Free radicals,antioxidants, damage caused by free radicals, prevention

1. Free Radical Injury & Antioxidants

2. Introduction It is believed that life has originated from basic chemicals by free radical reaction, largely initialled by ionising radiation from sun. Paradoxically the same reactions creating life may also be responsible for many diseases, ageing and death.

11. Superoxide Production from Mitochondrial Electron Transport Chain ‘ Leaking’ of electron (to oxygen) during electron transport leads to the formation of O 2  - (O 2 + e- O 2  - )

13. 0.1% to 4% of the O 2 used actively by respiring mitochondria forms O 2 - --- more than enough to have lethal effect on the cell unless the free radical is quickly disposed off.

16. Complex III

19. Respiratory Burst Myeloperoxidase Activity

22. Hydrogen Peroxide

33. Cell Signaling

35. Oxidative Stress Non-enzymatic sources Mitochondrial respiratory chain Glucose autoxidation Enzymatic sources NADPH oxidase Xanthine oxidase Cyclooxygenase O 2 O 2  - NO  ONOO - SOD H 2 O 2  OH H 2 O + O 2 GSH GSSG Fenton reaction (Fe or Cu) Catalase GPx

38. Molecular rearrangement Conjugated diene Lipid hydroperoxide Cyclic peroxide Cyclic endoperoxide • • -H Hydrogen abstraction I O 2 Oxygen uptake Peroxy radical: abstract H• rom another fatty acid causing an autocatalytic chain reactions Initiation Propagation (LH•) (LOO•) • • O O O O H • H P I P

39. Products of Lipid Peroxidation Reactive Oxygen Species Lipid peroxides Alkanes Conjugated dienes Aldehyde products Malondialdehyde (MDA) n -aldehydes  ,  -unsaturated aldehydes

41. A computer image depicts a hydroxyl radical attacking the sugar on the back bone of a DNA molecule

44. Protein Oxidation Oxidative protein degradations Modifications of amino acid chain Modifications of prosthetic group of enzymes Protein aggregation Protein fragmentation Activations of protease enzymes

45. Free Radical Toxicity

49. Ischemia-Reperfusion Injury ATP AMP Adenosine Hypoxanthine/Purine Xanthine dehydrogenase Xanthine oxidase REPERFUSION O 2 O 2 + H 2 O 2 OH - + Fe 2+ TISSUE INJURY i s c h e m i a Ca 2+ -dependent protease CO 2 pH TNF IL1 C5 O 2  - OH  Xanthine/Hypoxanthine O 2 .- + uric acid XOD O 2

53. ANTIOXIDANTS

55. Damage (Pro-oxidants) Defense (Antioxidants) Oxidant-Antioxidant Balance Damage (Pro-oxidants) Defense (Antioxidants) Decrease of antioxidant defense system Oxidative damage

58. Free radical scavenging systems

65. Glutathione Cycle Glutathione ~ Glu-Cys-Gly Reduced glutathione (GSH) Oxidized glutathione (GSSG) Function : gets rid of H 2 O 2 or ROOH (hydroperoxide) ROOH ROH + H 2 O 2 GSH GSSG NADPH NADP Glutathione peroxidase Glutathione reductase

67. Glutathione Peroxidase (GPx) Function : Removes H 2 O 2 & ROOH ROOH + 2 GSH ROH + H 2 O + GSSG Deficiency in GPX leads to oxidative hemolysis Protects against lipid peroxidation *Selenium*

72. Tocopherol “ Chain-breaking antioxidant” Scavenges peroxyl radical Inhibits chain reaction of lipid peroxidation Eight naturally-occurring substances d-  -, d-  -, d-  - tocopherols d-  -, d-  -, d-  - tocotrienols

76. Thank You ALL…