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

Abstract

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.

Identification of Modules With Similar Gene Regulation and Metabolic Functions Based on Co-expression Data

“…3.4.11.2] involved in the Glutathione metabolism; and SF4274, a NAD(P)H dehydrogenase (quinone) [EC:1.6.5.2] involved in Metabolic pathways (Figure 6B). This result correlates with the fact that glutathione and quinone metabolism play a major role in the defense against redox cycling-derived oxidative stress (Kelly et al, 2019), reinforcing the notion that common expression patterns identified in this work correlates with similar protein roles in the cell.…”

Role of Glutathione in Cancer: From Mechanisms to Therapies

“…However, with links between 10 metabolites in 13 reactions simulated using detailed kinetic equations, Reed’s model (available at Biomodels: BIOMD0000000268) is an excellent basis for further development of computer simulations of GSH metabolism for different applications. An interesting example of an extension to Reed’s GSH metabolism model has been presented by Kelly et al, [ 169 ] with the addition of quinone redox metabolism to the GSH model. With this addition, glutathione’s role in mitigating toxicity from quinone-derivatives is combined with its overall kinetics providing a link between glutathione depletion in different compartments with quinone redox.…”

“…Doxorubicin causes significant dose-dependent cardiotoxicity, possibly due to futile redox cycling. Cellular GSH is a major defense against the redox cycling-derived oxidative stress and therefore a detailed model of glutathione-quinone interplay is of great interest to cancer treatment and analysis of side effects [ 169 ].…”

Fruticuline A, a chemically-defined diterpene, exerts antineoplastic effects in vitro and in vivo by multiple mechanisms

“…TNF-α) 25 . As fruti is a quinone compound, which are known inducers of GSH adduct formation and oxidative stress 16,26 , we measured GSH content and ROS production on MCF-7 cells. However, curiously, neither short nor longer incubation times depleted GSH, showing no involvement of cellular death by oxidative stress.…”