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Modelling changes in glutathione homeostasis as a function of quinone redox metabolism

Kelly, RA, Leedale, J, Calleja, D, Enoch, SJ, Harrell, A, Chadwick, A and Webb, SD (2019) Modelling changes in glutathione homeostasis as a function of quinone redox metabolism. Scientific Reports. ISSN 2045-2322

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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 26 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.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Applied Mathematics (merged with Comp Sci 10 Aug 20)
Pharmacy & Biomolecular Sciences
Publisher: Nature Publishing Group
Date Deposited: 15 Apr 2019 08:13
Last Modified: 04 Sep 2021 09:30
DOI or ID number: 10.1038/s41598-019-42799-2
URI: https://researchonline.ljmu.ac.uk/id/eprint/10546
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