ENZYMATIC DEFENSES OF THE MOUSE HEART AGAINST REACTIVE OXYGEN METABOLITES - ALTERATIONS PRODUCED BY DOXORUBICIN
ENZYMATIC DEFENSES OF THE MOUSE HEART AGAINST REACTIVE OXYGEN METABOLITES - ALTERATIONS PRODUCED BY DOXORUBICIN
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DOI：
10.1172/jci109642
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发表时间：
1980-01-01
影响因子：
15.9
通讯作者：
MYERS, CE
中科院分区：
文献类型：
--
作者：
DOROSHOW, JH;LOCKER, GY;MYERS, CE
研究了小鼠心脏对活性O2代谢产物的内源性防御。在心脏和肝脏中测定了能够解毒活性O2的3种酶的活性;心肌含有比肝脏少150倍的过氧化氢酶和近4倍的超氧化物歧化酶。两种组织的谷胱甘肽过氧化物酶活性相似。用H2 O2和氢过氧化枯烯作为底物测定缺硒6周后心脏中的谷胱甘肽过氧化物酶，发现酶活性下降> 80%，但没有迹象表明小鼠心脏组织含有非硒依赖性谷胱甘肽过氧化物酶。缺硒状态的特征是心脏谷胱甘肽过氧化物酶水平显著降低，导致15 mg/kg i. p.剂量下多柔比星[抗肿瘤药物]毒性显著增强。在硒充足的动物中给予多柔比星导致心脏谷胱甘肽过氧化物酶活性呈剂量依赖性降低;酶活性的下降持续72小时后，15毫克/公斤的腹腔注射。相反，心脏超氧化物歧化酶和肝脏超氧化物歧化酶和谷胱甘肽过氧化物酶不受此剂量的阿霉素。心脏组织中活性氧代谢产物解毒的主要途径是通过超氧化物歧化酶和硒依赖性谷胱甘肽过氧化物酶的协同作用。后一种酶可能会因缺硒饮食或阿霉素治疗而耗尽，使心脏处理H2 O2或脂质过氧化物的机制有限。
The endogenous defenses of the mouse heart against reactive O2 metabolites were investigated. The activities of 3 enzymes capable of detoxifying activated O2 were determined in both the heart and liver; cardiac muscle ontains 150 times less catalase and nearly 4 times less superoxide dismutase than liver. Glutathione peroxidase activities were similar to the 2 tissues. Assay of glutathione peroxidase in the heart after 6 wk of Se depletion with both H2O2 and cumene hydroperoxide as substrates revealed a > 80% drop in enzyme activity and gave no indication that murine cardiac tissue contains nonselenium-dependent glutathione peroxidase. The Se-deficient state, which was characterized by markedly decreased cardiac glutathione peroxidase levels, led to significantly enhanced doxorubicin [antineoplastic drug] toxicity at a dose of 15 mg/kg i.p. Doxorubicin administration in Se-sufficient animals resulted in a dose-dependent decrease in cardiac glutathione peroxidase activity; the decrease in enzyme activity lasted 72 h after 15 mg/kg i.p. In contrast, cardiac superoxide dismutase and hepatic superoxide dismutase and glutathione peroxidase were unaffected by this dose of doxorubicin. The major pathway in cardiac tissue for detoxification of reactive O2 metabolites is via the concerted action of superoxide dismutase and Se-dependent glutathione peroxidase. The latter enzyme may be depleted by a Se-deficient diet or doxorubicin treatment, leaving the heart with limited mechanisms for disposing of H2O2 or lipid peroxides.