Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells
Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells
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DOI：
10.1016/j.taap.2009.05.006
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发表时间：
2009-07-15
影响因子：
3.8
通讯作者：
Le, X. Chris
中科院分区：
文献类型：
--
作者：
Naranmandura, Hua;Ogra, Yasumitsu;Le, X. Chris
砷的毒性取决于其化学形态。在人类中，膀胱是砷诱发的致癌性的主要靶器官之一。然而，很少有人知道砷诱导的致癌性的机制，以及砷的物种是负责这种致癌性。本研究旨在比较DMMTA（V）和无机亚砷酸盐（iAs（III））对人膀胱癌EJ-1细胞活力、摄取效率和活性氧（ROS）产生的毒性作用。结果进行了比较，与以前的研究，使用人表皮样癌A431细胞。虽然iAs（III）已知对大多数细胞具有毒性，但在此我们表明，iAs（III）（LC 50 = 112 μ M）在人膀胱EJ-1细胞中的细胞毒性远低于DMMTA（V）（LC 50 = 16.7 μ M）。有趣的是，五价含硫DMMTA（V）在EJ-1细胞中产生高水平的细胞内ROS。然而，在暴露于三价无机iAs（III）的细胞中，在其各自的LC 50剂量下未观察到这一点。此外，N-乙酰半胱氨酸的存在完全抑制DMMTA（V）的细胞毒性，但不抑制iAs（III），表明ROS的产生是暴露于DMMTA（V）而不是iAs（III）导致细胞死亡的主要原因。由于iAs（III）的细胞摄取是由水通道蛋白介导的，并且由于细胞对亚砷酸盐的抗性可以受到由于水通道蛋白（AQP 3，7和9）表达较低而导致的较低砷摄取的影响，因此还检查了水通道蛋白家族的几个成员的表达。在人膀胱EJ-1细胞中，AQP 3、7和9的mRNA和蛋白均未被逆转录聚合酶链反应（RT-PCR）/蛋白质印迹法检测到。A431细胞中仅检测到AQP 3的mRNA和蛋白。这两种细胞系之间毒性的巨大差异可能与它们对砷的吸收差异有关。(C)2009爱思唯尔公司All rights reserved.
Arsenic toxicity is dependent on its chemical species. In humans, the bladder is one of the primary target organs for arsenic-induced carcinogenicity. However, little is known about the mechanisms underlying arsenic-induced carcinogenicity, and what arsenic species are responsible for this carcinogenicity. The present study aimed at comparing the toxic effect of DMMTA(V) with that of inorganic arsenite (iAs(III)) on cell viability, uptake efficiency and production of reactive oxygen species (ROS) toward human bladder cancer EJ-1 cells. The results were compared with those of a previous study using human epidermoid carcinoma A431 cells. Although iAs(III) was known to be toxic to most cells, here we show that iAs(III) (LC50 = 112 mu M) was much less cytotoxic than DMMTA(V) (LC50 = 16.7 mu M) in human bladder EJ-1 cells. Interestingly, pentavalent sulfur-containing DMMTA(V) generated a high level of intracellular ROS in EJ-1 cells. However, this was not observed in the cells exposed to trivalent inorganic iAs(III) at their respective LC50 dose. Furthermore, the presence of N-acetyl-cysteine completely inhibited the cytotoxicity of DMMTA(V) but not iAs(III), suggesting that production of ROS was the main cause of cell death from exposure to DMMTA(V), but not iAs(III). Because the cellular uptake of iAs(III) is mediated by aquaporin proteins, and because the resistance of cells to arsenite can be influenced by lower arsenic uptake due to lower expression of aquaporin proteins (AQP 3, 7 and 9), the expression of several members of the aquaporin family was also examined. In human bladder EJ-1 cells, mRNA/proteins of AQP3, 7 and 9 were not detected by reverse transcription polymerase chain reaction (RT-PCR)/western blotting. In A431 cells, only mRNA and protein of AQP3 were detected. The large difference in toxicity between the two cell lines could be related to their differences in uptake of arsenic species. (C) 2009 Elsevier Inc. All rights reserved.