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Oxidative stress

- In reactions of activated oxygen in biological systems there are even more complications due to the
o surface properties of membranes,
o electrical charges,
o binding properties of macromolecules,
o compartmentalization of enzymes, substrates and catalysts
1. Oxidative damage to lipids
- Membranes are more sensitive to oxidative attack because of the presence of polyunsaturated fatty
acids (PUFA) in the membrane phospholipids.
- 3 steps for lipid peroxidation
o Initiation
Generation of PUFA radical from interaction of ROS such OH with PUFA.
PUFA radicals R & ROO
R & ROO are degraded to Malondialdehyde
o Malondialdehyde appearance in urine & blood is an indicator of
free radical damage
o Propagation
ROO radical generates another PUFA radical
o Termination
Collision of 2 radical species to form non-radical product.
- Lipid peroxidation increase with age.
LPO per Antioxidant Signaling Action Survival
No net production - -
Low LPO production Stress Antioxidant induction
Moderate LPO Stress Death program Apoptosis
production induction
High LPO - Membrane lysis Necrosis

- Hexanoyl lysine => lipid peroxide modified protein


o It is an addcut between LPO and protein.

2. Oxidative damage to proteins


- Sulphur containing amino acids (Cysteine & Methionine) and thiol groups are very susceptible sites
on proteins
o They form Disulphides (coss linkes) with other residues.
- Glycation (addition of Carbohydrates) increases the susceptibility of proteins to the attack by free
radicals.
- Lipofuscin an adduct of LPO and protein
o Seen in Lysosome of aged cells
o Alzheimers disease brain cells
o Fe overloaded hepatocytes.
- Cataractogenesis: Cataract formation in such a way
Involves Methionine and tryptophan degradation products.

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3. Oxidative damage to DNA
- Both Sugar and base moieties are susceptible to Oxidation
- Hydrogen Abstraction by hydroxyl radical results in DNA strand break.
- Addition of hydroxyl radical to DNA bases results in Nucleobase oxidation (e.g. 8-hydroxy-
desoxyguanosine).
- DNA:
o Adducts
o Apurinic or Apyridimic site occurs
o Strand breaks
- Mutation arising from selective modification of G: C sites specially indicates oxidative attack on
DNA by ROS.
- Paracetamol an analgesia drug that results in Hepatotoxicity through ROS.

Oxidative stress & disease


- All chronic diseases are associated with ROS.
- Brain is uniquely vulnerable to oxidative damage because:
o Intolerance of blood flow interruptions
o Limited regeneration
o Circuit based function (small defect have huge impacts)
o Aging sensitive
o Ca dependent processes
o PUFAs (because brain contains more lipids)
- ROS & RNS can function as signaling species in regulation of fundamental activities.
- Vascular Endothelium is a major target of oxidative stress.
- Factors contributing to Alzheimer disease are:
o Cholesterol metabolism abnormalities
o Oxidative stress
o Vascular lesion and Hypoperfusion
- Alzheimer disease:
o Described by many authors as ticking bomb
o Most common cause of Dementia.
o Commonly found in Developed countries specially China
o Polymerization of amyloid leads to production of ROS
o ROS leads to lipid peroxidation which leads to Tau Protein formation.
o Characterized by Extraneuronal amyloid plaques & Intraneuronal neurofibrillary tangles.
o Temporal & Parietal lobes are most likely to be affected thus causing Memory
impairments, anomia & Visuoconstructional drawing disability.
- Parkinsons Disease: - hand shaking symptom
o Increased H2O2 leads to increased dopamine oxidation.
o In Substantia Nigra:
Decreased Glutathione level
Increased Fe concentration leads to hydroxyl ion formation.
- Atherosclerosis:
o LDL oxidation by ROS => early Atherosclerosis.

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o Macrophages + Oxidized Lipid => Foam Cell
o Aggregation of Foam Cells on arterial wall => Fatty streak or Yellow patches
- ROS affect P53 gene (cell division regulating gene) thus causing uncontrolled cell division (Cancer)
o Thus the cells will be termed as neoplastic cells.

Antioxidants
- Compound that protect cells from the damage caused by oxidation; normally in balance with
oxidants.
- Function:
o Prevent transfer of electron from oxygen to organic molecule
o Stabilize & terminate free radicals
- Classification:
o Based on location
Plasma Cell membrane Intracellular
Vit C, Bilirubin, Uric acid, Vit E ( Tocopherol) SOD, Catalase, Glutathione
transferrin, ceruloplasmin, peroxidase
Carotene

o Based on Nature and action:


Enzymatic Non -enzymatic
Nutrient Metabolic
SOD, Catalase, Glutathione Carotene, Vit E, Vit C, Bilirubin, Uric acid, transferrin,
peroxidase & Glutathione Polyphenols (vegetable Albumin, Glutathione,
reductase (secondary enzyme) souces), Minerals (Zinc & Catechins, lipoic acid
selenium), lipoic acid

- SOD:
o Present in every cell
o 1st line of defense against Superoxide anion by changing it to H2O2
o 3 forms; difference is Metal prosthetic group:
Cu Zn SOD => Cytoplasm
Mn SOD => Mitochondrion
Cu SOD => Extracellular SOD
- Catalase and Glutathione Peroxidase
o Catalase:
Fe dependent
Present in all body organs but majorly in Liver and Erythrocytes.
Brain, skeletal muscle & heart contain only small amounts
o Glutathione peroxidase:
Selenium Dependent
Requires ATP where its production involves:
Thyroid hormone
Health Mitochondria
Active Pentose phosphate pathway.

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Requires reduced glutathione which needs
NADPH & Vit B2 (riboflavin) to be reduced
- Vit E ( Tocopherol):
o Most important lipid soluble antioxidant in human blood plasma
o Protects against lipid peroxidation
o More saturated than tocotrienol
o Contains methyl groups on both its R-groups
o Stored in adipose tissue because its lipid soluble
o Chain breaking antioxidant (interrupt free radical propagation)
- Vit C:
o Water soluble vitamin
o Chain breaking Antioxidant (interrupt free radical propagation)
o Scavenges free radicals and also inhibits lipid peroxidation.
o Promotes regeneration of Tocopherol reduced form
- Carotenoids
o Carotene
C40 compounds; strong light absorbers often showing Orange color.
Composed of two Vit A (retinol) joined together.
Converted to Vit A at Interistitial mucosa.
Can exert antioxidant effect as well as quench singlet oxygen (useful in treatment of
Erythropoietic protoporphyria)
o Lycopene
Shows red color, thus found in tomato.
Also an antioxidant.
- lipoic acid:
o Vitamin like compound
o Souce:
Plants and animals as diet
Synthesized in the body
o Recycles other antioxidants such as Ascorbic acid, tochopherol & glutathione.
- Glutathione (reduced form)
o A scavenger of hydroxyl radicals & singlet oxygen (just like Uric acid)
o Important role in Xenobiotic metabolism
- Catechins Of Green tea.
o Rich in Polyphenols
o 200x powerful than Vit E
Other things to note:
- Hormetic response curve
- Invoking transcription of stress response genes promotes cell survival.
- Strenuous exercise leads to activation of xanthine oxidase & our immune system to produce ROS.
- Adequate ROS are important to maintain Redox Allostatic Buffering Capacity (rABC)
Less & More ROS Weak rABC Weakened Physical fitness Accelerated Aging
Adequate Normal rABC Normal Physical fitness Normal Aging
Optimal Enhanced rABC Enhanced Physical fitness Decelerated Aging

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- Despite high levels of exogenous antioxidants, with appropriate high level of exercise for a very
short period, one can get higher endogenous & exogenous anti-oxidants for a period of a day.
- Dont consume foods containing trans-fats or hydrogenated oils.