Oxidative stress in di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV)-induced hepatotoxicity determined by proteomic profiles

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.

► Hepatotoxic mechanism induced by DBDCT was investigated using proteomics methods. ► Nine altered proteins associated with oxidative stress were identified. ► Up-regulated Trx1 may be a candidate biomarker for DBDCT-induced hepatotoxicity. ► DBDCT increased ROS and MDA expression while decreased GSH expression. ► Oxidative stress played a key role in DBDCT-induced hepatotoxicity.