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目的:研究Zn诱导金属硫蛋白(metallothionein,MT)表达对多柔比星(doxorubicin,DOX)心脏毒性的保护作用及其机制。方法:雄性C57／BL6J小鼠随机分成4组(n=6),即对照组(control)、给药组(DOX)、预处理组(Zn)、预处理给药组(Zn+DOX)。动物单次腹腔注射DOX(20 mg·kg-1)或等剂量的生理盐水(NS),此前24 h及48 h分别给予ZnSO4(300μmol·kg-1,sc)或等剂量的NS预处理。DOX给药后d 4,测定血浆肌酸激酶(CK)及乳酸脱氢酶(LDH)活性;光学显微镜检查心脏组织形态学改变;测定心脏组织匀浆中MT、丙二醛(MDA)和还原型谷胱甘肽(GSH)含量以及谷胱甘肽过氧化物酶(GSHpx)、超氧化物歧化酶(SOD)、过氧化氢酶((CAT)活性并测定组织过氧化氢(H2O2)浓度。结果:与对照组相比,Zn能显著诱导心脏MT的过表达,而对CK、LDH、MDA、GSHpx、SOD、CAT、GSH、H2O2以及组织形态学无明显影响;给药组病理学检查可见心肌纤维浊肿、肌浆溶解、胞核淡染或固缩,CK、LDH及MDA升高,组织GSHpx、SOD活性及GSH含量显著下降,CAT活性及H2O2浓度升高;Zn预处理能显著抑制DOX诱导的心脏毒性效应,心脏毒性损伤明显减轻。提示Zn预处理诱导心脏MT过表达后,MT可作为体内有效的抗氧化物拮抗DOX心脏毒性。结论:Zn诱导MT表达对DOX心脏毒性具有明显的保护作用,其机制可能与MT体内清除自由基功能有关。
AIM: To investigate the protective effects of metallothionein (MT) on cardiac toxicity induced by doxorubicin (DOX) and its mechanism. Methods: Male C57 / BL6J mice were randomly divided into 4 groups (n = 6): control group, DOX group, pretreatment group and Zn + DOX group. Animals were given intraperitoneal injection of DOX (20 mg · kg -1) or normal saline (NS) at 24 h and 48 h before ZnSO4 (300 μmol · kg-1, sc) or an equal dose of NS pretreatment. The levels of creatine kinase (CK) and lactate dehydrogenase (LDH) were measured after dosing with DOX. The morphological changes of heart tissue were examined by light microscopy. The levels of MT, malondialdehyde (MDA) and The contents of glutathione (GSH), glutathione peroxidase (GSHpx), superoxide dismutase (SOD) and catalase (CAT) and the concentration of hydrogen peroxide Results: Compared with the control group, Zn could significantly induce cardiac MT overexpression, but had no significant effect on CK, LDH, MDA, GSHpx, SOD, CAT, GSH, H2O2 and histomorphology Visible myocardial fibrosis, sarcoplasmic dissolved, stained nuclei or pyknosis, CK, LDH and MDA increased, tissue GSHpx, SOD activity and GSH content decreased significantly, CAT activity and H2O2 concentration increased; Zn pretreatment can be significant Inhibition of DOX-induced cardiotoxic effect, cardiac toxicity was significantly reduced.It is suggested that MT can be used as an effective antioxidant to antagonize DOX cardiotoxicity induced by Zn preconditioning.Conclusion: MT induced by Zn can inhibit DOX cardiotoxicity Significant protective effect, the mechanism may be with the body to eliminate free radical MT function turn off.