3. Categories Fat-soluble Dissolve in fat Water-soluble Dissolve in water Carried in bloodstream, A, D, E, K C and B-complex vitamins A and D excess can be harmful E and K usually not Excess amounts may cause extra work on kidneys

27. Stroke Lung Cancer Prostate Cancer Macular Degeneration & Cataracts Osteoarthritis Rheumatoid Arthritis Skin Cancer & Melanoma Photo-aging (wrinkles) Alzheimer’s Parkinson’s Periodontitis Emphysema Coronary Heart Disease Alcohol & Viral Liver Diseases Diabetes Hypertension & Chronic Kidney Disease Colo-rectal Cancer Peripheral Vascular Disease Free Radical Diseases

40. Superoxide Dismutase (SOD) is essential for the body and is: A metalloprotein – containing several sub units organised around a metallic group An enzyme – the antioxidant enzyme SOD eliminates, in a continuous way, superoxide radicals, precursors of other oxygen reactive forms (secondary free radicals) And most importantly

43. The BALANCE Between Pro-Oxidants and Antioxidants Pro-Oxidants ( Reactive Oxygen Species Free Radicals) Antioxidants OXIDATIVE STRESS Cell & Tissue Damage Protection / Tissue Repair Antioxidants Cell / Tissue Damage Oxidants

46. Oxidants and antioxidants in the body Under normal circumstances and conditions, the body’s endogenous antioxidant systems are able to neutralize the oxidant (free radical) molecules Therefore -> no oxidative stress means -> no cell damage

47. Oxidative stress… … is the result of an imbalance between oxidant and antioxidant production increase of free radicals -> antioxidant systems overpowered

49. O 2 Figure 5. Pathways for the formation of reactive oxygen species  Superoxide dismutase  Haber-Weiss reaction;  Fenton reaction  Singlet oxygen  Superoxide radical anion  Peroxyl radical  lipid radical  lipid peroxyl radical UV light heme Fe CoQ 1 O 2  NADPH or CoQ  O 2 -   H 2 O 2 H +  H + HOO   Lipid (LH) L  H 2 O  O 2 LOO    OH  Fe 2+ H 2 O, H +

50. The fight against secondary free radicals … … occurs with the secondary antioxidants (vitamins A,C, E, polyphenols etc) BUT antioxidants (acting 1 against 1) are quickly outnumbered and cannot eliminate a continuous and strong production of free radicals

51. Secondary antioxidants are vital but just slow down the oxidative stress – we need to do something extra…

53. Table 1 . Reactive Oxygen Species and Antioxidants that Reduce Them Reactive Species Antioxidant Singlet oxygen 1 O 2 Vitamin A, vitamin E Superoxide radical (O 2 -  ) superoxide dismutase, vitamin C Hydrogen peroxide (H 2 O 2 ) Catalase; glutathione peroxidase Peroxyl radical (ROO  ) Vitamin C, vitamin E Lipid peroxyl radical (LOO  ) Vitamin E Hydroxyl radical (OH  ) Vitamin C

54. Figure 6. Reactions of glutathione reduction and oxidation H 2 O 2 glutathione peroxidase 2 H 2 O 2 GSH GSSG glutathione reductase NADPH + H + NADP + pentose pathway

55. SUMMARY OF ANTI-OXIDANT ENZYMES Glutathione peroxidase: 2 GSH + H 2 O 2  GSSG + 2 H 2 O Uses selenium as a cofactor Catalase : 2 H 2 O 2  H 2 O + O 2 Superoxide dismutase: 2 O 2 -  + 2H +  H 2 O 2 + O 2 Mitochondrial - Mn 2+ cofactor Cytoplasmic – Cu 2+ -Zn 2+ cofactors; mutations associated with familial amyotrophic lateral sclerosis (FALS) Lipid Peroxidase: removes LOOH

57. Figure 7. Antioxidant cascade Reduced forms/reduction Oxidized forms/oxidation rxn 9 rxn 7 rxn 1 rxn 6 rxn 5 rxn 4 Vit E red VIT E ox Vit C red VIT C ox LOOH lipid peroxyl radical LOO  Glutathione red (GSH) NADP + NADPH + H + Glucose-6-P Ribulose-5-P Pentose phosphate pathway (rxn 8) +ROOH rxn 2 Glutathione ox (GSSG) H 2 O 2 2H 2 O hydroxyl radical (OH  ) superoxide radical (O 2 -  ) reduced products

58. Medical Scenario: If the antioxidant protective system in the red blood cell becomes defective, hemolytic anemia occurs; that is red blood cells undergo hemolysis and their concentration in the blood decreases. Such is the case if glucose 6-phosphate dehydrogenase is defective in the pentose phosphate pathway. In individuals whose glucose 6-phosphate dehydrogenase is defective, there is insufficient NADPH produced in red blood cells to maintain the ratio of reduced glutathione to oxidized glutathione at its normal value of well over 100. Hence, peroxides destroy the red cell membrane because of the limited protective mechanism in these cells.