Causes of Oxidative Stress
Oxidative stress is primarily caused by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms, leading to potential cellular and tissue damage. 1
Primary Sources of Oxidative Stress
Cellular and Metabolic Sources
- Mitochondrial dysfunction: Mitochondria are the major source (90%) of intracellular ROS production, particularly during ATP production via oxidative phosphorylation 1, 2
- NADPH oxidase system: A significant source of ROS, especially in phagocytes during immune responses 1
- Nutrient excess: Excessive nutrients prompt mitochondria to produce ATP at rapid rates, leading to higher production of ROS 3
Environmental and External Factors
- UV radiation and ionizing radiation 4
- Environmental pollutants and heavy metals 4
- Xenobiotics (including certain medications like antineoplastic drugs) 4
- Infectious agents that trigger inflammatory responses
Physiological and Pathological Conditions
- Hypermetabolism: States with pronounced ATP hydrolysis increase oxygen radical production 3
- Inflammation: Activation of polymorphonuclear cells and secretion of myeloperoxidase (MPO) links oxidative stress to inflammation 3
- Chronic diseases: Conditions like chronic kidney disease, diabetes, and cardiovascular disease can both cause and result from oxidative stress 3
- Aging processes: Natural aging is associated with increased oxidative stress 2
Mechanisms of Oxidative Damage
Molecular Targets of Oxidative Stress
- Lipids: Formation of malondialdehyde, F2-isoprostanes, and advanced lipoxidation end products 3
- Proteins: Creation of advanced oxidation protein products, carbonyl formation, and thiol oxidation 3
- DNA: Formation of 8-hydroxy-2'-deoxyguanosine and other DNA adducts 3
- Carbohydrates: Generation of reactive aldehydes and advanced glycation end-products (AGEs) 3
Cellular Consequences
- Activation of multiple stress-sensitive signaling pathways (nuclear factor-κB, p38 mitogen-activated protein kinase, c-Jun terminal kinase) 3
- Reduced insulin sensitivity at the cellular level 3
- Endothelial dysfunction contributing to atherosclerosis 3
- Altered redox signaling affecting normal cell functions 1
Antioxidant Defense Mechanisms
Endogenous Antioxidant Systems
- Enzymatic systems (superoxide dismutase, catalase, glutathione peroxidase)
- Non-enzymatic antioxidants (glutathione, vitamin C, vitamin E)
- Several deficiencies in these defense mechanisms have been demonstrated in chronic diseases 3
Exogenous Antioxidants
- Vitamin E (α-tocopherol): The most important lipid-soluble antioxidant that protects membrane lipids from peroxidation 3
- Vitamin D: May play a role in reducing oxidative stress in certain conditions 3
- Other dietary antioxidants: Flavonoids and polyphenols 4
Clinical Implications and Pitfalls
Important Considerations
- Oxidative stress is not always harmful—ROS play essential physiological roles in cell signaling and immune defense 4, 5
- "Antioxidative stress" (excessive antioxidant activity) can also be harmful and may interfere with beneficial ROS functions 5
- Overconsumption of synthetic antioxidants may have detrimental effects in certain conditions like cancer 5
Common Pitfalls
- Assuming all oxidative stress is harmful—some level is necessary for normal physiological functions
- Indiscriminate use of antioxidant supplements without considering the specific oxidative imbalance
- Failing to address the underlying causes of oxidative stress rather than just treating symptoms
Understanding the complex balance between oxidants and antioxidants is crucial for developing effective therapeutic approaches that target oxidative stress without disrupting essential physiological functions.