Paul C, Tomingas A, Rajs J, Anundi I, Högberg J, Peterson C
Acta Pharmacol Toxicol (Copenh). 1982 Oct;51(4):292-9. doi: 10.1111/j.1600-0773.1982.tb01029.x.
Isolated cardiac myocytes from adult rats were used as a model to study the cardiotoxicity of free and DNA-linked daunorubicin. The toxic effects on the myocytes were evaluated by studying morphological changes, trypan blue exclusion and cell membrane permeability to NADH, as determined by LDH-activity. At a concentration of 100 microM daunorubicin caused an increased plasma membrane permeability within 30 min. Using light microscopy, the myocytic injury induced by daunorubicin could be distinguished from that induced by anoxia or elevated pH. In contrast to the effect of the free drug, no toxic effects could be demonstrated after incubation with DNA-linked daunorubicin (100 microM) for 5 hours. The higher toxicity of the free drug was related to a much higher intracellular accumulation of daunorubicin. No fluorescent metabolites of daunorubicin could be detected in the myocardial cells. Daunorubicin did not induce lipid peroxidation, as judged by the absence of malondialdehyde production and evolution of ethane. It is concluded that daunorubicin exerts toxic effects on rat cardiac myocytes by mechanisms that do not involve lipid peroxidation. Isolated cardiac cells from adult rats seem to be a useful model for the further study of such mechanisms.
成年大鼠的分离心肌细胞被用作研究游离柔红霉素和与DNA结合的柔红霉素心脏毒性的模型。通过研究形态变化、台盼蓝排斥试验以及通过乳酸脱氢酶活性测定的细胞膜对NADH的通透性来评估对心肌细胞的毒性作用。在浓度为100微摩尔时，柔红霉素在30分钟内导致质膜通透性增加。使用光学显微镜，柔红霉素诱导的心肌细胞损伤可与缺氧或pH升高诱导的损伤区分开来。与游离药物的作用相反，与DNA结合的柔红霉素（100微摩尔）孵育5小时后未显示出毒性作用。游离药物较高的毒性与柔红霉素在细胞内的大量蓄积有关。在心肌细胞中未检测到柔红霉素的荧光代谢产物。根据丙二醛生成的缺乏和乙烷的释放判断，柔红霉素未诱导脂质过氧化。结论是柔红霉素通过不涉及脂质过氧化的机制对大鼠心肌细胞发挥毒性作用。成年大鼠的分离心脏细胞似乎是进一步研究此类机制的有用模型。
