Sokolove P M, Shinaberry R G
Department of Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore 21201.
Biochem Pharmacol. 1988 Mar 1;37(5):803-12. doi: 10.1016/0006-2952(88)90165-7.
The effect of adriamycin aglycones on Ca2+ retention by isolated, preloaded rat heart mitochondria was assessed. After an initial lag, which decreased with increasing drug concentration, the 7-hydroxy-aglycone (5-20 microM) triggered Ca2+ release. Aglycone-induced Ca2+ release was correlated with Ca2+-dependent mitochondrial swelling, Ca2+-dependent collapse of the mitochondrial membrane potential, Ca2+-dependent oxidation of mitochondrial pyridine nucleotides, and a transition from the condensed to the orthodox configuration. Aglycone-induced Ca2+ release was inhibited by dibucaine, dithiothreitol, ATP, and bovine serum albumin. It can be concluded, therefore, that aglycone-induced Ca2+ release reflects the Ca2+-dependent increase in the permeability of the inner mitochondrial membrane to solutes of molecular weight less than 1000 which has been observed with other triggering agents [R. A. Haworth and D. R. Hunter, Archs Biochem. Biophys. 195, 460 (1979); I. Al-Nasser and M. Crompton, Biochem. J. 239, 19 (1986)]. In particular, the 7-hydroxy-aglycone decreased the amount of Ca2+ required to trigger the permeability increase. No effect of the aglycone on Ca2+ uptake could be discerned. 7-Deoxy-adriamycin aglycone, the more prominent biological metabolite of adriamycin, was similarly effective in inducing Ca2+ release, and both aglycones were substantially more effective than the parent drug. Adriamycin and related anthracyclines are potent antineoplastic agents, the clinical use of which is limited by severe cardiotoxicity. These results suggest that aglycone formation and the resultant disruption of both cellular Ca2+ homeostasis and metabolite compartmentation may mediate anthracycline cardiotoxicity.
评估了阿霉素苷元对分离的、预先加载钙的大鼠心脏线粒体保留钙离子的影响。在最初的延迟期后（延迟期随药物浓度增加而缩短），7-羟基苷元（5-20微摩尔）引发了钙离子释放。苷元诱导的钙离子释放与钙离子依赖性线粒体肿胀、线粒体膜电位的钙离子依赖性崩溃、线粒体吡啶核苷酸的钙离子依赖性氧化以及从致密构象向正统构象的转变相关。苷元诱导的钙离子释放受到丁卡因、二硫苏糖醇、ATP和牛血清白蛋白的抑制。因此可以得出结论，苷元诱导的钙离子释放反映了线粒体内膜对分子量小于1000的溶质的钙离子依赖性通透性增加，这与其他触发剂所观察到的情况相同[R. A. 霍沃思和D. R. 亨特，《生物化学与生物物理学文献》195, 460 (1979); I. 阿尔-纳赛尔和M. 克朗普顿，《生物化学杂志》239, 19 (1986)]。特别是，7-羟基苷元降低了引发通透性增加所需的钙离子量。未观察到苷元对钙离子摄取有影响。7-脱氧阿霉素苷元是阿霉素更主要的生物代谢产物，在诱导钙离子释放方面同样有效，并且两种苷元都比母体药物有效得多。阿霉素和相关蒽环类药物是有效的抗肿瘤药物，其临床应用受到严重心脏毒性的限制。这些结果表明，苷元的形成以及由此导致的细胞钙离子稳态和代谢物分隔的破坏可能介导了蒽环类药物的心脏毒性。
