Summary
Exposure of mammalian cells to oxidative stress induced by redox-active quinones and other prooxidants results in glutathione and NAD(P)H oxidation, followed by the modification of protein thiols, ATP depletion and the loss of cell viability. Protein thiol modification is normally associated with the impairment of various cell functions, including inhibition of agonist-stimulated phosphoinositide metabolism, disruption of intracellular Ca2+ homeostasis, and perturbation of cytoskeletal organization. The latter effect appears to be responsible for the formation of the numerous plasma membrane blebs, typically seen in cells exposed to cytotoxic concentrations of prooxidants. Following the disruption of thiol homeostasis in prooxidant-treated cells, there is a perturbation of intracellular Ca2+ homeostasis with a sustained increase in intracellular Ca2+ concentration.This Ca2+ overload can cause activation of various Ca2+-dependent degradative enzymes (phospholipases, proteases, endonucleases) and may contribute to the mitochondrial damage seen in oxidative stress. Severe oxidative stress is also associated with extensive DNA damage which, in turn, may lead to excessive stimulation of poly (ADP-ribose) polymerase activity and subsequent NAD+ and ATP depletion which may contribute to cell killing. In contrast with the cytotoxic effects of severe oxidative stress, low levels of oxidative stress can lead to the activation of enzymes involved in cell signaling. In particular, the activity of protein kinase C is markedly increased by redox-cycling quinones through a thiol/disulfide exchange mechanism, and this may represent a mechanism by which prooxidants can modulate cell growth and differentiation.
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Orrenius, S. (1993). Mechanisms of Oxidative Cell Damage. In: Poli, G., Albano, E., Dianzani, M.U. (eds) Free Radicals: from Basic Science to Medicine. Molecular and Cell Biology Updates. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-9116-5_5
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