Department of Applied Mathematics, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
EPSRC Liverpool Centre for Mathematics in Healthcare, Department of Mathematical Sciences, University of Liverpool, Liverpool, L69 7ZL, UK.
Sci Rep. 2019 Apr 19;9(1):6333. doi: 10.1038/s41598-019-42799-2.
Redox cycling is an understated mechanism of toxicity associated with a plethora of xenobiotics, responsible for preventing the effective treatment of serious conditions such as malaria and cardiomyopathy. Quinone compounds are notorious redox cyclers, present in drugs such as doxorubicin, which is used to treat a host of human cancers. However, the therapeutic index of doxorubicin is undermined by dose-dependent cardiotoxicity, which may be a function of futile redox cycling. In this study, a doxorubicin-specific in silico quinone redox metabolism model is described. Doxorubicin-GSH adduct formation kinetics are thermodynamically estimated from its reduction potential, while the remainder of the model is parameterised using oxygen consumption rate data, indicative of hydroquinone auto-oxidation. The model is then combined with a comprehensive glutathione metabolism model, facilitating the simulation of quinone redox cycling, and adduct-induced GSH depletion. Simulations suggest that glutathione pools are most sensitive to exposure duration at pharmacologically and supra-pharmacologically relevant doxorubicin concentrations. The model provides an alternative method of investigating and quantifying redox cycling induced oxidative stress, circumventing the experimental difficulties of measuring and tracking radical species. This in silico framework provides a platform from which GSH depletion can be explored as a function of a compound's physicochemical properties.
氧化还原循环是与多种外源化学物质相关的毒性的一种被低估的机制，它可导致疟疾和心肌病等严重疾病的治疗效果不佳。醌类化合物是臭名昭著的氧化还原循环物，存在于多种药物中，如阿霉素，阿霉素用于治疗多种人类癌症。然而，阿霉素的治疗指数因剂量依赖性的心脏毒性而降低，而这种毒性可能是无效氧化还原循环的一种功能。在本研究中，描述了一种阿霉素特异性的计算醌氧化还原代谢模型。通过还原电势对阿霉素-GSH 加合物形成动力学进行热力学估算，而模型的其余部分则使用氧消耗速率数据进行参数化，该数据表明对苯二酚的自动氧化。然后将该模型与全面的谷胱甘肽代谢模型相结合，从而可以模拟醌氧化还原循环和加合物诱导的 GSH 耗竭。模拟表明，在药理学和超药理学相关的阿霉素浓度下，谷胱甘肽池对暴露持续时间最为敏感。该模型提供了一种替代方法，可用于研究和量化氧化还原循环引起的氧化应激，避免了测量和跟踪自由基的实验困难。该计算框架为研究作为化合物物理化学性质函数的 GSH 耗竭提供了一个平台。
