Trost L C, Wallace K B
Department of Pharmacology, School of Medicine, University of Minnesota, Duluth 55812.
Biochem Biophys Res Commun. 1994 Oct 14;204(1):30-7. doi: 10.1006/bbrc.1994.2421.
Numerous mechanisms have been invoked to explain the cardiotoxicity of Adriamycin, most of which share a requirement for iron. Adriamycin is chemically reactive with iron loosely associated with subcellular membranes as well as with ferritin and the heme iron of hemoglobin. The present investigation examined whether Adriamycin also reacts with myoglobin, an abundant source of iron in cardiac muscle. Adriamycin caused a 4-fold stimulation of the autoxidation of oxymyoglobin to metmyoglobin. Hydrogen peroxide is an obligatory intermediate as catalase completely inhibited the reaction. Superoxide dismutase, however, was without effect. This interaction of Adriamycin with myoglobin may impose significant restrictions on oxygen storage and delivery in vivo. In light of the abundance of myoglobin and the deficiency of catalase in the heart, this interaction with myoglobin may be an important determinant of the cardioselective toxicity of Adriamycin.
人们提出了许多机制来解释阿霉素的心脏毒性，其中大多数都需要铁。阿霉素在化学反应上与松散结合在亚细胞膜上的铁、铁蛋白以及血红蛋白的血红素铁发生反应。本研究考察了阿霉素是否也与肌红蛋白发生反应，肌红蛋白是心肌中铁的丰富来源。阿霉素使氧合肌红蛋白自氧化为高铁肌红蛋白的速率增加了4倍。过氧化氢是一个必需的中间产物，因为过氧化氢酶完全抑制了该反应。然而，超氧化物歧化酶没有作用。阿霉素与肌红蛋白的这种相互作用可能会对体内氧气的储存和运输造成重大限制。鉴于心脏中肌红蛋白含量丰富而过氧化氢酶缺乏，这种与肌红蛋白的相互作用可能是阿霉素心脏选择性毒性的一个重要决定因素。
