Nitric oxide-induced resistance to hydrogen peroxide stress is a glutamate cysteine ligase activity-dependent process |
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Authors: | Ridnour Lisa A Sim Julia E Choi Jinah Dickinson Dale A Forman Henry J Ahmad Iman M Coleman Mitchell C Hunt Clayton R Goswami Prahbat C Spitz Douglas R |
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Affiliation: | Division of Radiation and Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Boulevard, Room 411, St. Louis, MO 63108, USA. ridnourl@mail.nih.gov |
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Abstract: | Nitric oxide (*NO) is a reactive nitrogen species known to be involved in cytotoxic processes. Cells respond to cytotoxic injury by stress response induction leading to the development of cellular resistance. This report describes an *NO-induced stress response in Chinese hamster fibroblasts (HA1), which leads to glutathione synthesis-dependent resistance to H2O2-mediated oxidative stress. The development of resistance to H2O2 was completely abolished by the inhibition of glutamate cysteine ligase (GCL) during the first 8 h of recovery after *NO exposure. Altered thiol metabolism was observed immediately after *NO exposure as demonstrated by up to 75% decrease in intracellular thiol pools (glutathione, gamma-glutamylcysteine, and cysteine), which then reaccumulated during the *NO-mediated development of resistance. Immunoreactive protein and activity associated with GCL decreased immediately after exposure to *NO and then reaccumulated during the development of resistance to H2O2 challenge. Moreover, compared to N2 controls the activity levels of GCL in *NO-exposed cells increased approximately twofold 24 h after H2O2 challenge. These results demonstrate that *NO exposure is capable of inducing an adaptive response to H2O2-mediated oxidative stress in mammalian cells, which involves alterations in thiol metabolism and is dependent upon glutathione synthesis and increased GCL activity. |
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