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Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 269371, 9 pages
Research Article

Regulation of System by Pharmacological Manipulation of Cellular Thiols

Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Room 426, Milwaukee, WI 53233, USA

Received 10 December 2014; Revised 23 March 2015; Accepted 25 March 2015

Academic Editor: Noriko Noguchi

Copyright © 2015 Rebecca Albano et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The cystine/glutamate exchanger (system ) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, system can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and may protect cells against oxidative stress. We tested two different compounds that deplete primary cortical cultures containing both neurons and astrocytes of intracellular GSH, L-buthionine-sulfoximine (L-BSO), and diethyl maleate (DEM). Both compounds caused significant concentration and time dependent decreases in intracellular GSH levels. However; DEM caused an increase in radiolabeled cystine uptake through system , while unexpectedly BSO caused a decrease in uptake. The compounds caused similar low levels of neurotoxicity, while only BSO caused an increase in oxidative stress. The mechanism of GSH depletion by these two compounds is different, DEM directly conjugates to GSH, while BSO inhibits γ-glutamylcysteine synthetase, a key enzyme in GSH synthesis. As would be expected from these mechanisms of action, DEM caused a decrease in intracellular cysteine, while BSO increased cysteine levels. The results suggest that negative feedback by intracellular cysteine is an important regulator of system in this culture system.