DOXORUBICIN CARDIOTOXICITY MAY BE CAUSED BY ITS METABOLITE, DOXORUBICINOL
DOXORUBICIN CARDIOTOXICITY MAY BE CAUSED BY ITS METABOLITE, DOXORUBICINOL
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DOI：
10.1073/pnas.85.10.3585
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发表时间：
1988-05-01
影响因子：
11.1
通讯作者：
BOUCEK, RJ
中科院分区：
文献类型：
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作者：
OLSON, RD;MUSHLIN, PS;BOUCEK, RJ
阿霉素(原名阿霉素)是一种高效药物，具有心脏毒性，限制了其治疗潜力。这种心脏毒性的机制仍然难以捉摸。我们的数据表明，这种毒性可能涉及阿霉素的主要循环代谢物阿霉素。阿霉素在降低心脏收缩和舒张期功能方面明显比阿霉素强。同样，阿霉素对肌浆网钙泵[ATP磷酸水解酶(钙转运)，EC 3.6.1.38]、肌膜Na+/K+泵[ATP磷酸水解酶(Na+/K+转运)，EC 3.6.1.37]和线粒体F0F1质子泵[ATP磷酸水解酶(H+转运)，EC 3.6.1.34]的抑制作用比阿霉素强得多。我们发现这种高毒性的代谢物是由暴露于阿霉素的心脏组织产生的，这表明阿霉素可以在心脏中蓄积，并在阿霉素治疗的慢性累积心脏毒性中起重要作用。我们观察到阿霉素在体外对肿瘤细胞生长的抑制作用比阿霉素更强，提示阿霉素的心脏毒性与其抗癌活性是分离的。
Doxorubicin (former generic name, adriamycin), a highly effective drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting), EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.