Olson R D, Mushlin P S, Brenner D E, Fleischer S, Cusack B J, Chang B K, Boucek R J
VA Medical Center, Boise, ID 83702.
Proc Natl Acad Sci U S A. 1988 May;85(10):3585-9. doi: 10.1073/pnas.85.10.3585.
Doxorubicin (former generic name, adriamycin), a highly effective anticancer 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.
阿霉素（原通用名，阿霉素）是一种高效抗癌药物，但会产生心脏毒性，这限制了其治疗潜力。这种心脏毒性的机制一直难以捉摸。我们的数据表明，这种毒性可能与阿霉素醇有关，它是阿霉素的主要循环代谢产物。在损害心脏收缩和舒张功能方面，阿霉素醇比阿霉素明显更具毒性。同样，在抑制肌浆网的钙泵[ATP磷酸水解酶（钙转运），EC 3.6.1.38]、肌膜的Na+/K+泵[ATP磷酸水解酶（Na+/K+转运），EC 3.6.1.37]以及线粒体的F0F1质子泵[ATP磷酸水解酶（H+转运，EC 3.6.1.34]方面，阿霉素醇比阿霉素更具效力。我们发现这种高毒性代谢产物是由暴露于阿霉素的心脏组织产生的，这表明阿霉素醇可能在心脏中积累，并对阿霉素治疗的慢性累积心脏毒性有显著贡献。我们观察到阿霉素在体外抑制肿瘤细胞生长方面比阿霉素醇更有效，这表明阿霉素的心脏毒性与其抗癌活性是可分离的。
