NMR Center, Department of Biochemistry, Apartado 3126, University of Coimbra, 3001-401 Coimbra, Portugal.
Toxicology. 2010 Apr 11;270(2-3):92-8. doi: 10.1016/j.tox.2010.01.019. Epub 2010 Feb 1.
Doxorubicin (Adriamycin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is restricted by a cumulative and progressive cardiomyopathy that develops with repeated dosing. Fundamental to the cardiac failure is an interference with mitochondrial respiration and inhibition of oxidative phosphorylation. Global gene expression arrays in cardiac tissue indicate that inhibition of mitochondrial oxidative phosphorylation by doxorubicin (DOX) is accompanied by a decreased expression of genes related to aerobic fatty acid oxidation and a corresponding increase in expression of genes involved in anaerobic glycolysis, possibly as an alternate source for ATP production. The aim of this investigation was to determine whether this is also manifest at the metabonomic level as a switch in metabolic flux in cardiac tissue, and whether this can be averted by co-administering the cardioprotective drug, dexrazoxane (DZR). (13)C-isotopomer analysis of isolated perfused hearts from male Sprague-Dawley rats receiving 6 weekly s.c. injections of 2mg/kg DOX demonstrated a shift from the preferential oxidation of fatty acids to enhanced oxidation of glucose and lactate plus pyruvate, indicative of a compensatory shift towards increased pyruvate dehydrogenase activity. Substrate-selective isotopomer analysis combined with western blots indicate an inhibition of long-chain fatty acid oxidation and not MCAD activity or fatty acyl-carnitine transport. Co-administering DZR averted many treatment-related changes in cardiac substrate metabolism, consistent with DZR being an effective cardioprotective agent against DOX-induced cardiomyopathy. This switch in substrate metabolism resembles that described for other models of cardiac failure; accordingly, this change in metabolic flux may represent a general compensatory response of cardiac tissue to imbalances in bioenergetic demand and supply, and not a characteristic unique to DOX-induced cardiac failure itself.
多柔比星（阿霉素）是一种强效广谱抗肿瘤药物，但由于重复给药会导致累积性、进行性心肌病，限制了其临床应用。这种心脏衰竭的根本原因是线粒体呼吸受到干扰和氧化磷酸化受到抑制。心脏组织的全基因表达谱表明，多柔比星（DOX）抑制线粒体氧化磷酸化会伴随着与有氧脂肪酸氧化相关的基因表达下调，以及与无氧糖酵解相关的基因表达上调，可能作为 ATP 产生的替代来源。本研究旨在确定这是否也表现在代谢组学水平上，即心脏组织代谢通量的转变，以及是否可以通过联合使用心脏保护药物右雷佐生（DZR）来避免这种转变。（13）C-同位素标记分析接受 6 周皮下注射 2mg/kg DOX 的雄性 Sprague-Dawley 大鼠分离的心脏灌流实验表明，从优先氧化脂肪酸转变为增强葡萄糖和乳酸加丙酮酸的氧化，表明丙酮酸脱氢酶活性增加的代偿性转变。底物选择性同位素标记分析结合 Western blot 表明长链脂肪酸氧化受到抑制，而不是 MCAD 活性或脂肪酸酰基辅酶 A 转运受到抑制。联合使用 DZR 可避免心脏底物代谢的许多治疗相关变化，表明 DZR 是对抗 DOX 诱导的心肌病的有效心脏保护剂。这种底物代谢的转变类似于其他心力衰竭模型所描述的；因此，这种代谢通量的变化可能代表心脏组织对能量需求和供应不平衡的一般代偿反应，而不是 DOX 诱导的心力衰竭本身所特有的特征。
