown of ABCB6 expression using ABCB6-specific small interfering RNA sensitized the cells to arsenite toxicity. In contrast, stable overexpression of ABCB6 conferred a strong survival advantage toward arsenite-induced oxidative stress. Collectively, these results, obtained by both loss of function and gain of function analysis, suggest that ABCB6 expression in response to sodium arsenite might be an endogenous protective mechanism activated to protect cells against arsenite-induced oxidative stress.