صدق الله العظيم الروم ـ 54

Visible light and infra red RADIATION Non-ionizing radiation Ionizing radiation Particulate Alpha-, Beta-particles & Neutrons Non-particulate X- and Gamma-rays

Radiation cellular damage Neutron Alpha X- & gamma rays H2OH2O Free radicals Damaged molecules Macromolecules biomembranes Cell death Superoxides Peroxides O2O2 Direct Indirect

Radiolysis of water and free radicals formation. OH H2O2H2O2 H.H. HO. 2 O.- 2 H2H2 Free radicals Molecules

Oxidative damage by free radicals Oxidative damage by free radicals DNA Protein Lipids Cross- linkage Oxidized bases Strand breaks Hydroxylation Peroxidation Alcohols Ketones Aldehydes Dialdehydes R Phenylalanine. OH R OH O-Tyrosine

LIPID MEMBRANE OXIDATION HO. 2 or. OH + LH L. + H 2 O 2 or H 2 O L. + O 2 LOO. LOO. + L`H LOOH + L`. L`. + O 2 L`OO. L`OO. + L``H L`OOH + L``. Fe ++ + LOOH LO. + Fe OH - And so on

Proposes that aging is the cumulative result of oxidative damage to the cell’s macromolecules (DNA, lipid, protein) that arises primarily as a result of aerobic metabolism. Several lines of evidence have been used to support this hypothesis including the claims that: Free radical theory 1- variation in species life span is correlated with metabolic rate and protective antioxidant activity. 2- enhanced expression of antioxidative enzymes in experimental animals can produce a significant increase in longevity 3- cellular levels of free radical damage increases with age. 4- reduced calorie intake leads to a decline in the production of reactive oxygen species and an increase in life span.

EVIDENCE OF OXIDATIVE INJURY WITH ADVANCING AGE IN HUMAN Erythrocytes fibroblasts protein Liver and kidney mtDNA Heart mtDNA Brain mtDNA/nDNA Skeletal muscle mtDNA Heart mtDNA Protein carbonyl 5 kb deletion 8-OH-dg mtDNA deletions 8-OH-dg mtDNA Rearrangement

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