Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin
Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin
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DOI：
10.1182/blood-2003-03-0869
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发表时间：
2003-10-01
期刊：
影响因子：
20.3
通讯作者：
Santos, MM
中科院分区：
文献类型：
--
作者：
Miranda, CJ;Makui, H;Santos, MM
阿霉素（DOX）是一种蒽环类化疗药物，临床使用受到心脏毒性的限制。铁可能参与dox诱导的心脏毒性的研究表明，铁螯合剂具有心脏保护作用。铁超载见于遗传性血色素沉着症，这是一种在欧洲人后裔中普遍存在的遗传性疾病。我们假设缺铁可能会增加对dox诱导的毒性的易感性。研究了DOX对Hfe敲除小鼠（Hfe(-/-)）和野生型小鼠的急性心脏毒性和铁的变化。dox诱导的铁代谢变化在Hfe（-/-）小鼠中加剧，与野生型小鼠相比，Hfe（-/-）小鼠在心脏、肝脏和胰腺中积累的铁明显更多，但在脾脏中积累的铁较少。此外，缺铁小鼠对dox诱导的血清肌酸激酶和天冬氨酸转氨酶升高表现出更大的敏感性。与野生型小鼠相比，慢性DOX治疗后Hfe（-/-）小鼠和Hfe（+/-）小鼠的死亡率增加。与野生型小鼠相比，经dox处理的Hfe（-/-）小鼠线粒体损伤程度和心脏铁沉积程度更高。这些数据表明，小鼠的铁缺乏增加了对dox诱导的心脏毒性的易感性，并表明与铁代谢缺陷相关的基因突变可能有助于其对人类的心脏毒性。(C) 2003年由美国血液病学会出版。
The clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe(-/-)) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe(-/-) mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe(-/-) mice and Hfe(+/-) mice compared with wild-type mice. DOX-treated Hfe(-/-) mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans. (C) 2003 by The American Society of Hematology.