الله صدق

العظيم ـ 54الروم

Visible light and infra red

RADIATIONRADIATION

Non-ionizing radiation

Ionizing radiation

ParticulateAlpha-, Beta-particles

& Neutrons

Non-particulateX- and Gamma-rays

Radiation cellular damageRadiation cellular damage

Neutron Alpha X- & gamma rays

H2O

Free radicalsDamaged molecules

Macromoleculesbiomembranes

Cell death SuperoxidesPeroxides

O2

Direct Indirect

Radiolysis of water and free radicals formation

.OH H2O2

H.

HO.2

O.-

2

H2

Free radicals Molecules

Oxidative damage by freeradicals

Oxidative damage by freeradicals

DNADNA ProteinProtein

LipidsLipids

Cross-linkage

Oxidized bases

Strandbreaks Hydroxylation

Peroxidation

Alcohols Ketones Aldehydes Dialdehydes

RPhenylalanine

.OH

ROH

O-Tyrosine

LIPID MEMBRANE OXIDATION

HO.2 or

.OH + LH L

. + H2O2 or H2O

L.

+ O2 LOO.

LOO. + L`H LOOH + L`

.

L`. + O2 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 radicaltheory

Free radicaltheory

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

Erythrocytesfibroblasts

proteinLiver and

kidney mtDNA

Heart mtDNA

Brain mtDNA/nDNA

Skeletal musclemtDNA

HeartmtDNA

Protein carbonyl

5 kb deletion

8-OH-dg

mtDNA deletions

8-OH-dg

mtDNARearrangement

PROTECTION REPAIR REGENERATION

GENETICS

Reduce concentration of reactive intermediates

Restore molecular function

Stimulate proliferationof surviving stem cells

X and gamma

rays

Indirect

H2O Free radicals

Scavenging HypoxiaAntioxidantsDetoxification

Superoxides peroxidesO2

Neutrons and alpha

Direct DNA strands

Hydrogen transfer

Enzymatic

repair

Damaged

moleculesCell

death

Stem cell

depletionOrganism

death

STRATEGIES FOR REDUCING RADIATION INJURYSTRATEGIES FOR REDUCING RADIATION INJURY

Repopulation

Increased survival

PROTECTION AGAINST CELLULAR DAAMGE

HYPOXIAHYPOXIA SCAVENGINGSCAVENGING

Genetic approachesGenetic

approachesAminothiolsAminothiols AntioxidantsAntioxidants EicosanoidsEicosanoids

Cysteine analogues

Arachidonicacid

* Define encoding

gene sequences for

enzymes involved

increasing SOD

synthesis* Define sequence of

sensitive sites and

targeting protective

agents to these sites

Non-enzymaticEnzymatic

* Vit. E, A, C,

* Minerals:Se

* Gluitathione

* Melatonin

* SOD

* GSH-Px

* GSH-Rd

* Catalase

* Ex. WR

compounds

* 1/2 hr before

irradiation

* DRF

* PAF

* DiPGE2

* GE2

* LTC4

ENZYMATIC SCAVENING

O2

Catalase

H2O

Glutathione peroxidase

H2O

2GSH

Glutathione reductase

GSSG

SODH2O2

Lipid peroxidation

MitochondriaP450 oxidases

O.-

2

Fe++ Fe+++

OH-+

.OH

Membrane

Cytosol

Extracellular fluid

LOOH

LH

H2O

LOO.

HO.

O2

TocO.

Vit. Cred

GSH

TocOH

Vit. Coxd GS-SG

Catalase

H2O LOH

SOD

.O2

Superoxide

GlutathioneperoxidaseSe

GSH

GS-SG

NON-ENZYMATIC SCAVENING

LOOH, H2O2

Phospholipase A2

Free radical chain reaction