Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA.
Toxicol Appl Pharmacol. 2010 May 1;244(3):366-73. doi: 10.1016/j.taap.2010.01.019. Epub 2010 Feb 11.
Arsenic is a widespread environmental toxicant with a diverse array of molecular targets and associated diseases, making the identification of the critical mechanisms and pathways of arsenic-induced cytotoxicity a challenge. In a variety of experimental models, over a range of arsenic exposure levels, apoptosis is a commonly identified arsenic-induced cytotoxic pathway. Human lymphoblastoid cell lines (LCL) have been used as a model system in arsenic toxicology for many years, but the exact mechanism of arsenic-induced cytotoxicity in LCL is still unknown. We investigated the cytotoxicity of sodium arsenite in LCL 18564 using a set of complementary markers for cell death pathways. Markers indicative of apoptosis (phosphatidylserine externalization, PARP cleavage, and sensitivity to caspase inhibition) were uniformly negative in arsenite exposed cells. Interestingly, electron microscopy, acidic vesicle fluorescence, and expression of LC3 in LCL 18564 identified autophagy as an arsenite-induced process that was associated with cytotoxicity. Autophagy, a cellular programmed response that is associated with both cellular stress adaptation as well as cell death appears to be the predominant process in LCL cytotoxicity induced by arsenite. It is unclear, however, whether LCL autophagy is an effector mechanism of arsenite cytotoxicity or alternatively a cellular compensatory mechanism. The ability of arsenite to induce autophagy in lymphoblastoid cell lines introduces a potentially novel mechanistic explanation of the well-characterized in vitro and in vivo toxicity of arsenic to lymphoid cells.
砷是一种广泛存在的环境毒物，具有多种分子靶标和相关疾病，因此确定砷诱导细胞毒性的关键机制和途径是一项挑战。在各种实验模型中，在一系列砷暴露水平下，细胞凋亡是一种常见的砷诱导细胞毒性途径。人类淋巴母细胞系（LCL）多年来一直被用作砷毒理学的模型系统，但 LCL 中砷诱导细胞毒性的确切机制仍不清楚。我们使用一组细胞死亡途径的互补标志物研究了亚砷酸钠对 LCL18564 的细胞毒性。凋亡标志物（磷脂酰丝氨酸外翻、PARP 切割和对 caspase 抑制的敏感性）在暴露于亚砷酸钠的细胞中均呈阴性。有趣的是，电镜、酸性囊泡荧光和 LCL18564 中 LC3 的表达鉴定出自噬是一种砷诱导的过程，与细胞毒性有关。自噬是一种细胞程序性反应，与细胞应激适应和细胞死亡都有关，似乎是砷诱导 LCL 细胞毒性的主要过程。然而，目前尚不清楚 LCL 自噬是砷细胞毒性的效应机制，还是细胞的代偿性机制。亚砷酸钠能够诱导淋巴母细胞系发生自噬，这为砷对淋巴细胞的体内和体外毒性的特征明确的机制提供了一个潜在的新的解释。
