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Invited Symposium: Oxidative Stress and the CNS






Abstract

Introduction

Materials & Methods

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References




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Multiple Consequences of Glutathione Peroxidase Modulation on Cellular Responses to Oxidative Stress

Mirault, M.-E. (Department of Medicine, CHUL Research Center and Laval University, Canada)
Legault, J. (Department of Medicine, CHUL Research Center and Laval University, Canada)
Furling, D. (Department of Medicine, CHUL Research Center and Laval University, Canada)
Petrov, P. (Department of Medicine, CHUL Research Center and Laval University, Canada)
Carrier, C. (Department of Medicine, CHUL Research Center and Laval University, Canada)

Contact Person: Marc-Edouard Mirault (memirault@crchul.ulaval.ca)


Abstract

We review here some of our work focussing on the specific contribution of peroxide-derived free radicals to oxidative stress responses, using human cell and transgenic mouse models that overexpress selenium-dependent glutathione peroxidase-1 (GPx-1). Apoptosis induced by the superoxide/hydrogen peroxide-generator 6-hydroxydopamine was strongly inhibited by GPx-1 or iron[III] chelation in human neuroblastoma transfectants. This inhibition apparently occurred upstream of caspase activation and was not observed in staurosporine-treated cells. Since mitochondria play a central role in stress-related apoptotic processes, and mitochondrial dysfunction is a documented source of oxygen radicals in many neurotoxic processes, we investigated the role of intramitochondrial GPx-1 level in mitochondrial function homeostasis in conditions of oxidative stress. Intramitochondrial GPx-1 activity accounts for about 15% of total cellular activity in human WI38-VA13 fibroblasts and T47D carcinoma cells transfected or not by GPx-1 (high and low GPx activity). GPx-1 antigen detected by immuno-electron microscopy is about 20-fold more concentrated in mitochondria than in cytosol, irrespective of GPx-1 overexpression. Following 1h-oxidant challenge by menadione, both mtDNA strand breakage (relaxation) and 8-oxo-2'-deoxyguanosine formation in mtDNA were significantly lower in GPx-1-transfected T47D cells, suggesting reduced formation of hydroxyl radicals in GPx-1-rich mitochondria. Work supported by the National Cancer Institute of Canada with funds of the Canadian Cancer Society

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Presentation Number SAmirault0746
Keywords: Apoptosis, mitochondrial DNA, 8-oxoguanine, DNA strand breaks, neuroblastoma cells


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Mirault, M.-E.; Legault, J.; Furling, D.; Petrov, P.; Carrier, C.; (1998). Multiple Consequences of Glutathione Peroxidase Modulation on Cellular Responses to Oxidative Stress. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/juurlink/mirault0746/index.html
© 1998 Author(s) Hold Copyright