Glutathione Export by Human Lymphoid Cells: Depletion of Glutathione by Inhibition of Its Synthesis Decreases Export and Increases Sensitivity to Irradiation

Glutathione (in the form of GSH) is transported out of cultured human lymphoid cells at rates proportional to the intracellular glutathione levels. Inhibition of glutathione synthesis by buthionine sulfoximine, a potent selective inhibitor of γ -glutamylcysteine synthetase, leads to exponential decr...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1981-12, Vol.78 (12), p.7492-7496
Main Authors: Dethmers, Judy K., Meister, Alton
Format: Article
Language:English
Subjects:
Biochemistry
Biological Transport
Borates
Buthionine Sulfoximine
Cell lines
Cell Survival - drug effects
Cell Survival - radiation effects
Cells, Cultured
Extracellular Space - metabolism
Gamma Rays
Glutathione - biosynthesis
Glutathione - metabolism
Humans
Irradiation
Kidneys
Liver
Liver cells
Lymphocytes
Lymphocytes - metabolism
Methionine Sulfoximine - analogs & derivatives
Methionine Sulfoximine - pharmacology
Radiation effects
Viability
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Summary:Glutathione (in the form of GSH) is transported out of cultured human lymphoid cells at rates proportional to the intracellular glutathione levels. Inhibition of glutathione synthesis by buthionine sulfoximine, a potent selective inhibitor of γ -glutamylcysteine synthetase, leads to exponential decrease in intracellular glutathione, a large fraction of which appears extracellularly, indicating that glutathione turnover is associated with its export. Although cells with 0.09 mM glutathione (4% of controls) were 85% viable, further decrease was associated with marked loss of viability. Cells with 4-5% of control glutathione levels were much more sensitive than control cells to the effects of γ radiation and of 5,5′-dithiobis(2-nitrobenzoate). Depletion of glutathione by use of buthionine sulfoximine has advantages over other reagents (such as diamide, other oxidizing agents, and diethylmaleate, which affect other cellular components and may increase glutathione disulfide levels) and therefore has potential usefulness in sensitizing cells to the effects of radiation and to therapeutic agents that are detoxified by reactions involving glutathione.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.78.12.7492