The role of glutathione and glutathione peroxidase in regulating cellular level of reactive oxygen and nitrogen species.

Abstract Glutathione (GSH) and GSH/glutathione peroxidase (GPX) enzyme system is essential for normal intracellular homeostasis and gets disturbed under pathophysiologic conditions including endothelial dysfunction. Overproduction of reactive oxidative species (ROS) and reactive nitrogen species (RNS) including superoxide (O2•−), and the loss of nitric oxide (NO) bioavailability is a characteristic of endothelial dysfunction. The GSH/GPX system play an important role in eliminating ROS/RNS. Studies have provided important information regarding the interactions of ROS/RNS with the GSH/GPX in biological systems; however, it is not clear how this cross talk affect these reactive species and GSH/GPX enzyme system, under physiologic and oxidative/nitrosative stress conditions. In the present study, we developed a detailed endothelial cell kinetic model to understand the relationship amongst the key enzyme systems including GSH, GPX, peroxiredoxin (Prx) and reactive species, such as hydrogen peroxide (H2O2), peroxynitrite (ONOO−), and dinitrogen trioxide (N2O3). Our simulation results showed that the alterations in the generation rates of O2•− and NO led to the formation of a wide range of ROS and RNS. Simulations performed by varying the ratio of O2•− to NO generation rates as well as GSH and GPX concentrations showed that the GPX reducing capacity was dependent on GSH availability, level of oxidative/nitrosative stress, and can be attributed to N2O3 levels, but not to H2O2 and ONOO−. Our results showed that N2O3 mediated switch-like depletion in GSH and the incorporation of Prx had no considerable effect on the ROS/RNS species other than ONOO− and H2O2. The analysis presented in this study will improve our understanding of vascular diseases in which the levels and oxidation states of GSH, GPX and/or Prx are significantly altered and pharmacological interventions show limited benefits.