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Free radicals and Antioxidants

Free radicals and Antioxidants. When The free radical speaks: “we exists as independent molecular species; generated by cellular metabolism & environmental effects; Implicated in the causation of several disease; Destroyed by antioxidants to protect cells/tissues/body.”.

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Free radicals and Antioxidants

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  1. Free radicals and Antioxidants

  2. When The free radical speaks: • “we exists as independent molecular species; generated by cellular metabolism & environmental effects; Implicated in the causation of several disease; Destroyed by antioxidants to protect cells/tissues/body.”

  3. Leading Causes of Death • Heart diseases • Cancers • Diabetes Mellitus • Stroke • Liver Disease indicates diet-related diseases (65%) >90% of disease incidence involves free radical damage

  4. The supply of oxygen is absolutely essential for the existence of higher organisms. • Very high concentration of O2 are found to be toxic, and can damage tissues. • Oxygen toxicity is due to formation of oxygen free radicals or reactive oxygen species (ROS).

  5. And about chemistry of an atom or molecule • The outermost orbital in an atom or molecule contains two electrons, each spinning in opposite directions. • The chemical covalent bond consists of a pair of electrons, each component of the bond donating one electron each.

  6. Definition • A free radical is a molecule or a molecular fragment that contains one or more unpaired electrons in its outer orbital and is capable of independent existence. • Free radical is generally represented by a superscript dot R.

  7. Oxidation reactions ensures complete reduction of oxygen and converted to water. • However if the reduction of O2 is incomplete , a series of reactive radicals called as reactive oxygen species or ROS .

  8. Types of free radicals 1. Superoxide, O2- 2. Hydrogen peroxide, H2O2 3. Hydroxyl radical, OH- 4. Singlet oxygen, 1O2 5. Hydroperoxy radical, HOO- 6. Lipid peroxide radical, ROO- 7. Nitric oxide, NO- 8. peroxynitrite, ONOO-

  9. Out of the above, hydrogen peroxide H2O2 & singlet oxygen are not free radicals (they do not have superscript dot ).because of their extreme reactivity ,they are included in the group of reactive oxygen species .

  10. e- e-, 2H+ e-, H+ e-, H+ O2 O2- H2O2 OH- H2O H2O Hydrogen peroxide Hydroxyl radical Superoxide The sequential univalent reduction steps of oxygen may be represented as above.

  11. Important characteristics of the ROS are • Extreme reactivity • Short life span • Generation of new ROS by chain reaction • Damage to various tissues.

  12. Sources and generation of free radicals The major sources responsible for the generation of free radicals may be considered into two categories… 1) Due to normal biological processes (or cellular metabolism) 2) Due to environmental effects.

  13. 1) Cellular metabolism as a source 1) They are constantly produced during the normal oxidation of foodstuffs due to leakage of electrons from the respiratory chain (ETC) And about 1-4% of oxygen taken up in the body is converted to free radicals. 2)Due to chain reaction of membrane lipid peroxidation.

  14. 3) Peroxisomal generation of O2 and H2O2. 4) During the synthesis of prostaglandins 5) Macrophages also produce NO from Arginine by the enzyme nitric oxide synthase

  15. Respiratory burst 6.NADPH oxidase in the inflammatory cells (neutrophils, eosinophils, monocytes and macrophages ) produce superoxide anion by the process of respiratory burst during Phagocytosis. 7.As a result of auto oxidation of metal ions (Fe2+ cu2+) ascorbic acid, glutathione, flavin coenzymes.

  16. 2. Environmental sources • Ionizing radiations damages tissues by producing hydroxyl radicals , hydrogen peroxide and superoxide anion. • Light of appropriate wavelength can cause photolysis of oxygen to produce singlet oxygen. • Cigarette smoke contains high concentrations of various free radicals.. • Inhalation of air pollutants will increase the production of free radicals . • As a result of drug metabolism ..

  17. FREE RADICALS : THE CAUSE OF VIRTUALLY ALL DISEASES Environmental pollution FREE RADICAL FORMATION Industrial pollution Excessive Alcohol & smoking Pesticides & herbicides High fat foods

  18. Harmful effects of free radicals A. Free Radical on biomolecules • Proteins • Cause oxidation of sulfhydryl groups, and modification of AA. ROS may damage protein by fragmentation, aggregation results in the loss of biological activity of proteins. 2. Lipids • The polyunsaturated lipid molecules of cell membranes are particularly susceptible to damaging free radicals process and contribute to the uncontrolled chain reaction (lipid peroxidation).

  19. Lipid peroxidation refers to the oxidative degradation of lipids. It is the process whereby free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids(PUFA). In addition, end products of lipid peroxidation may be mutagenic and carcinogenic Lipid peroxidation

  20. Harmful effects of free radicals A. Free Radical onbiomolecules 3. Carbohydrates • Glycationincreases the susceptibility of proteins to the attack by free radicals. 4. Nucleic acid • cause DNA strand breaks, fragmentation of bases and deoxyribose results in cytotoxicity and mutations.

  21. Oxidative Damage Free Radicals Proteins Lipids DNA/RNA (-SH) (R-OO.) (-OH.)

  22. Harmful effects of free radicals B. Diseases 1. Cardiovascular diseases (CHD):ox-LDL, formed by the action of free radicals, promote CHD and atherosclerosis (AS). 2. Cancers:damage DNA and cause mutation and cytotoxicity, play a key role in carcinogenesis. 3. Inflammatory diseases: damage on the extracellular components such as collagen and hyaluronic acid, promote glomerulonephritis and ulcerative colitis. 4. Respiratory diseases: destroy endothelium and cause lung edema. Cigarette smoke contains free radicals and promotes the production of more free radicals.

  23. Macrophage take up oxidized LDL, when overload with lipid, become “foam cells”. Conglomerate of foam cells form fatty streaks or yellow patches visible in the arterial wall. Dying foam cells release lipid that form lipid pool within the arterial wall.

  24. Harmful effects of free radicals B. Free Radical and diseases 5. Diabetes mellitus: Destruction of islets results in pathogenesis.

  25. Harmful effects of free radicals 6. Cataract 7. Aging process 8. Others: such as • Parkinson’s disease, • Alzheimer’s disease, • multiple sclerosis, • Liver cirrhosis, • muscular dystrophy.

  26. Antioxidants in biological system To mitigate the harmful/damaging effects of free radicals, the aerobic cells have developed antioxidant defense mechanisms.

  27. Definition of Antioxidant • A biological antioxidant may be defined as a substance (present in low concentration ) that significantly delays or inhibits oxidation of a substrate. • Antioxidants may be considered as the scavengers of free radicals.

  28. Antioxidants • The production of free radicals and their neutralization by antioxidants is a normal bodily process.

  29. Free radicals and Antioxidants

  30. Different ways of Classification of Antioxidants I. Antioxidants in relation to lipid peroxidation A) Preventive antioxidants that will block the initial production of free radicals e.g. catalase, glutathione peroxidase. B) Chain breaking antioxidants that inhibit the propagative phase of lipid peroxidation e.g. superoxide dismutase, vitamin E, uric acid.

  31. Different ways of Classification of Antioxidants…. II. Antioxidants according to their nature and action A) Enzymatic Antioxidants e.g. superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase. B) Non-enzymatic Antioxidants 1) Nutrient Antioxidants e.g. carotenoidsβ-carotene , α-tocopherol ,ascorbic acid, selenium. 2) Metabolic Antioxidants e.g. glutathione, ceruloplasmin, albumin, bilirubin, transferrin, ferritin, uric acid.

  32. Enzymatic free radical scavenging systems (antioxidant system ) 1.Superoxide Dismutase (SOD). It converts superoxide to hydrogen peroxide and O2..it is the first line of defense to protect cells from superoxide. 2. Glutathione Peroxidase in this step the H2O2 is removed by glutathione peroxidase (POD). It is a selenium dependent enzyme. 3.Glutathione Reductase . The oxidized glutathione in turn is reduced by the glutathione reductase (GR),in the presence of NADPH.

  33. Enzymatic free radical scavenging systems (antioxidant system )…. 4.Catalase. When H2O2 is generated in large quantities the enzyme catalase is also used for its removal 2H2O2 catalase O2 +2H2O.

  34. Nutrient antioxidants Tocopherols (vitamin E): • It is fat soluble vitamin (lipid phase antioxidant ) • Among the tocopherols, αtocopherol is biologically the most active . • Present in cellular membranes, and protects from lipid peroxidation by directly acting on oxyradicals ( singlet oxygen, hydroxyl radical ) and serves as chain breaking antioxidant .

  35. Ascorbic acid (vitamin C): it is a water soluble vitamin and biologically important antioxidant in body fluids.(aqueous phase antioxidant ) • It effectively scavenges free radicals and also promotes the regeneration of αtocopherol ( from αtocopheroxyl radical produced during scavenging of ROS)

  36. Carotenoids : • Natural compounds with lipophilic properties. • 500 different kinds identified …β carotene is most important . • Can act as antioxidant at low pp of oxygen . • Usually functions with vit C and E • Lycopene, fat soluble pigment is responsible for colour of fruits n vegetables is a carotenoid and possess a antioxidant property . • Lutein and Zeaxanthinimpart yellow colour to fruits n veg can also serve as antioxidant .

  37. Selenium : • Essential trace element, • Significant antioxidant • Works with vitamin E • Required for functioning of glutathione peroxidase enzyme. • αLipoic acid : vitamin like compound ,produced in body ,besides supply from plants and animals …helps in reclycing of other antioxidants like ascorbic acid , tocopherol and glutathione

  38. Caffeine • Coffee contains flavanoides which are antioxidants in nature.

  39. Metabolic antioxidants : • Glutathione • Uric acid: scavenger of singlet oxygen and hydroxyl radical • Ceruloplasmin inhibits iron and copper dependent lipid peroxidation • Transferrin binds to iron and prevents iron catalysed free radical formation • Albumin can scavenge the free radicals formed on its surface. • Bilirubin : protects albumin bound FFA from peroxidation • Haptoglobin binds to free hemoglobin and prevents lipid peroxidation.

  40. THANK YOU

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