Free radical induced injury
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Transcript of Free radical induced injury
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