Olson R D, Li X, Palade P, Shadle S E, Mushlin P S, Gambliel H A, Fill M, Boucek R J, Cusack B J
Pharmacology and Gerontology Unit, Veterans Affairs Medical Center, Boise, Idaho 83702, USA.
Toxicol Appl Pharmacol. 2000 Dec 1;169(2):168-76. doi: 10.1006/taap.2000.9065.
Cardiac effects of anthracyclines or their metabolites may include both the stimulation and inhibition of Ca(2+) release from sarcoplasmic reticulum. In this study, the ability of daunorubicin and its primary metabolite, daunorubicinol, to stimulate and inhibit Ca(2+) release from canine sarcoplasmic reticulum (SR) vesicles was investigated. It was observed that both daunorubicin and daunorubicinol were several fold more potent at inhibiting than they were at stimulating SR Ca(2+) release. Respective IC50 inhibition of daunorubicin and daunorubicinol for caffeine-induced calcium release was 1.2 and 0.6 microM, and for spontaneous Ca(2+) release was 3 and 1 microM. EC50's for daunorubicin- and daunorubicinol-induced calcium release were 30 and 15 microM, respectively. Inhibition of either spontaneous or caffeine-induced SR Ca(2+) release was inversely related to the amount of Ca(2+) loaded into the SR before exposure to daunorubicin or daunorubicinol. The free-radical scavenger dithiothreitol did not attenuate the ability of anthracyclines to inhibit SR Ca(2+) release. A nonquinone daunorubicin derivative, 5-iminodaunorubicin, was less potent than daunorubicin at inhibiting caffeine-induced Ca(2+) release. These data suggest anthracyclines and their metabolites may produce cardiotoxicity through free-radical independent, concentration-dependent effects on SR Ca(2+) release. These effects involve either inhibition or stimulation of SR Ca(2+) release and are partly dependent upon the presence of the quinone moiety.
蒽环类药物及其代谢产物对心脏的影响可能包括刺激和抑制肌浆网释放钙离子。在本研究中，研究了柔红霉素及其主要代谢产物柔红霉素醇刺激和抑制犬肌浆网（SR）囊泡释放钙离子的能力。观察到柔红霉素和柔红霉素醇在抑制SR钙离子释放方面的效力比刺激作用强几倍。柔红霉素和柔红霉素醇对咖啡因诱导的钙离子释放的IC50抑制值分别为1.2和0.6微摩尔，对自发性钙离子释放的IC50抑制值分别为3和1微摩尔。柔红霉素和柔红霉素醇诱导钙离子释放的EC50分别为30和15微摩尔。抑制自发性或咖啡因诱导的SR钙离子释放与暴露于柔红霉素或柔红霉素醇之前加载到SR中的钙离子量呈负相关。自由基清除剂二硫苏糖醇不会减弱蒽环类药物抑制SR钙离子释放的能力。一种非醌类柔红霉素衍生物5-亚氨基柔红霉素在抑制咖啡因诱导的钙离子释放方面比柔红霉素效力低。这些数据表明，蒽环类药物及其代谢产物可能通过对SR钙离子释放产生自由基非依赖性、浓度依赖性效应而导致心脏毒性。这些效应包括抑制或刺激SR钙离子释放，并且部分取决于醌部分的存在。
