ABSTRACT
In considering the interactions of ionizing radiationwithmammalian cells, the first thought is usually directed towards damage to nuclear DNA and the signaling which is initiated by this damage. This will be described in ensuing chapters. Less attention is paid to cytoplasmic radiation interactions; however, a considerable body of published information indicates that irradiation of the cytoplasm perturbs intracellular metabolic oxidation=reduction (redox) reactions and that systems affected by this initial insult may remain perturbed for minutes, hours, or days. It would seem logical that these cellular redox reactions might contribute to the activation of protective or damaging processes that could impact upon the damaging effects of radiation. These processes include redox-sensitive signaling pathways, transcription factors, gene expression, and the metabolic activities that govern the formation of intracellular oxidants and reductants. While a great deal is known about the molecular changes associated with the initial production of free radicals at the time of irradiation, the contribution of perturbations in redox-sensitive metabolic processes to biological outcomes following radiation exposure are only becoming appreciated recently. Ionizing radiation results in the formation of free radicals in living sys-
tems that are believed to persist for milliseconds and to result in oxidative damage to biomolecules such as DNA, proteins, and lipids that contribute to the biological effects of radiation. In the presence of oxygen, radiation leads to the formation of reactive oxygen species (ROS) such as the superoxide anion (O2 ), hydrogen peroxide (H2O2), hydroxyl radical (
.OH), and singlet oxygen (described in detail in Chapter 2). The generation of intracellular ROS (and reactive nitrogen species [RNS]) by radiation takes place against the backdrop of normal cellular oxidative metabolism since ROS are constantly generated in aerobic cells as a result of electron-transfer processes. Although low amounts of ROS are easily tolerated by the cell, abnormally high levels of ROS, that might result from disruption in the balance between
oxidant production and antioxidant defense, produce a state of oxidative stress, which is characteristic of some pathological conditions. ROS are produced concomitant to oxidative metabolism and after exposure to ionizing radiation, chemotherapeutic agents, hyperthermia, inhibition of antioxidant enzymes, and depletion of cellular reductants such as NADPH and glutathione (GSH).
