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Am J Physiol Cell Physiol 292: C1440-C1449, 2007. First published December 27, 2006; doi:10.1152/ajpcell.00366.2006
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CELLULAR METABOLISM

Nitric oxide increases toxicity of hydrogen peroxide against rat liver endothelial cells and hepatocytes by inhibition of hydrogen peroxide degradation

Institut für Physiologische Chemie, Universitätsklinikum Essen, Essen, Germany

Submitted 5 July 2006 ; accepted in final form 20 December 2006

Nitric oxide (NO) and hydrogen peroxide (H₂O₂) show cooperativity in their cytotoxic action. The present study was performed to decipher the mechanisms underlying this phenomenon. In cultured liver endothelial cells and in cultured, glutathione-depleted hepatocytes, the combined exposure to NO (released by spermine NONOate, 1 mM) and H₂O₂ (released by glucose oxidase) induced cell injury that was far higher than the injury elicited by NO or H₂O₂ alone. In both cell types, the addition of the NO donor increased H₂O₂ steady-state levels, although with different kinetics: in hepatocytes, the increase in H₂O₂ levels was already evident at early time points while in liver endothelial cells it became evident after 2 h of incubation. NO exposure inhibited H₂O₂ degradation, assessed after addition of 50 µM, 200 µM, or 4 mM authentic H₂O₂, significantly in both cell types. However, again, early and delayed inhibition was observed. The late inhibition of H₂O₂ degradation in endothelial cells was paralleled by a decrease in glutathione peroxidase activity. Glutathione peroxidase inactivation was prevented by hypoxia or by ascorbate, suggesting inactivation by reactive nitrogen oxide species (NO_x). Early inhibition of H₂O₂ degradation by NO, in contrast, could be mimicked by the catalase inhibitor azide. Together, these results suggest that the cooperative effect of NO and H₂O₂ is due to inhibition of H₂O₂ degradation by NO, namely to inhibition of catalase by NO itself (predominant in hepatocytes) and/or to inhibition of glutathione peroxidase by NO_x (prevailing in endothelial cells).

nitrogen monoxide; catalase; glutathione peroxidase

This article has been cited by other articles:

				M. M. Cortese-Krott, C. V. Suschek, W. Wetzel, K.-D. Kroncke, and V. Kolb-Bachofen Nitric oxide-mediated protection of endothelial cells from hydrogen peroxide is mediated by intracellular zinc and glutathione Am J Physiol Cell Physiol, April 1, 2009; 296(4): C811 - C820. [Abstract] [Full Text] [PDF]