Solem L E, Wallace K B
Department of Pharmacology, University of Minnesota, School of Medicine, Duluth 55812.
Toxicol Appl Pharmacol. 1993 Jul;121(1):50-7. doi: 10.1006/taap.1993.1128.
Various potentially cytopathic actions of doxorubicin have been implicated in the development of cardiotoxicity. However, inhibition of mitochondrial respiration and disruption of calcium homeostasis are emerging as possible primary determinants of toxicity. The objective of this investigation was to identify the specific ion channel by which doxorubicin interferes with calcium homeostasis in isolated rat heart mitochondria. Calcium accumulation by tightly coupled mitochondria was determined spectrophotometrically using arsenazo III and membrane potential was monitored fluorometrically with rhodamine 123. Incubation of cardiac mitochondria with doxorubicin caused a decrease in net accumulation and a delayed spontaneous release of calcium. There was no discernable dissipation of membrane potential and no detectable effect of the drug on the electrophoretic uniport. Diltiazem had no effect while cyclosporin A completely inhibited doxorubicin-induced calcium release. Addition of cyclosporin A prior to calcium prevented the doxorubicin-induced inhibition of calcium accumulation and the release of calcium from cardiac mitochondria. These data suggest that doxorubicin has a specific action on the mitochondrial ADP/ATP antiport, independent of the electrophoretic uniport and the sodium-dependent antiport, which may initiate calcium cycling and the consequential inhibition of oxidative phosphorylation.
阿霉素的各种潜在细胞病变作用与心脏毒性的发展有关。然而，线粒体呼吸的抑制和钙稳态的破坏正成为毒性的可能主要决定因素。本研究的目的是确定阿霉素干扰离体大鼠心脏线粒体钙稳态的特定离子通道。使用偶氮胂III通过分光光度法测定紧密偶联线粒体的钙积累，并使用罗丹明123通过荧光法监测膜电位。用阿霉素孵育心脏线粒体导致净积累减少和钙的延迟自发释放。膜电位没有明显消散，药物对电单转运没有可检测的影响。地尔硫卓没有作用，而环孢素A完全抑制阿霉素诱导的钙释放。在钙之前添加环孢素A可防止阿霉素诱导的钙积累抑制和心脏线粒体钙释放。这些数据表明，阿霉素对线粒体ADP/ATP反向转运体有特异性作用，独立于电单转运体和钠依赖性反向转运体，这可能启动钙循环并导致氧化磷酸化的抑制。
