新型铂类化合物LLC-0601与舒铂对SD大鼠的肝毒性

摘要

目的 观察新型铂类化合物LLC-D601与舒铂对SD大鼠的肝毒性,探讨其可能的毒性作用机制.方法 雄性SD大鼠尾静脉iv给予顺铂2mg·kg(阳性对照)、舒铂40 mg·kg、LLC-0601 40和70mg·kg,连续2 d,间隔5 d,共6次,末次给药后恢复期28 d,观察动物一般状况,并于给药末期和恢复28 d后检测血清谷丙转氨酶(GPT),谷草转氨酶(GOT),碱性磷酸酶(ALP),总蛋白(TP),白蛋白(ALB)和总胆红素(T-Bil),肝质量与系数,组织匀浆谷胱甘肽过氧化物酶(GSH-P),超氧化物歧化酶(T-SOD),微量丙二醛(MDA)及光学显微镜进行病理组织学检查.结果 与正常对照组相比,LLC-0601 40mg·kg组各项检测指标未见明显异常,其余给药组动物均出现精神差、少食、少动、竖毛、毛发无光泽以及体质量下降;给药末期血清生化检测舒铂组GPT升高,TP和ALB降低(P组肝质量明显降低(P组肝组织匀浆中GSH-PT和T-SOD降低,各给药组MDA均升高(P组肝病理组织学均出现不同程度肝细胞点灶状坏死,肝窦内淋巴细胞浸润,以舒铂组病变程度最重.恢复期顺铂组病理组织学病变较给药末期重,出现延迟性毒性反应,其余各给药组各项检测指标均基本恢复.结论 顺铂、舒铂和LLC-0601均可引起大鼠肝损伤,其机制与药物引起的组织过氧化损伤有关.%OBJECTIVE To investigate the hepatotoxicity of heptaplatin and LLC-0601 in SD rats, and to explore the toxic mechanisms. METHODS Rats were respectively injected with cisplatin 2 mg·kg-1 (positive control), heptaplatin 40 mg·kg-1 and LLC-0601 40 and 70 mg·kg-1,once a day, for 2 d, and then an inteval for 5 d, all 3 courses for 6 injections, and then rats restored for 28 d. After the last 24 h after administration and after restoration 28 d, the rats were inspected for their general condition. Serum biochemistry indices glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase(GOT), alkaline phosphatase(ALP), total protein(TP), albumin (ALB) and total bilirubin (T-Bil) were detected. Liver mass and coefficients were detected. The activity of glutathione peroxidase (GSH-Px), total superoxide dismutase(T-SOD) and malondialdehyde (MDA) was examined and liver histopathology was observed. RESULTS Compared with normal control group, rats in treated groups except LLC-0601 70 mg·kg-1 appeared to be dispirited,and mat, food intake decreased, significant vertical hair phenomena, with a reduction of activity.GPT was higher, but TP and ALB were lower in heptaplatin group ( P ＜ 0.05 ). Compared with normal control group, liver mass and organ coefficients, GSH-Px and T-SOD were lower in the drugtreated groups ( P ＜ 0.05 ). While MDA was significantly higher ( P ＜ 0.05 ). Liver tissue in cisplatin, heptapletin and LLC-0601 70 mg·kg -1 groups showed focal necrosis and sinusoidal lymphocytic infiltration of liver cells. After 28 d restoration all indices returned to normal except cisplatin group.CONCLUSION Heptaplatin and LLC-0601 can induce liver damage and the mechanism may be related to their oxidative damage.