Makindo Medical Notes

Therapeutic trials of antioxidants such as Vitamin C, Vitamin E, Flavonoids and Beta-carotene have all been disappointing

Overview of Free Radicals

Free radicals are unstable molecules with unpaired electrons. They can cause cellular damage through oxidative stress and are implicated in various diseases and aging processes.

Key Concepts

• Types of Free Radicals:
  • Reactive Oxygen Species (ROS): Include superoxide anion (O2•-), hydroxyl radical (•OH), and hydrogen peroxide (H2O2).
  • Reactive Nitrogen Species (RNS): Include nitric oxide (NO•) and peroxynitrite (ONOO-).
• Sources of Free Radicals:
  • Endogenous Sources:
    • Mitochondrial electron transport chain.
    • Enzymatic reactions (e.g., NADPH oxidase, xanthine oxidase).
    • Peroxisomes.
    • Inflammatory cells (e.g., neutrophils, macrophages).
  • Exogenous Sources:
    • Environmental pollutants.
    • Radiation (UV, X-rays).
    • Tobacco smoke.
    • Chemicals and drugs.
• Oxidative Stress:
  • Imbalance between free radicals and antioxidants.
  • Can lead to cellular damage to lipids, proteins, and DNA.
• Antioxidants:
  • Molecules that neutralize free radicals and reduce oxidative stress.
  • Endogenous Antioxidants:
    • Superoxide dismutase (SOD).
    • Catalase.
    • Glutathione peroxidase.
  • Exogenous Antioxidants:
    • Vitamin C.
    • Vitamin E.
    • Beta-carotene.
    • Polyphenols.

Detailed Pathways

• Formation of ROS:
  • Superoxide Anion (O2•-):
    • Produced primarily in the mitochondria during electron transport.
    • Converted to hydrogen peroxide by superoxide dismutase (SOD).
  • Hydroxyl Radical (•OH):
    • Formed from hydrogen peroxide via the Fenton reaction.
    • Highly reactive and damaging to cellular components.
  • Peroxynitrite (ONOO-):
    • Formed from the reaction of superoxide with nitric oxide.
    • Can cause nitration and oxidation of proteins and lipids.
• Damage Mechanisms:
  • Lipid Peroxidation:
    • Free radicals attack polyunsaturated fatty acids in cell membranes.
    • Results in loss of membrane integrity and function.
  • Protein Oxidation:
    • Oxidative modification of amino acids.
    • Can lead to loss of enzyme activity and structural integrity.
  • DNA Damage:
    • Oxidative modifications to nucleotides.
    • Can result in mutations and contribute to cancer development.
• Antioxidant Defense Mechanisms:
  • Enzymatic Antioxidants:
    • Superoxide Dismutase (SOD): Converts superoxide to hydrogen peroxide.
    • Catalase: Converts hydrogen peroxide to water and oxygen.
    • Glutathione Peroxidase: Reduces hydrogen peroxide and lipid peroxides.
  • Non-Enzymatic Antioxidants:
    • Vitamin C: Scavenges free radicals and regenerates other antioxidants.
    • Vitamin E: Protects cell membranes from lipid peroxidation.
    • Glutathione: A tripeptide that directly scavenges free radicals and serves as a substrate for glutathione peroxidase.

Clinical Relevance

• Cancer:
  • Oxidative DNA damage can lead to mutations and cancer development.
  • Chronic inflammation and ROS are linked to cancer progression.
• Cardiovascular Diseases:
  • Oxidative stress contributes to atherosclerosis and hypertension.
  • ROS can damage endothelial cells and promote inflammation.
• Neurodegenerative Diseases:
  • Oxidative stress is implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
  • ROS can damage neurons and impair mitochondrial function.
• Aging:
  • Accumulation of oxidative damage over time contributes to the aging process.
  • Free radical theory of aging suggests that managing oxidative stress can influence lifespan.

Summary

Free radicals play a dual role in physiology and pathology. While they are essential for certain cellular functions, their overproduction or inadequate removal leads to oxidative stress and cellular damage. Understanding the balance between free radicals and antioxidants is crucial for managing various diseases and the aging process.