Study On Mechanisms Of Doxorubicin-Induced Cardiotoxicity In Rats Using Metabonomics Technology

The diseases due to the drug adverse reaction have evolved into a serious clinical problem. So, it's very significant to identify exactly the relation between the patient reaction and the drug during new drug development or post-marketing evaluation. Functional genomics technology makes a new way available for predicting drug toxicity and studying its mechanism. Doxorubicin (DOX), an anthracycline antibiotic, is a potent broad spectrum chemotherapeutic agent that is effective against a variety of human molignancies. However, the clinical use of DOX is limited by its severe, cumulative, dose-dependent cardiotoxicity. The cardiotoxicity of DOX has attracted great attention of many drug toxicologists in the cast decades, but the precise mechanisms of DOX- induced cardiotoxicity is not entirely clear. This dissertation studies the mechanism from the aspects of systematical biology and the global assessment of function cellular alterations. So our work is further to study the characteristics of DOX-induced cardiotoxicity with proteomics and metabonomics, combined with conventional toxical technologies, so as to exploring the unknown toxicity targets and selecting biomarkers to detecting the adverse effects.Firstly, different doses of DOX are administered to rats, and then such changes at several time points are detected as the ones of blood biochemical parameters, histopathology and oxidation/antioxidation indexes. 60 rats are divided into 3 experimental groups and 1 control group at random. Through single intraperitoneal injection, DOX is administered to the rats from the experimental groups at the doses of 5mg/kg, 10mg/kg and 20mg/kg respectively, and the rats in control are treated with equal volume of salive. 5 rats of each group are sacrificed on the 1st day, 2nd day and 4th day after administration. Serum is used for detecting blood biochemical parameters. The ventricular muscle was used to histopathological study and tissue homogenate test. In tissue homogenate test, MDA, TSH, NPSH, PSH and NO are detected. The results from biomedical and histopathology examinations prove the appearance of cardiotoxic reaction with a dose-time-dependant manner. The increased MDA and NO, the indexes for oxidation, and the decreased NPSH, the index for antioxidation, are also determined. So, these results indicated that the mechanisms of DOX-induced cardiotoxity is related with the generation of free radicals with the result that the increase of lipid peroxidation, as well as the decreased of GSH level.Secondly, proteomics technology is used to find the difference of the proteins...