How do antioxidants work?

How Antioxidants Work

Antioxidants work primarily by neutralizing reactive oxygen species (ROS) and preventing oxidative damage to cellular components, thereby protecting against oxidative stress-related conditions and potentially reducing morbidity and mortality associated with various diseases. 1, 2

Mechanism of Action

Antioxidants function through several key mechanisms:

1. Direct neutralization of free radicals:

   • Antioxidants donate electrons to unstable free radicals, converting them to harmless chemical configurations 3
   • This prevents the sequential damage reaction that can affect multiple cellular components

2. Redox signaling modulation:

   • Antioxidants influence the reversible and compartmentalized oxidation of protein cysteine (thiols) and methionine residues 1
   • This regulates essential cellular processes from apoptosis to metabolism

3. Activation of protective pathways:

   • Some antioxidants, particularly polyphenols, activate the cyto-protective xenobiotic response via Nrf2-Keap1 signaling 1
   • This enhances endogenous antioxidant systems rather than directly scavenging ROS

Types of Antioxidants

Endogenous Antioxidants

• Enzymatic systems: Superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) 4
• Non-enzymatic molecules: Glutathione (GSH), thioredoxin 4

Exogenous (Dietary) Antioxidants

• Vitamins: C (ascorbic acid), E (tocopherols)
• Carotenoids: Beta-carotene, lycopene
• Polyphenols: Flavonoids, phenolic acids
• Trace elements: Selenium (as part of glutathione peroxidase) 5

Clinical Significance

Oxidative Stress and Disease

Oxidative stress occurs when there's an imbalance between free radical production and antioxidant defenses 1, contributing to:

• Cardiovascular disease and atherosclerosis
• Cancer development
• Neurodegenerative disorders
• Inflammatory conditions

Evidence for Antioxidant Benefits

The European Society of Cardiology suggests that targeted antioxidant therapies enhancing endogenous antioxidant systems may be more effective than direct ROS scavengers in improving endothelial function 2.

However, clinical evidence for supplemental antioxidants shows mixed results:

• Food sources vs. supplements: The American Cancer Society recommends consuming antioxidants through food sources rather than supplements 1
• Limited evidence for disease prevention: Clinical studies of antioxidant vitamin/mineral supplements have not consistently demonstrated reduction in cancer incidence 1, 6

Important Considerations and Caveats

Potential Pro-oxidant Effects

• Some antioxidants can act as pro-oxidants under certain conditions 1, 5
• For example, manganese porphyrins can act as pro-oxidants in certain tumor cells 1

Context-Dependent Efficacy

• Antioxidant effectiveness depends on:
  • Reactive species identity, source, duration, and amplitude 1
  • Bioavailability of the antioxidant 1
  • Spatio-temporal fidelity (right place, right time) 1

Cancer Treatment Considerations

• Caution during chemotherapy/radiation: Most oncologists advise against high-dose antioxidant supplements during cancer treatment as they might protect cancer cells from oxidative damage induced by these therapies 1
• Prudent recommendation: Cancer patients receiving chemotherapy or radiation therapy should avoid dietary supplements exceeding 100% of the Daily Value for antioxidant vitamins 1

Practical Recommendations

1. Focus on food sources: Consume a variety of antioxidant-rich foods (fruits, vegetables) daily rather than relying on supplements 1

2. Consider targeted approaches: Enhancing endogenous antioxidant systems may be more effective than direct ROS scavengers 2

3. Be aware of context: Recognize that antioxidant effects are highly dependent on specific biochemical contexts and may not universally prevent oxidative damage 6, 7

4. Exercise caution with supplements: High-dose antioxidant supplementation may interfere with beneficial adaptive responses to exercise or certain medical treatments 1