多柔比星对大鼠心肝肾及免疫器官的长期毒性作用

Long-term toxic effects of doxorubicin on heart,liver,kidney and immune organs in rats

目的探讨多柔比星(DOX)对大鼠心肝肾及免疫器官的长期毒性作用。方法将48只健康SD大鼠随机分为DOX 7.0、14.0、28.0 mg/m^2组及溶剂对照组,分别给予0.23、0.47、0.93 mg/L DOX 30 mL/m^2及等体积的5%葡萄糖注射液经尾静脉推注,每3周给药1次,共给药4次。给药结束,用20%乌来糖腹腔注射麻醉,经腹主动脉取血,剖取心脏、肝脏、肾脏、胸腺、脾和肠系膜淋巴结以备用。用罗氏全自动生化分析仪检测血液生化指标,用流式细胞术检测外周血淋巴细胞亚群,计算脏器系数,观察脏器组织病理变化。结果与溶剂对照组比较,DOX 7.0 mg/m^2组血液生化指标变化不明显(P均>0.05),DOX 14.0、28.0 mg/m^2组天门冬氨酸氨基转移酶、血尿素氮、肌酐高(P均<0.05),DOX 28.0 mg/m^2组丙氨酸氨基转移酶高(P<0.05);各组血清肌酸激酶水平比较差异无统计学意义(P均>0.05)。DOX 14.0、28.0 mg/m^2组CD3+、CD4+、CD8+T细胞亚群及CD45RA+B细胞亚群计数、CD4+/CD8+与溶剂对照组比较差异有统计学意义(P均<0.05)。DOX 14.0 mg/m^2组肝脏、肾脏、胸腺脏器系数及DOX 28.0 mg/m^2组的各器官脏器系数与溶剂对照组比较差异有统计学意义(P均<0.05)。DOX 7.0、14.0、28.0 mg/m^2组见心脏心肌细胞空泡变性、坏死;DOX 28.0 mg/m^2组见肝细胞空泡变性;DOX 14.0、28.0 mg/m^2组见肾病综合征表现;DOX 14.0、28.0 mg/m^2组胸腺、脾脏、淋巴结发生萎缩。结论DOX对SD大鼠的心脏、肝脏、肾脏和免疫器官有明显的长期毒性作用,表现为心肌细胞的变性坏死、肝细胞变性、肾病综合征、免疫器官萎缩。

Objective To investigate the long-term toxicity of doxorubicin(DOX)on heart,liver,kidney,and immune organs in rats.Methods Forty-eight healthy SD rats were randomly divided into the DOX 7.0,14.0,28.0 mg/m^2 groups and solvent control group,which were injected intravenously via tail vein with 0.23,0.47,and 0.93 mg/L DOX 30 mL/m^2,and an equal volume of 5%glucose.The drug was administered once every 3 weeks,for 4 times.At the end of the administration,they were anesthetized intraabdominal with 20%urai sugar.Blood was taken through the abdominal aortic artery and the heart,liver,kidney,thymus,spleen and mesenteric lymph nodes were cut out for backup.The blood biochemical indexes of rats were detected by Roche automatic biochemical analyzer,the peripheral blood lymphocyte subsets of rats were detected by flow cytometry,the organ coefficient was calculated,and the pathological changes of rat organs were observed.Results Compared with the solvent control group,there was no significant change in blood biochemical indexes in the DOX 7.0 mg/m^2 group(P>0.05),AST,BUN,and CRE were higher in the DOX 14.0 and 28.0 mg/m^2 groups(all P<0.05),and ALT was higher in the DOX 28.0 mg/m^2 group(P<0.05);there was no significant difference in serum CK level between groups(P>0.05).Significant differences were found in the number of CD3+,CD4+,CD8+T cell subpopulation,CD45RA+B cell subpopulation and and CD4/CD8 between the solvent control group and the DOX 14.0 and 28.0 mg/m^2 groups(all P<0.05).Compared with the solvent control group,the organ coefficients of heart,liver and kidney were higher in the DOX 7.0,14.0 and 28.0 mg/m^2 groups,the organ coefficients of thymic gland and spleen were lower.The organ coefficients of liver,kidney,thymus in DOX 14.0 mg/m^2 group and organ coefficient of each organ in DOX 28.0 mg/m^2 were significantly different from those in the control group(P<0.05).DOX 7.0,14.0,28.0 mg/m^2 group showed vacuole degeneration and necrosis of cardiac myocytes;DOX 14.0,28.0 mg/m^2 groups showed nephrotic syndrome;atrophy of the thymus,spleen and lymph nodes occurred in the DOX 14.0 and 28.0 mg/m^2 groups.Conclusion DOX has obvious toxic effects on heart,liver,kidney and immune organs of SD rats,such as degeneration and necrosis of cardiac myocytes,degeneration of liver cells,nephrotic syndrome,and atrophy of immune organs,and the effect is dose-dependent.