School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
Toxicol Lett. 2012 Sep 3;213(2):167-73. doi: 10.1016/j.toxlet.2012.06.008. Epub 2012 Jun 23.
Significant attention has been paid to the antitumor diorganotin(IV) compounds during the last few decades. However, severe toxicity limits their application and the toxic mechanism is still unclear. Of these toxicities, liver is the most important target organ. In this study, di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) (DBDCT), an antitumor agent with high activity and obvious hepatotoxicity was chosen as a typical diorganotin(IV) compound to investigate the hepatotoxic mechanism using proteomics methods for the first time. The cell growth, cell morphology, proteomics, ROS, MDA, and GSH were assessed in this study. The results showed that cell growth was inhibited and cell morphology was changed after DBDCT treatment. A total of nine significantly and consistently altered proteins associated with oxidative stress were identified. Among the altered proteins, Trx1 and protein DJ1, that could regulate the oxidative stress process, were chosen for a detailed analysis. They were demonstrated to be up-regulated following exposure to DBDCT at both protein and mRNA levels in a dose- and time-dependant manner, and the consequences were concordant with the experimental results of ROS, MDA and GSH. These findings showed that oxidative stress played a key role in DBDCT-mediated toxicity, and Trx1 may be a potential biomarker for the early diagnosis of hepatotoxicity.
在过去的几十年中，人们对有机锡（IV）抗肿瘤化合物给予了极大的关注。然而，严重的毒性限制了它们的应用，其毒性机制仍不清楚。在这些毒性中，肝脏是最重要的靶器官。在这项研究中，选择具有高活性和明显肝毒性的二正丁基二（4-氯苯羟肟酸）锡（IV）（DBDCT）作为典型的有机锡（IV）化合物，首次采用蛋白质组学方法研究其肝毒性机制。本研究评估了细胞生长、细胞形态、蛋白质组学、ROS、MDA 和 GSH。结果表明，DBDCT 处理后细胞生长受到抑制，细胞形态发生变化。共鉴定出 9 种与氧化应激相关的显著且一致改变的蛋白质。在改变的蛋白质中，Trx1 和蛋白 DJ1 可以调节氧化应激过程，选择它们进行详细分析。结果表明，它们在蛋白和 mRNA 水平上均呈剂量和时间依赖性上调，其结果与 ROS、MDA 和 GSH 的实验结果一致。这些发现表明氧化应激在 DBDCT 介导的毒性中起关键作用，Trx1 可能是肝毒性早期诊断的潜在生物标志物。
