Graduate School of Chemistry, Westfälische Wilhelms-Universität Muenster, Wilhelm-Klemm-Straße 10, 48149 Muenster, Germany; Institute of Food Chemistry, Westfälische Wilhelms-Universität Muenster, Corrensstraße 45, 48149 Muenster, Germany.
Toxicology. 2013 Mar 8;305:109-19. doi: 10.1016/j.tox.2013.01.007. Epub 2013 Jan 23.
Inorganic arsenic is a well-documented, exposure relevant human carcinogen. A promising starting point to further understand the mechanisms behind inorganic arsenic carcinogenicity might be a formation of reactive, highly toxic metabolites during human arsenic metabolism. This study characterises the toxicity of recently identified S-containing arsenic metabolites in cultured human A549 lung adenocarcinoma epithelium cells. In direct comparison to arsenite, thio-dimethylarsinic acid (thio-DMA(V)) and dimethylarsinic glutathione (DMAG) exerted a 5- to 20-fold stronger cytotoxicity and showed a 2- to 20-fold higher cellular bioavailability, respectively. All three arsenicals disturbed cell cycle progression at cytotoxic concentrations, but failed to increase the level of reactive oxygen and nitrogen species (RONS) in healthy A549 cells. However, a strong disturbance of the oxidative defense system was observed after incubation with absolutely sub-cytotoxic, pico- to nanomolar concentrations of arsenite and thio-DMA(V), respectively. Thus, both GSH and GSSG levels were significantly decreased by up to 40%. Accordingly, RONS levels of oxidatively (H2O2) stressed cells were strongly increased by the arsenicals. Since in vivo RONS are permanently endogenously and exogenously produced, this boost of the existing oxidative stress by arsenite and thio-DMA(V) might contribute to the process of inorganic arsenic induced carcinogenicity.
无机砷是一种有充分文献记录的、与暴露相关的人类致癌物。进一步了解无机砷致癌性背后机制的一个有希望的起点可能是在人类砷代谢过程中形成反应性的、高毒性代谢物。本研究描述了最近在培养的人 A549 肺腺癌细胞中鉴定出的含硫砷代谢物的毒性。与亚砷酸盐直接比较，硫代二甲基砷酸（thio-DMA(V)）和二甲基砷酸谷胱甘肽（DMAG）的细胞毒性分别强 5 至 20 倍，细胞内生物利用度分别高 2 至 20 倍。这三种砷化合物在细胞毒性浓度下均干扰细胞周期进程，但未能增加健康 A549 细胞中活性氧和氮物种 (RONS) 的水平。然而，在用绝对亚细胞毒性、皮摩尔至纳摩尔浓度的亚砷酸盐和 thio-DMA(V)孵育后，观察到氧化防御系统的强烈干扰。因此，GSH 和 GSSG 水平分别显著降低了 40%。相应地，氧化应激（H2O2）细胞中的 RONS 水平被砷化合物强烈增加。由于体内 RONS 是内源性和外源性持续产生的，因此亚砷酸盐和 thio-DMA(V)对现有氧化应激的这种增强可能有助于无机砷诱导的致癌过程。
