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.
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
Li
L
Tang
Yun-lan
YL
Li
Rui
R
Ge
Qing-Shan
QS
Li
D000970:Antineoplastic Agents / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008315:Malondialdehyde / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009947:Organotin Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D012313:RNA / Q000737:chemistry / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D009947:Organotin Compounds; D017382:Reactive Oxygen Species; C542282:dibutyldi(4-chlorobenzohydroxamato)tin(IV); D008315:Malondialdehyde; D012313:RNA; D005978:Glutathione