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This variability in drug action within the unique CNS tumor microenvironment further complicates the therapeutic efficacy and predictability of these agents (110)

Although the actual mechanisms of MTX-induced liver and kidney damage are unknown, one of the hypotheses is the breakdown in cellular antioxidant defences, which increases the production of reactive oxygen species and nitrogen species, inhibits cytosolic NADP-dependent dehydrogenase and NADP malic enzyme, lowers glutathione (GSH), superoxide dismutase (SOD) and catalase levels and reduces the effectiveness of the antioxidant defence system protecting the cell against reactive oxygen species (Reference Savran, Cicek and Doguc7)

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Role of Glutathione in Detoxification GSH is fundamental in neutralizing harmful endogenous and exogenous substances, including xenobiotics, reactive metabolites, and environmental toxins