Takahashi S, Denvir M A, Harder L, Miller D J, Cobbe S M, Kawakami M, MacFarlane N G, Okabe E
Department of Pharmacology and ESR Laboratory, Kanagawa Dental College, Yokosuka, Japan.
Jpn J Pharmacol. 1998 Apr;76(4):405-13. doi: 10.1254/jjp.76.405.
Doxorubicin is an anthracycline antibiotic that is used widely as a chemotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this cardiotoxicity remain essentially unknown, despite numerous studies describing a range of structural and functional abnormalities. The purpose of the present study was to determine the in vivo and in vitro effects of doxorubicin exposure on sarcoplasmic reticulum (SR) Ca2+-content and contractile protein function. The Ca2+-content of SR is shown to have a biphasic response to in vivo and in vitro doxorubicin exposure that is time- and dose-dependent. In vitro doxorubicin exposure initially reduces the SR Ca2+-content, but the predominant action to block the SR Ca2+-release channel increases SR Ca2+-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca2+-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca2+-overload.
阿霉素是一种蒽环类抗生素，被广泛用作化疗药物。然而，由于其心脏毒性作用，该药物的用途受到限制。尽管有大量研究描述了一系列结构和功能异常，但与这种心脏毒性相关的机制基本上仍不清楚。本研究的目的是确定阿霉素暴露对肌浆网（SR）Ca2+含量和收缩蛋白功能的体内和体外影响。结果表明，SR的Ca2+含量对体内和体外阿霉素暴露有双相反应，且具有时间和剂量依赖性。体外阿霉素暴露最初会降低SR的Ca2+含量，但阻断SR Ca2+释放通道的主要作用会在60分钟内增加SR的Ca2+含量。体内阿霉素暴露也观察到类似结果：它会导致Ca2+过载。这些数据与阿霉素的作用方式与ryanodine相似且因Ca2+过载导致心肌病的观点一致。
