Novel Catalytic Antioxidative Activity of Nitroxide Radicals in the Heme/H2O2 system

Abstract

Deleterious reactive oxygen species (ROS), are involved in cellular damage, dysfunction and diseases. Cell-permeable stable nitroxide radicals (RNO.), effectively protect against ROS-induced injury in cell-free, cellular, isolated organs models as well as in whole animals. Unlike common antioxidants, which operate stoichiometrically, and are progressively depleted particularly under oxidative stress, RNO. can provide cytoprotection even at extremely low concentrations suggesting a catalytic mechanism. RNO. antioxidative activity involves 1-electron exchange between its reduced (RNOH) and oxidized (RN+=O) states, which allows its recycling. However, in spite of the significant therapeutic potential of nitroxides still, their protective mechanism(s) from ROS are not fully clear. A better mechanistic understanding of nitroxides activity in particular in the presence of heme proteins is essential for better selection of desired nitroxides, improvement of their efficacy, and minimizing potential adverse effects. Our objective is to elucidate the catalytic mechanism of nitroxides reaction under oxidative stress in the presence of heme proteins. We have studied RNO. reaction in the heme/ H2O2 system and have found the kinetics to be far more complex than previously assumed. Our recent electron paramagnetic resonance (EPR) spectrometry results indicate transient oscillatory changes in [RNO.] during the catalytic dismutation of H2O2 and detoxification of the deleterious oxidized heme species such as heme protein radical and ferryl. Our results suggest that a key element in the catalytic antioxidative activity of nitroxides in the presence of heme/ H2O2 is a Belousov-Zhabotinsky like reaction mechanism, involving two reaction pathways (possibly ionic and radical).