Jiang Xuejun, Chen Chengzhi, Liu Yuan, Zhang Ping, Zhang ZunZhen
Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu 610041, People's Republic of China.
Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA.
Mutat Res Genet Toxicol Environ Mutagen. 2014 Aug;770:35-45. doi: 10.1016/j.mrgentox.2014.04.016. Epub 2014 May 9.
Trivalent inorganic arsenic (iAs(3+)) is a powerful carcinogen that enhances the risk of lung cancer. Paradoxically, iAs(3+) also shows substantial efficacy in the treatment of lung tumors. However, the exact molecular mechanisms underlying iAs(3+)-induced toxicity and therapeutic effect in lung remain unclear. In this study, the effects of iAs(3+), sodium arsenite (NaAsO2) and arsenic trioxide (As2O3), on cell viability, apoptosis, genotoxicity and oxidative stress in cultured human bronchial epithelial cells were observed. Our results showed that NaAsO2 and As2O3 exposure could result in defects in cell proliferation and greatly enhance the level of oxidative damage. To clarify the critical role of glutathione (GSH) homeostasis in oxidative damage induced by iAs(3+), we further measured the content of GSH, ratio of GSH to GSSG, and the activities of GSH-related enzymes involved in the process of GSH synthesis, recycling and utilization. Our data demonstrated that NaAsO2 and As2O3 disrupted the balance of GSH homeostasis, and NaAsO2- and As2O3-induced oxidative damage was closely associated with the imbalance in GSH synthesis, recycling and utilization. To better understand the physiologic significance of Nrf2 in maintaining GSH-homeostasis, the expression level of Nrf2 was measured after iAs(3+) exposure. We found that the protein expression levels of Nrf2 were increased in both NaAsO2- and As2O3-treated cells. Collectively, our findings suggest that disturbed Nrf2-regulated GSH-homeostasis is associated with the oxidative damage triggered by iAs(3+), and loss of GSH homeostasis might implicate in both the pathogenesis of iAs(3+)-induced lung diseases and anticancer activity of iAs(3+).
三价无机砷（iAs(3+)）是一种强大的致癌物，会增加患肺癌的风险。矛盾的是，iAs(3+)在肺癌治疗中也显示出显著疗效。然而，iAs(3+)在肺部诱导毒性和治疗效果的具体分子机制仍不清楚。在本研究中，观察了iAs(3+)、亚砷酸钠（NaAsO2）和三氧化二砷（As2O3）对培养的人支气管上皮细胞的细胞活力、凋亡、遗传毒性和氧化应激的影响。我们的结果表明，暴露于NaAsO2和As2O3会导致细胞增殖缺陷，并大大提高氧化损伤水平。为了阐明谷胱甘肽（GSH）稳态在iAs(3+)诱导的氧化损伤中的关键作用，我们进一步测量了GSH的含量、GSH与GSSG的比值以及参与GSH合成、循环利用和利用过程的GSH相关酶的活性。我们的数据表明，NaAsO2和As2O3破坏了GSH稳态的平衡，并且NaAsO2和As2O3诱导的氧化损伤与GSH合成、循环利用和利用的失衡密切相关。为了更好地理解Nrf2在维持GSH稳态中的生理意义，在iAs(3+)暴露后测量了Nrf2的表达水平。我们发现，在NaAsO2和As2O3处理的细胞中，Nrf2的蛋白表达水平均升高。总的来说，我们的研究结果表明，Nrf2调节的GSH稳态紊乱与iAs(3+)引发的氧化损伤有关，GSH稳态的丧失可能与iAs(3+)诱导的肺部疾病发病机制和iAs(3+)的抗癌活性都有关。
