锌诱导金属硫蛋白表达对多柔比星心脏毒性的保护作用及其机制(英文)

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。

Protective effects of metallothionein induced by zinc against doxorubicin-caused cardiotoxicity and its potential mechanisms

AIM: To investigate the effects of metallothionein (MT) induced by zinc on doxorubicin (DOX)-treated mice and to explore the potential mechanisms. METHODS: Male C57BL/6J mice were divided randomly into 4 groups (n = 6) following control, DOX, Zn and Zn plus DOX. Mice were pretreated with eikg-1, ip) or equal volume of saline, and were killed on d 4 after the last injection. Serum and hearts were collected for examination. RESULTS: Zinc pretreatment elevated cardiac MT levels significantly while other antioxidants in heart including glutathione (GSH), glutathione peroxidase (GSHpx) , superoxide dismutase (SOD), and catalase (CAT) were not altered. Severe oxidative injury occurred in the mice treated with DOX as myocardial lipid peroxidation and morphological changes manifested by myocardial fibers swelling and vacuolization and nuclear condensation or dissolution, with increased activities of serum creatine kinase and lactate dehydrogenase and depletion of GSH, GSHpx, and SOD while CAT activity was increased in compensation. However, pre-induction of MT with zinc attenuated all of these toxic changes significantly. Furthermore, DOX induced elevation of hydrogen peroxide in heart tissues was greatly inhibited by zinc pretreatment. CONCLUSION: Preinduction of MT by zinc protects the heart from DOX-induced cardiotoxicity, and this effect is possibly correlated with the property of MT on scavenging free radicals in vivo.