Free radical-Free radical-induced injuryinduced injury

By: Pulak AgrawalRoll. No.: 01

Chemical species with single unpaired electron in outer most orbit.(highly unstable)

Reactive oxygen and nitrogen species (RONS)

Attack & degrade membranes,protiens& nuclic acid to gain stability.

Initiate autocatalytic reactions.

Free radical - what is it?Free radical - what is it?

Important free radicalImportant free radical

ROS/RNS Free radicals

superoxide radical

hydroperoxyl radical

hydroxyl radical

nitric oxide

hydrogen peroxide

Generation of free radicals:-Generation of free radicals:-

1. Redox reaction eg:- oxidative phosphorylation in mitochondria2. Enzymatic metabolism of exogenous/endogenous chemicals or drug. eg:- CCl4 can generate CCl3•3. Absorption of radiant energy (UV,X- ray) eg:-

4. Transition metals ( Cu&Fe) accept or donate free electrons during intracellular process.

eg:- Fenton reaction

5. During inflamation –ROS are produced by activated leucocytes.

6. Nitric oxide(potent vasodialator)- produced by endothelial cell,macrophages,neurons.

H 2 O O H + H

i o n i z i n g r a d i a t i o n

h ν

F e 2 + + H 2 O 2 F e 3 + + H O + O H -

Sources of ROS, RNS and other oxidantsSources of ROS, RNS and other oxidants

Cellular sources of ROSCellular sources of ROS

xanthine oxidasehemoglobinriboflavincatecholamines

Cytochrome P450

electron transport chain

lipid peroxidationNADPH oxidase (oxidative burst: phagocytes)

oxidasesflavoproteins

myeloperoxidase (oxidative burst: phagocytes)

transient metals

Formation of ROS during ischemia and reperfusionFormation of ROS during ischemia and reperfusion

ATP

ADP

AMP

adenosine

inosine

hypoxanthine

Xanthine dehydrogenase

Xanthine oxidaseXanthine + •O2

- + H2O2

I S

C H

E M

I A

R E P E R F USION

Ca2+ proteolysis

Mechanism of damage/pathological Mechanism of damage/pathological effects of free radicalseffects of free radicals

1. Damage of Membranes(Lipid peroxidation in membranes) -Autocatalytic chain reaction

2. Damage of protiens(Oxidative modification of protiens) -Protein fragmentation and protein-protein cross-linkage

2. Damage to DNA (lesion in DNA) -Single strand breaks (genomic and mitochondrial)

Oxidative modification of proteinsOxidative modification of proteins::

OH OH

R R

dityrosine

OH

NO2

R

3-nitrotyrosine

dityrosine and 3-nitrotyrosine –markers of protein damage by ROS and RNS

Oxidative damage to DNA:Formation of thymine dimers

Modification of purines – 8-hydroxy-deoxyguanosine Marker of the oxidative damage to DNA

Protective/scavanging mechanism of Protective/scavanging mechanism of Free radical removalFree radical removal

◦ Spontaneous decay ◦ Anti-oxidants

E.g. Vitamin E, vitamin A, vitamin C, glutathione

◦ Storage proteins E.g. transferrin, ferritin, ceruloplasmin

◦ Enzymes Catalase, Superoxide dismutase(SOD), glutathione peroxidase

Examples of free radical injury:Examples of free radical injury:

Chemical injuryRadiation injuryMicrobial killingCellular agingInflamatory damageIschemic reperfussion injuryHypoxic/ischemic injury

Major diseases/disorders linked to ROS/RNSMajor diseases/disorders linked to ROS/RNS •Respiratory system•Inhalation of oxidants (SO2, NO2, O3)•Smoking

•Brain•Alzheimer`s disease•Parkinson`s disease•Amyotrophic lateral sclerosis•Down syndrome•Traumatic injury

•Cardiovascular system•Atherosclerosis•Ischemia-reperfusion injury•Myocardial infarction and heart failure•Selenium deficiency (Keshan disease)

SkinIonizing radiationThermal injuryPorphyriasPhotosenzitizers and other reagents

MuscleExerciseMuscular dystrophy

OthersAgingCancerCataractsDiabetes mellitusInflamatory and autoimmune diseasesLiver damage by endotoxins

or halogen derivatives of hydrocarbonsKidney diseases/disordersAIDS

Thank YouThank You