Preliminary Discussion On The Mechanism Of Hepatotoxicity Induced By Oxaliplatin And The Treatment Effects Of GSH

Objective:To explore the method of establishing mouse model of hepatotoxicity with oxaliplatin,and to illuminate the mechanism.Then to investigate the protective effect of GSH on oxaliplatin induced liver injury in mice.Method:1、The male KM mice were injected intravenous with different dosages of oxaliplatin.Twelve hours later,the serum of ALT were measured and the liver tissues were observed by light microscope.Besides the general toxicity will be observed in one week for different dosages.The aim was to explore the relative suitable dosage that to induce the liver injury.Then oxaliplatin solution were injected intravenous to mice in dose of 8mg/kg for 3,4,5,6,7days respectively.The levels of ALT,AST in serum and SOD,GSH,GSH-PX,MDA in liver were measured.At the same time,liver tissues were observed by light microscope.The mice received iv.8mg/kg of oxaliplatin consecutively with the suitable time,and were sacrificed by cervical dislocation 2,3,4,5 and 6 days after the last injection.The other procedure and the indicators examined were the same as above.2、Based on the result of experiment 1,30 male KM mice were randomly divided into three groups that were control group,oxaliplatin group and combination of GSH with oxaliplatin group.Combination therpy group was first ip.with GSH at the time that given oxaliplatin every day until the end of experiment.The level of serum ALT,AST and SOD,GSH,GSH-PX,MDA level of liver tissues were measured;at the same time,liver tissues were observed by light microscope.Result:1、At the dosages of 5-30mg/kg,the serum level of ALT was highest with 30mg/kg,which was increased significantly compared with control group.However,no liver pathological change were observed.At the dosages of 15-30mg/kg,death rate was higher in one week.A large number of death in mice appeared in 5 to 7 days after the treatment.Weight loss and diarrhea occurred obviously after administration,.At the dosage of 5-10mg/kg,no death,diarrhea and weight loss were found in one week.2、At the dosages of 8mg/kg for 3 to 7 days,the leval of ALT and AST in serum were significantly increased,which were positively correlated with the times of treatment.The level of MDA and activity of GSH-PX in hepatic tissues were significantly increased.Few mice existed liver cell edema.3、At the dosages of 8mg/kg for 7 days,the leval of ALT、AST in serum and the level of MDA in liver tissues were continued increased.However,the activity of SOD、GSH-PX in liver tissues were decreased gradually after drug withdrawal.Besides,the liver cells impaired obviously at the third or fourth day after the last administration of oxaliplatin,which included cellular swelling,degeneration,fatty degeneration and necrosis.4、Compared with the model group,Reduced glutathione can reduce the levels of serum ALT and AST,increase GSH-PX,and reduce MDA and ameliorate the histopathological changes.Conclusion:1、After single mediation,acute liver-injury caused by oxaliplatin was not obvious but the general toxicity was positively correlated with dosage.2、There was an obvious liver injury of mice with 8mg/kg dose of oxaliplatin for 7 days,The hepatotoxicity was most obviously at the third or fourth day after the last administration.3、The liver-injury mechanism caused by oxaliplatin may be closely related with lipid peroxidation.Meanwhile,the compensative reaction against the oxidative stress induced by oxaliplatin.4、GSH can clearly reduce the liver injury degree that caused by oxaliplatin.