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Variation in Extracellular Detoxification Is a Link to Different Carcinogenicity among Chromates in Rodent and Human Lungs
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-08-20 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00172
Casey Krawic 1 , Michal W. Luczak 1 , Anatoly Zhitkovich 1
Affiliation  

Inhalation of soluble chromium(VI) is firmly linked with higher risks of lung cancer in humans. However, comparative studies in rats have found a high lung tumorigenicity for moderately soluble chromates but no tumors for highly soluble chromates. These major species differences remain unexplained. We investigated the impact of extracellular reducers on responses of human and rat lung epithelial cells to different Cr(VI) forms. Extracellular reduction of Cr(VI) is a detoxification process, and rat and human lung lining fluids contain different concentrations of ascorbate and glutathione. We found that reduction of chromate anions in simulated lung fluids was principally driven by ascorbate with only minimal contribution from glutathione. The addition of 500 μM ascorbate (∼rat lung fluid concentration) to culture media strongly inhibited cellular uptake of chromate anions and completely prevented their cytotoxicity even at otherwise lethal doses. While proportionally less effective, 50 μM extracellular ascorbate (∼human lung fluid concentration) also decreased uptake of chromate anions and their cytotoxicity. In comparison to chromate anions, uptake and cytotoxicity of respirable particles of moderately soluble CaCrO4 and SrCrO4 were much less sensitive to suppression by extracellular ascorbate, especially during early exposure times and in primary bronchial cells. In the absence of extracellular ascorbate, chromate anions and CaCrO4/SrCrO4 particles produced overall similar levels of DNA double-stranded breaks, with less soluble particles exhibiting a slower rate of breakage. Our results indicate that a gradual extracellular dissolution and a rapid internalization of calcium chromate and strontium chromate particles makes them resistant to detoxification outside the cells, which is extremely effective for chromate anions in the rat lung fluid. The detoxification potential of the human lung fluid is significant but much lower and insufficient to provide a threshold-type dose dependence for soluble chromates.

中文翻译:

细胞外排毒的变化是啮齿动物和人肺中铬酸盐之间不同致癌性的联系

吸入可溶性铬(VI)与人类罹患肺癌的较高风险紧密相关。但是,在大鼠中进行的比较研究发现,对于中等溶解度的铬酸盐,其肺致瘤性很高,但对于高度可溶性的铬酸盐,则没有肿瘤。这些主要的物种差异仍然无法解释。我们调查了细胞外还原剂对人和大鼠肺上皮细胞对不同Cr(VI)形式的反应的影响。Cr(VI)的细胞外还原是一个解毒过程,大鼠和人的肺内衬液中含有不同浓度的抗坏血酸和谷胱甘肽。我们发现,模拟肺液中铬酸根阴离子的减少主要是由抗坏血酸引起的,而谷胱甘肽的贡献很小。向培养基中添加500μM抗坏血酸(大鼠肺液浓度)会强烈抑制细胞吸收铬酸根阴离子,即使在其他致命剂量下也能完全防止其细胞毒性。尽管成比例的效果不佳,但50μM的细胞外抗坏血酸(人肺液浓度)也降低了铬酸根阴离子的摄取及其细胞毒性。与铬酸根阴离子相比,中度可溶性CaCrO的可吸入颗粒物的吸收和细胞毒性4和SrCrO 4对细胞外抗坏血酸抑制的敏感性要低得多,尤其是在早期暴露时间和原代支气管细胞中。在不存在细胞外抗坏血酸,铬酸根阴离子和CaCrO 4 / SrCrO 4的情况下颗粒产生的DNA双链断裂总体水平相似,而可溶性较低的颗粒则显示出较慢的断裂速率。我们的结果表明,逐渐的细胞外溶解以及铬酸钙和铬酸锶颗粒的快速内在化使其对细胞外的排毒具有抵抗力,这对于大鼠肺液中的铬酸根阴离子非常有效。人肺液的解毒潜力很大,但是要低得多,并且不足以为可溶性铬酸盐提供阈值型剂量依赖性。
更新日期:2017-08-20
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