Applová Lenka, Dudášová-Hatoková Paulína, Kubeš Jan, Váňová Nela, Keresteš Veronika, Reguli Adam, Jirkovská Anna, Roh Jaroslav, Štěrba Martin, Štěrbová-Kovaříková Petra, Šimůnek Tomáš
Faculty of Pharmacy in Hradec Králové, Department of Biochemical Sciences, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Arch Toxicol. 2025 Jun 7. doi: 10.1007/s00204-025-04095-z.
Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotoxicity. Anthracyclines undergo metabolic reduction of the side chain carbonyl group, producing hydroxy metabolites implicated in the cardiotoxicity. This study investigated toxicity, metabolism and cellular disposition of daunorubicin and its hydroxy metabolite, daunorubicinol, in isolated rat neonatal cardiomyocytes. Daunorubicin induced concentration-dependent cytotoxicity, whereas the toxicity of exogenously administered daunorubicinol was significantly lower despite induction of similar DNA damage. UHPLC-MS analyses revealed that daunorubicin rapidly penetrates cardiomyocytes and is metabolized to daunorubicinol, which is then released from the cells. The intracellular concentration of daunorubicinol was consistently lower than that of daunorubicin, indicating a reduced tendency for daunorubicinol to accumulate in cardiomyocytes. P-glycoprotein 1 has been shown to actively facilitate the efflux of both daunorubicin and daunorubicinol from cardiomyocytes. Dexrazoxane, the only approved agent for anthracycline cardiotoxicity prevention, did not affect the cellular metabolism or disposition of daunorubicin or its hydroxy metabolite, but it effectively reduced not only daunorubicin-induced cardiotoxicity, but also provided protection against the lower toxicity of daunorubicinol. Moreover, dexrazoxane reduced DNA damage induced by both daunorubicin and its hydroxy metabolite. These findings suggest that daunorubicin is the primary driver of cardiomyocyte cytotoxicity, while its hydroxy metabolite, daunorubicinol, plays a more limited role, challenging the notion that it serves as a significant toxic reservoir.
蒽环类抗癌药物，如柔红霉素和阿霉素，是最有效且应用最广泛的抗癌药物之一。然而，严重心脏毒性的风险显著降低了它们的疗效。蒽环类药物会使侧链羰基发生代谢还原，产生与心脏毒性有关的羟基代谢物。本研究调查了柔红霉素及其羟基代谢物柔红霉醇在离体大鼠新生心肌细胞中的毒性、代谢和细胞分布情况。柔红霉素诱导浓度依赖性细胞毒性，而外源性给予柔红霉醇的毒性显著较低，尽管诱导了相似的DNA损伤。超高效液相色谱-质谱分析显示，柔红霉素迅速穿透心肌细胞并代谢为柔红霉醇，然后从细胞中释放出来。柔红霉醇的细胞内浓度始终低于柔红霉素，表明柔红霉醇在心肌细胞中积累的倾向较低。已证明P-糖蛋白1能积极促进柔红霉素和柔红霉醇从心肌细胞中流出。右丙亚胺是唯一被批准用于预防蒽环类心脏毒性的药物，它不影响柔红霉素或其羟基代谢物的细胞代谢或分布，但它不仅有效降低了柔红霉素诱导的心脏毒性，还提供了针对柔红霉醇较低毒性的保护作用。此外，右丙亚胺减少了柔红霉素及其羟基代谢物诱导的DNA损伤。这些发现表明，柔红霉素是心肌细胞毒性的主要驱动因素，而其羟基代谢物柔红霉醇的作用较为有限，这对它作为重要毒性储存库的观点提出了挑战。
