Radiobiology 6 PDF

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury  Out line 1.Introduction 2. Primary effects of ionizing radiation  Water radiolysis and generation of reactive oxygen species  Generation of reactive nitrogen species Ionizing radiation...

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury  Out line 1.Introduction 2. Primary effects of ionizing radiation  Water radiolysis and generation of reactive oxygen species  Generation of reactive nitrogen species Ionizing radiation track structure and the nature of induced biological effects  Endogenous and radiation-induced DNA alterations 3. Reactive oxygen species and cellular homeostasis  Introduction The absorption of ionizing radiation by living cells can directly disrupt atomic structures, producing chemical and biological changes. It can also act indirectly through radiolysis of water, thereby generating reactive chemical species that may damage nucleic acids, proteins and lipids. Both, the direct and indirect effects of radiation initiate a series of biochemical and molecular signaling events that may repair the damage or culminate in permanent physiological changes or cell death Remarkably, the early biochemical modifications, which occur during or shortly after the radiation exposure, were thought to be responsible for most of the effects of ionizing radiation in mammalian cells. However, oxidative changes may continue to arise for days and months after the initial exposure presumably because of continuous generation of reactive oxygen (ROS) and nitrogen (RNS) species. Remarkably, these processes occur not only in the irradiated cells but also in their progeny. Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide nitric oxide is a signaling molecule in many physiological and pathological processes Furthermore, radiation induced oxidative stress may spread from targeted cells to non-targeted bystander cells through intercellular communication mechanisms. Nitric oxide (NO) is an intra- and extracellular messenger that mediates diverse signaling pathways in target cells and is known to play an important role in many physiological processes including neuronal signaling, immune response, inflammatory response, modulation of ion channels, phagocytic defense mechanism, penile erection, and cardiovascular homeostasis and its decompensation in atherogenesis. One of the very important systems, the cardiovascular system, is affected by NO production, as this bioactive molecule is involved in the regulation of cardiovascular motor tone, modulation of myocardial contractivity, control of cell proliferation, and inhibition of platelet activation, aggregation, and adhesion. These discoveries led to the proposal that the cellular biochemical machinery responsible for the metabolic production of free radicals and other reactive oxygen and nitrogen species derived from superoxide and nitric oxide could remain perturbed for minutes, hours, days, and even years after exposure to ionization radiation.  Reactive nitrogen species(RNS) In the past, reactive oxygen and nitrogen species (RONS) were shown to cause oxidative damage to biomolecules, contributing to the development of a variety of diseases. However, recent evidence has suggested that intracellular RONS are an important component of intracellular signaling cascades. Critical consideration of the literature reveals that : deleterious effects do not a ppear if only one primary species  (superoxide radical O−2, nitric oxide NO ) is present in a biological system, even at high concentrations. The prerequisite of deleterious effects is the formation of highly reactive secondary species (hydroxyl radical OH, peroxy nitrite ONOO−), emerging exclusively upon reaction with another primary species or a transition metal. Radical refers to an atom or molecule that contains an unpaired electron The secondary species are toxic, not well controlled, causing irreversible damage to all classes of biomolecules. (In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders.) In contrast, primary RONS are well controlled (superoxide dismutase, catalase), and their reactions with biomolecules are reversible, making them ideal for physiological/pathophysiological intracellular signaling. Effects of ionizing radiation (a)Physical stage: The energy deposition is caused by the incident radiation and secondary electrons are generated. (b)Physicochemical stage: In this process radical and molecular products of radiolysis that are distributed in a highly non-homogeneous track structure. Secondary electrons slow down to sub-excitation energies and following thermalization, they become trapped (e−tr) and hydrated (e−aq). The electron is captured by water through dipolar interactions, becoming solvated, and referred to as an aqueous electron or a solvated electron e¯ + H2O → eaq - surrounded by a “cage” of water; (thermalize electron) to energies below 7.4 eV (c).Non-homogeneous chemistry:During this stage, the various chemically reactive species diffuse and react with one another or with the environment, until all intra-track reactions are complete. (d).Biological stage: The cells respond to the damage resulting from the products formed in the preceding stages. During this stage the biological responses affecting the long-term consequences of radiation exposure are induced.