Mechanisms for the cytotoxicity of cysteamine.
The major aim of this study was to quantitatively assess the contribution of H2O2 generation to the cytotoxicity induced by cysteamine. Cysteamine produces H2O2 at levels that correlate with its toxicity between 23 and 160 microM. A maximum of 6.9 microM H2O2 is generated by 625 microM cysteamine. When compared to the toxicity of exogenous H2O2, cysteamine-derived peroxide accounted for 57% of its toxicity. This corresponded to the percent toxicity due to 23 to 91 microM cysteamine. The remaining 43% toxicity appears to involve the inhibition of glutathione peroxidase, because activity of both the cellular and purified enzyme were inhibited by 200 microM cysteamine concentrations. CCRF-CEM cells have no catalase activity, so the inhibition of glutathione peroxidase may sensitize these cells to the less than toxic levels of peroxide generated by this aminothiol. Cysteamine also stimulated the production of cellular glutathione in a manner that was not related to its H2O2 generation. The production of glutathione did not influence toxicity but may reflect the accumulation of cysteamine to levels that inhibit glutathione peroxidase.
Jeitner
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Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, New York 12201-0509, USA. tjeitner@burke.org
Lawrence
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DA
D002470:Cell Survival / Q000187:drug effects; D003543:Cysteamine / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D003543:Cysteamine; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D005978:Glutathione