Twelfth lecture

PROTECTIONREPAIRREGENERATION GENETICS Reduce concentration of reactive intermediates Restore molecular function Stimulate proliferation of surviving stem cells X and gamma rays Indirect H2OH2O Free radicals Scavenging Hypoxia Antioxidants Detoxification Superoxides peroxides O2O2 Neutrons and alpha Direct DNA strands Hydrogen transfer Enzymatic repair Damaged molecules Cell death Stem cell depletion Organism death STRATEGIES FOR REDUCING RADIATION INJURY Repopulation Increased survival

PROTECTION AGAINST CELLULAR DAAMGE HYPOXIA SCAVENGING Genetic approaches Genetic approaches Aminothiols Antioxidants Eicosanoids Cysteine analogues Arachidonic acid * Define encoding gene sequences for enzymes involved increasing SOD synthesis * Define sequence of sensitive sites and targeting protective agents to these sites Non-enzymatic Enzymatic * Vit. E, A, C, * Minerals:Se * Gluitathione * Melatonin * SOD * GSH-Px * GSH-Rd * Catalase * Ex. WR compounds * 1/2 hr before irradiation * DRF * PAF * DiPGE 2 * GE 2 * LTC 4

ENZYMATIC SCAVENING O2O2 Catalase H2OH2O Glutathione peroxidase H2OH2O 2GSH Glutathione reductase GSSG SOD H2O2H2O2 Lipid peroxidation Mitochondria P450 oxidases O.- 2 Fe ++ Fe +++ OH - +. OH

Membrane Cytosol Extracellular fluid LOOH LH H2OH2O LOO. HO.HO. O2O2 TocO. Vit. C red GSH TocOH Vit. C oxd GS-SG Catalase H 2 O LOH SOD. O 2 Superoxide Glutathione peroxidase Se GSH GS-SG NON-ENZYMATIC SCAVENING LOOH, H 2 O 2 Phospholipase A 2 Free radical chain reaction

MELATONIN Enzymes Potential changes resulting from the action of melatonin GSH NADPH Nitric oxide synthase Glutathione reductase Gamma-GCS G-6-PDase Superoxide dismutase Catalase Glutathione peroxidase NO., ONOO - O 2.- H2O2H2O2 H2O2H2O2