The production of oxygen free radicals intermediates.
Oxygen free radical intermediates, also known as reactive oxygen species (ROS), are highly reactive molecules derived from molecular oxygen. These intermediates are produced through both endogenous cellular processes and exogenous environmental factors. The primary ROS include superoxide anion (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH). Below is a detailed explanation of their production mechanisms:
Endogenous Production of Oxygen Free Radicals
- Mitochondrial Electron Transport Chain (ETC):
- During aerobic respiration, electrons are transferred through complexes I-IV in the mitochondrial ETC to reduce oxygen to water.
- However, approximately 1-3% of electrons leak prematurely and react with molecular oxygen, forming superoxide anion (O2•−) at complexes I and III.
- Superoxide dismutase (SOD) converts O2•− into H2O2, which can further generate hydroxyl radicals (•OH) via Fenton or Haber-Weiss reactions in the presence of transition metals like iron or copper.
- Enzymatic Reactions:
- NADPH oxidase, present in immune cells such as neutrophils and macrophages, produces superoxide during the respiratory burst to combat pathogens.
- Xanthine oxidase generates superoxide and H2O2 during purine metabolism.
- Nitric oxide synthase (NOS) produces nitric oxide (NO•), which can react with O2•− to form peroxynitrite (ONOO−), a potent oxidant.
- Lipid Peroxidation:
- Free radicals abstract hydrogen atoms from polyunsaturated fatty acids in cell membranes, initiating lipid peroxidation.
- This process generates lipid radicals that propagate chain reactions, producing secondary products like malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE).
Exogenous Sources of Oxygen Free Radicals
- Environmental Factors: Ultraviolet radiation, ionizing radiation, cigarette smoke, air pollution, and heavy metal exposure contribute significantly to ROS production.
- Hyperoxia: Excessive oxygen levels increase ROS generation due to enhanced mitochondrial activity.
- Ionizing Radiation: Radiation interacts with water molecules in cells to produce hydroxyl radicals via radiolysis.
The cellular antioxidant defenses pathways.
To counteract oxidative damage caused by ROS, cells have evolved intricate antioxidant defense systems that include enzymatic antioxidants, non-enzymatic antioxidants, and repair mechanisms.
Enzymatic Antioxidant Pathways
- Superoxide Dismutase (SOD):
- SOD catalyzes the dismutation of superoxide anion into hydrogen peroxide and molecular oxygen: 2O2⋅− + 2H+ → H2O2 + O2. There are three isoforms:
- Cu/Zn-SOD in the cytoplasm,
- Mn-SOD in mitochondria,
- EC-SOD in extracellular spaces.
- SOD catalyzes the dismutation of superoxide anion into hydrogen peroxide and molecular oxygen: 2O2⋅− + 2H+ → H2O2 + O2. There are three isoforms:
- Catalase:
- Catalase decomposes hydrogen peroxide into water and oxygen: 2H2O2 → 2H2O + O2. It is primarily located in peroxisomes.
- Glutathione Peroxidase (GPx):
- GPx reduces hydrogen peroxide or organic hydroperoxides using reduced glutathione (GSH): H2O2 + 2GSH → 2H2O + GSSG. Glutathione reductase regenerates GSH from its oxidized form GSSG using NADPH.
- Peroxiredoxins and Thioredoxin Systems:
- Peroxiredoxins reduce peroxides while thioredoxin acts as an electron donor for redox reactions.
- These systems maintain cellular redox homeostasis.
Non-Enzymatic Antioxidants
- Vitamin E:
- A lipid-soluble antioxidant that protects cell membranes by scavenging lipid peroxyl radicals.
- Vitamin C:
- A water-soluble antioxidant that neutralizes ROS directly and regenerates vitamin E from its oxidized form.
- Glutathione:
- A tripeptide that serves as a major intracellular antioxidant by participating in redox reactions.
- Flavonoids and Polyphenols:
- Plant-derived compounds with strong free radical-scavenging properties.
Repair Mechanisms
Cells also possess mechanisms to repair oxidative damage:
- DNA repair enzymes correct base modifications caused by ROS.
- Proteasomal degradation removes oxidatively damaged proteins.
- Phospholipases degrade peroxidized lipids for membrane repair.
These antioxidant defenses work synergistically to maintain redox balance under physiological conditions but may become overwhelmed during oxidative stress associated with diseases like cancer, neurodegeneration, diabetes, and cardiovascular disorders.
