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Antioxidants
- 1. Dr Aswathi T
- 2. • Oxidation – removal of electrons • Reduction – gain of electrons Atomic stability of any orbital • Atleast 2 electrons • Spinning in opposite directions • Most biological molecules • Non-radicals (non-free radicals)
- 4. Free radicals • Unpaired electron • Unstable • Highly reactive – oxidize biomolecules • Formed constantly in human system Accidental products during metabolism Deliberately during the process of phagocytosis Tissue injury and cell death
- 5. Sources of free radicals in the body • Cyclooxygenation • Lipooxygenation • Lipid peroxidation (auto-oxidation on exposure to oxygen) • Neutrophils (stimulated by exposure to microbes) • Re-perfusion of ischemic organs
- 6. Other sources • Toxic environmental pollutants (motor car exhaust) • UV & Ionizing radiations • Ozone • Heavy metal poisoning • Cigarette smoking • Chronic alcohol intake
- 7. Types of Free Radicals 1. Superoxide Radicals (O₂●) • Superoxide ion • Oxygen molecule deficient of one electron • Derived from i) Inevitable leakage from the mitochondrial electron transport chain reactions ii) Metabolism of various drugs by cytochrome P-450 microsomal oxidative system (eg: paracetamol or alcohol) iii) Action of some enzymes
- 8. • Hypoxanthine Xanthine Uric acid Oxidation Superoxide ion Hydrogen peroxide
- 9. 2. Other Free Radicals • Hydroxyl (OH●) • Peroxyl (ROO●) • Nitric oxide free radical (NO●) Oxidative destruction of PUFAs of cell membrane (Lipid peroxidation)
- 10. • Directly disrupts the integrity and function of biological cell membranes • Destabilizes membrane receptors • Damage to cellular components ( due to reactive aldehyde production) • Attack on proteins – inactivates enzymes • Damage to nucleic acid – breaks in DNA strands Free radicals are Carcinogenic
- 11. • Nitric oxide (NO) – cytotoxicity mechanism • Very high affinity to even low concentrations of superoxide ion (O₂●) • In oxidative stress – plenty of superoxide free radical – NO reacts very rapidly • Unstable peroxynitrite (ONOO●) • Instantly gets degraded to hydroxyl (OH●) & nitrite free radical (NO₂●)
- 12. Nitric oxide (NO ) + Superoxide (O₂●) Peroxynitrite (ONOO● - unstable) Hydroxyl (OH●) + Nitrite (NO₂●) Cytotoxicity of NO During oxidative stress
- 13. How they are stabilized? • Donate its unpaired electron • Accept one from other biomolecules • Non-free radical free radical Disastrous chain reaction
- 14. But! • If 2 unpaired electrons are shared by each other • Covalent bond formation • Reactivity terminated X● + X● X-X
- 15. Reactive Oxygen Species (ROS) • Highly reactive species – not free radicals in true sense • Free radicals positively charged negatively charged electrically neutral Inorganic species (H₂O₂, HOCl, O●)
- 16. • H₂O₂ & HOCl – not free radicals - very powerful oxidizing agents • Nascent oxygen – transient atomic state of oxygen – highly reactive than O₂ - causation of oxidative processes & photosensitization reactions Symbol Name ¹O₂ R + O⁻ LOOH Singlet oxygen Alkoxy free radical Lipid peroxide
- 17. Promoters of Free Radicals • Transition metals – iron, copper • Variable oxidation number (valency) • Can accept a single electron or donate it • Fe³⁺ + e⁻ = Fe²⁺ • Cu²⁺ + e⁻ = Cu⁺ • H₂O₂ OH● (Hydroxyl radical) Promoters of free radicals Iron & copper ions Accelerate lipid peroxidation Accumulation of highly cytotoxic end products
- 18. How free radicals are removed? Enzymatic and non-enzymatic antioxidant defense mechanisms If it is inadequate Free radical scavenging Oxidative stress an imbalance between free radicals and antioxidants in body
- 19. Lipid peroxidation Protein and DNA damage Tissue injury & cell death
- 20. Free Radicals and Diseases • Autoimmune diseases • Rheumatoid arthritis • Paracetamol and alcohol toxicity • Radiation injury • Carcinogenesis • Amyloidosis • Aging
- 21. System / organ Disease 1. CNS Parkinsonism, Alzheimer’s disease, Huntington’s disease, multiple sclerosis 2. CVS MI, Ischemic perfusion injury, Atherosclerosis 3. Endocrine Diabetes mellitus 4. GIT Peptic ulcer, Cirrhosis, Pancreatitis 5. Renal Nephrotoxicity (due to aminoglycosides & heavy metal poisoning) 6. RS Toxicity due to cigarette smoking 7. Eyes Cataract, Retinopathy
- 23. Antioxidants and their Clinical Use • Free radical generation causation of tissue injury i) Blockade of generation of toxic free radical ii) Blockade of the chain reaction set by free radical iii) Scavenging of free radical iv) Blocking the secondary generation of toxic metabolite or mediator V) Enhancing antioxidant capability
- 24. • At low concentration – prevent or delay the oxidation of lipids, carbohydrates, proteins and nucleic acids • Improve the quality of life by retarding the ageing process
- 25. Body defenses against oxidants Intracellular enzymes • Catalases, superoxide dismutases, glutathione peroxidases • Dispose of the oxidants Antioxidants obtained along with nutrients • Vitamins A, C, E • Trace elements – selenium • Flavonoids and polyphenolic substances present in plant foods (fruits, vegetables, amla, tea, garlic and others) • Others present in spices (coriander, clove, cardamom)
- 26. Endogenous Antioxidants Exogenous (Pharmacological) Antioxidants Superoxide Dismutase (SOD) Glutathione Reduced form (G-SH) Carotenoids (beta-carotene) Melatonin Alfa-Tocopherol (Vit. E) Ascorbic acid (Vit. C) Miscellaneous Adenosine Lactoferrin Transferrin Nicotinamide Agents augmenting endogenous antioxidants N-acetylcysteine Ebselen DesferoxamineCeruloplasmin Allopurinol Oxypurinol Selegiline Trace Elements and Minerals Selenium Manganese Zinc Copper Chromium From plant sources Garlic, grape, soyabean (isoflavones), turmeric (curcuminoids), tomato (lycopene, a red carotenoid pigment), herbal preparations containing bioflavonoids (phenolic chain breaking anto-oxidant), spirulina
- 27. 1. Superoxide Dismutase (SOD) • Found in all cells • Scavenges superoxide ion - Prevents its accumulation • Cells are protected from oxidative stress • Catalyses dismutation reaction • O₂● + O₂● + 2H H₂O₂ + O₂ • 2H₂O₂ 2 H₂O + O₂ H₂O₂ can still oxidise and damage many cellular components Removed by catalases and glutathione peroxidase
- 28. SOD afford protection against • Ischemic reperfusion injury • Pancreatitis • Gastrointestinal ischemia • Myocardial infarction • Endotoxic shock • Organ transplant
- 29. 2. Glutathione Reduced form (G-SH) • Excellent antioxidant & cytoprotective • Prevents free radical induced oxidation of SH groups of various proteins to disulfide (-S-S-) derivatives • Also protects hemoglobin from getting oxidized by H₂O₂ • Glutathione peroxidase (Selenium containing enzyme) scavenges toxic amounts of peroxides, H₂O₂ and free radicals • NADPH regenerates G-SH (reduced form) from G-S-S-G (oxidized form) by glutathione reductase
- 31. G-SH improves the outcome of • Organ transplant • Cystic fibrosis • Reperfusion injury • Diseases in AIDS patients
- 32. 3. Carotenoids (Beta-Carotene) • Vitamin-A precursor • Reduces the risk of cancers due to free radical damage • Provide protection from heart attack and photo-sensitisation
- 33. 4. Melatonin • Hormone from pineal gland • Potent scavenger of OH● radicals • Neutralizes nascent oxygen • Removes H₂O₂ and NO • Inactivates peroxynitrite (ONOO●) • Catalyses action of various enzymes involved in the activity of endogenous antioxidants
- 34. 5. Alfa-Tocopherol (Vit. E) Protection against • Neurological damage • Atherosclerosis • Thrombotic vascular disease • Retrolental fibroplasia
- 35. 6. Ascorbic Acid (Vit. C) • Reacts with H₂O₂ , peroxide and superoxide free radicals • Itself gets oxidized to Dehydroascorbate Ascorbic Acid Deficiency of Vit. C predisposes to Atherosclerosis Carcinogenicity
- 36. Tobacco (chewing and smoking) – rich in free radicals Damage DNA Throat and lung cancer Vit. C and E inhibits Nitrosamine formation
- 37. 7. Miscellaneous i) Adenosine • Endogenous anti-inflammatory-antioxidant • Inhibits superoxide generation by NADPH oxidase in neutrophils and macrophages • Affords protection against reperfusion injury ii) Lactoferrin and Transferrin • Circulating iron binding proteins • Reduce iron-dependent free radical toxicity • Afford natural protection against lung cancer iii) Nicotinamide
- 38. Agents Augmenting Endogenous Antioxidants i) N-acetylcysteine – glutathione precursor ii) Ebselen – congener of glutathione peroxidase • N-acetylcysteine – treating paracetamol toxicity & in AIDS patients iii) Desferoxamine Iv) Ceruloplasmin . Augment endogenous glutathione peroxidase activity . Promote endogenous antioxidant activity Bind free Fe²⁺ Detoxify superoxide anion Inhibit iron-dependent lipid peroxidation
- 39. Exogenous (Pharmacological) Antioxidants i) Allopurinol ii) Oxypurinol • Reperfusion injury • Myocardial infarction • Cerebral and gastrointestinal reoxygenation injury iii) Selegiline Antigout drugs Xanthine oxidase inhibitors Inhibiting the process of superoxidation Xanthine oxidase promotes superoxidation
- 40. Trace Elements and Minerals • Selenium • Enhance antioxidant activity of vitamin E • Promotes synthesis of glutathione peroxidase • Stimulate the immune system of the body • Most favoured ingredient in various antioxidant formulations • Manganese, Zinc, Copper and Chromium • Good sources for generating SOD, glutathione peroxidase and catalase enzymes
- 41. Antioxidants From Plant Sources • Garlic, grape fruit juice, soyabean (isoflavones), turmeric (curcuminoids), tomato (lycopene, a red carotenoid pigment), herbal preparations containing bioflavonoids (phenolic chain breaking anto- oxidant), spirulina
- 42. Coenzyme Q10 (Ubiquinone) • Fat-soluble antioxidant • Humans synthesize as well as obtained it from dietary sources • Present in mitochondria of human cells • High concentrations found in heart, liver, kidney and skeletal muscle • Tissue concentration decline with age • Sold as a dietary supplement • Involved in ATP generation
- 43. • Usual dose: 100-200 mg/day in divided doses • Beneficial effects in - Parkinson's disease - CHF • Well tolerated • Adverse reactions – mild – nausea, vomiting & abdominal discomfort • Decrease response to warfarin
- 44. Spirulina • Marine blue-green algae • “Most powerful food on earth” • Good source of SOD, beta-carotene and B-complex vitamins • Contain 70% by weight of protein and many micronutrients • 2 tablets per day (each containing 500 mg of spirulina)
- 45. Summary…..
- 46. THANK YOU