4.3 Free radical formation and oxidative stress

Radiation exposure triggers free radical formation, causing cellular damage. These unstable molecules wreak havoc on DNA, proteins, and lipids, leading to oxidative stress. Understanding this process is crucial for grasping radiation's biological effects.

Cells have defense mechanisms against free radicals, but high radiation doses can overwhelm them. This balance between damage and protection determines cell survival, influencing radiation therapy outcomes and long-term health effects after exposure.

Free Radicals and Radiation Exposure

Formation and Characteristics of Free Radicals

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• Free radicals manifest as highly reactive molecules or atoms with unpaired electrons in their outer shell causing instability and increased reactivity
• Ionizing radiation generates free radicals through radiolysis of water initiating primary free radical formation in biological systems
• Common radiation-produced free radicals encompass hydroxyl radicals (OH•), superoxide anion radicals (O2•-), and hydrogen atoms (H•)
• Free radical formation occurs rapidly within 10^-10 seconds post-radiation exposure triggering a cascade of chemical reactions
• Linear energy transfer (LET) of radiation influences the density and distribution of free radicals along the radiation track
  • High LET radiation (alpha particles) produces more concentrated free radical clusters
  • Low LET radiation (X-rays) generates more dispersed free radical formation

Mechanisms of Free Radical Generation

• Direct free radical formation occurs through ionization of target molecules by radiation
  • Example: Radiation directly ionizes a DNA molecule, creating a DNA radical
• Indirect free radical formation involves interactions between radiation and water molecules or other cellular components
  • Example: Radiation interacts with water to produce hydroxyl radicals, which then damage nearby biomolecules
• Free radical formation initiates radiation-induced cellular damage leading to various biological effects
  • DNA damage (mutations, strand breaks)
  • Lipid peroxidation (membrane damage)
  • Protein oxidation (enzyme inactivation)

Reactive Oxygen Species in Oxidative Stress

Types and Sources of Reactive Oxygen Species

• Reactive oxygen species (ROS) comprise a subset of free radicals and oxygen-containing reactive molecules
  • Examples: Hydrogen peroxide (H2O2), singlet oxygen, hydroxyl radicals
• ROS play a central role in radiation-induced oxidative stress by damaging cellular macromolecules
  • DNA oxidation leads to base modifications and strand breaks
  • Protein oxidation causes structural changes and loss of function
  • Lipid peroxidation disrupts membrane integrity
• Mitochondria serve as major sources of ROS production following radiation exposure
  • Electron transport chain dysfunction increases superoxide production
  • Mitochondrial DNA damage further amplifies ROS generation

Cellular Responses to ROS

• ROS production can overwhelm cellular antioxidant defenses resulting in oxidative stress and potential cell death or mutation
• Radiation-induced ROS activate various signaling pathways influencing cellular responses
  • Inflammation (NF-κB activation)
  • Cell cycle arrest (p53 pathway)
  • Apoptosis (caspase activation)
• The "oxygen effect" in radiobiology partially stems from increased production and reactivity of ROS in the presence of molecular oxygen
  • Oxygen enhances the fixation of radiation-induced damage
  • Hypoxic cells show increased radioresistance due to reduced ROS formation
• The bystander effect in radiation biology involves ROS diffusion to neighboring cells
  • Non-irradiated cells near irradiated cells experience oxidative stress
  • This phenomenon extends radiation impact beyond directly irradiated cells

Antioxidant Defense Mechanisms

Enzymatic Antioxidant Systems

• Cellular antioxidant defense mechanisms include enzymatic systems neutralizing free radicals and ROS
• Key enzymatic antioxidants target specific types of ROS:
  • Superoxide dismutase (SOD) converts superoxide to hydrogen peroxide
  • Catalase breaks down hydrogen peroxide to water and oxygen
  • Glutathione peroxidase reduces hydrogen peroxide and lipid peroxides
• The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway regulates cellular antioxidant response
  • Nrf2 activates transcription of various antioxidant genes
  • Example: Nrf2 upregulates glutathione synthesis enzymes

Non-Enzymatic Antioxidants and Cellular Redox Balance

• Non-enzymatic antioxidants act as scavengers directly neutralizing free radicals and ROS
  • Glutathione serves as a major cellular antioxidant and redox buffer
  • Vitamin C (ascorbic acid) neutralizes various ROS and regenerates vitamin E
  • Vitamin E (tocopherols) protects cell membranes from lipid peroxidation
• Cellular antioxidant defenses maintain redox homeostasis preventing excessive oxidative damage from radiation exposure
• The balance between ROS production and antioxidant defenses determines cell survival following radiation exposure
  • Moderate ROS levels activate adaptive responses and enhance radioresistance
  • Excessive ROS overwhelm antioxidant defenses leading to cell death
• High radiation doses can overwhelm antioxidant defense mechanisms
  • This principle finds application in radiation oncology for tumor cell killing
  • Normal tissue toxicity results from antioxidant depletion in healthy cells

Consequences of Oxidative Stress

Biomolecular Damage and Cellular Dysfunction

• Oxidative stress induces DNA damage potentially leading to mutations and genomic instability
  • Single and double-strand breaks disrupt DNA structure
  • Base modifications (8-oxoguanine) cause mispairing during replication
  • DNA-protein crosslinks interfere with transcription and replication
• Lipid peroxidation disrupts cell membrane integrity and function affecting cellular homeostasis
  • Increased membrane permeability alters ion balance
  • Disruption of membrane-bound proteins impairs signaling and transport
• Protein oxidation leads to structural changes, loss of function, and aggregation
  • Enzyme inactivation impairs cellular metabolism
  • Oxidized proteins can form toxic aggregates (neurodegenerative diseases)

Signaling Pathway Activation and Long-term Effects

• Oxidative stress activates stress-responsive signaling pathways influencing cell fate decisions
  • MAPK pathway activation regulates cell proliferation and differentiation
  • NF-κB pathway mediates inflammatory responses and cell survival
  • p53 pathway determines cell cycle arrest or apoptosis
• Chronic oxidative stress contributes to various pathological conditions
  • Cancer development through sustained DNA damage and genomic instability
  • Neurodegenerative diseases (Alzheimer's, Parkinson's) via protein aggregation
  • Cardiovascular disorders through endothelial dysfunction and atherosclerosis
• Radiation-induced oxidative stress modulates epigenetic marks altering gene expression patterns
  • DNA methylation changes affect gene silencing or activation
  • Histone modifications alter chromatin structure and accessibility
• Cellular response to oxidative stress involves complex interplay between pro-survival and pro-death signaling
  • Low-level oxidative stress activates adaptive responses (hormesis)
  • Severe oxidative stress triggers apoptosis or necrosis
  • The balance determines the ultimate fate of irradiated cells