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Free Radical Injury by prof dr naseer ppt
1.
2. Free radicals are chemical species that have
single unpaired electron in their outer orbit.
Examples of pathological conditions due to
free radical:
1. Chemical and radiation injury
2. Ischemic reperfusion injury
3. Cellular aging
4. Microbial killing by phagocytes
3. Free radicals usually attacks:
Proteins , Lipids, Carbohydrate, Nucleic acids
Characteristic of free radicals:
1. they initiate autocatalytic reaction.
2. Molecules with which they reacts are
themselves converted into free radicals.
3. They propagate chain damage reactive
oxygen species are a type of oxygen derived
free radicals.
4. Normally free radicals(ROS) are produced
normally in all cells during mitochondrial
respiration.
Which are degraded by cellular defense system.
So Ros are presents in low concentration and do
not damage the cell.
Oxidative stress:
when production of ROS increase or
scavenging system are ineffective leads to excess
of free radicals called Oxidative stress which
play role in cell injury.
5. 1. Cancer.
2. Aging.
3. some degenerative disease like Alzheimer.
4. Ros also produced in large amount by
neutrophil and macrophages for destroying
microbes, dead tissue and other un wanted
substances.
5. Injury caused by free radicals often
accompanies inflammatory reaction.
6. 1. Reduction oxidative reaction:
During normal metabolic process normally
O2 reduced by four electron to H2 to
generate water molecule during this process
small amount of physically reduced
intermediate product are produced.
These include :
1. O2 ( one electron)
2. H2O2 (two electron)
3. OH (three electron)
7. 2. Absorption of radiant energy:
Ultraviolet rays , X-rays( ionizing radiation
can hydrolyze water into H and OH free radical.
3. Rapid burst of ROS:
Produced in activated leukocytes during
inflammation .
uses NAPDPH oxidase for redox reaction – in
addition in some xanthine oxidase generate O2.
4. Enzymatic metabolism of chemical drugs:
Generate free radicals e.g. from CCL4 –> CCL3
are produced.
8. 5. Transition metals:
As iron and copper donates or accept free
electron during intracellular reactions and
catalyze free radicals formations.
As in Fenton reaction
H202 + Fe (2+)Fe(3+)+OH+OH-
As most of intracellular free iron in ferric(Fe3+)
must be reduced to ferrous form for Fenton
reaction this reduction enhanced by O2.
So O2 and iron co operate in oxidative cell
damage.
9. 6. Nitric Oxide (NO):
Important chemical meditator generalised by
– Endothelial cells, macrophages, neuron.
Act as free radical
Can also be converted to reactions
peroxynitrate(ONOO-)as well NO2 and NO3+
10. Three reactions relevant to cell injury
1. Lipid peroxidation in membrane:
Free radicals cause peroxidadtion of lipids in
membrane .
Lipids are attacked by O2 derivatives
particularly off to double bond-- yields lipid
peroxide as they are unstable and reactive so
autocatalytic reaction ensues causes
extensive membrane damage.
11. 2. Oxidative modification of protein:
Free radical promote oxidation of amino acids.
Formation of protein – protein ion
kafe(disulphide bond) and oxidation protein
backbone.
Oxidative modification:
Damage the active site of enzyme.
Disrupt the structural protein
Enhance proteo somal degradation of
unfolded protein.
Raising havoc throughout cell.
12. Lesion in DNA:
Free radical react with thymine in nuclear and
mitochondrial DNA .
Produced single and double strands breaks in
DNA and then cross linking of DNA and
formation of adduce implicated in
1. Cell aging
2. Malignant transformation
13. Removal of free radicals:
1. Free radicals are there and unstable so decay
spontaneous .
2. Cells have developed – Non enzymatic &
enzymatic mechanism to remove free radicals.
Antioxidants:
Either block the initiation of free radical formation or
inactive them.
Vitamin E,A and ascorbic acid and glutathione in
cytoplasm act as auto oxidant.
Transport protein like:
Transferrin ,ferritin lacto ferritin and ceruplasmin–
binds with iron and copper and minimizing free
14. Scavenging system:
Series of enzyme breakdown free radicals into
H2O2, O2.
1. Catalase:
Present in peroxisomes decompose H2O2.
2. Superoxide dismutase(SOD)
Convert O2 to H2O2
2O2+2HH2O2+O2
This group include magnese SOD localised in
mitochondria and copper zinc SOD found in
cytosol.
15. Glutathione peroxidase:
Catalyse free radicals breakdown.
H2O2+2GSHGSSG + 2H2O
2OH + 2GSHGSSG + 2H2O
Ratio of oxidised glutathione GSSG to reduced
glutathione GSH is important.
16. More cell injury and inflammation
Chemical Toxic injury
Chemical injury remained as frequent problem in
clinical medicine is major limitation to drug
therapy.
Drugs are metabolised in liver so the organ is
frequent target of drug toxicity .
Toxic liver injury the most frequent reason for
terminating the therapeutic use or development
of a drug.
Two general mechanism of chemical injury are:
Direct Toxicity
Cyanide poisoning
17. Direct Toxicity:
Mercury chloride poisoning --- mercury binds to
sulphidial groups of cell membrane .protein
causing increased membrane permeability and
inhibition of ion transport.
The poison cells that absorb, excrete or concentrate
the chemicals so cells of GIT & Kidneys .
Cyanide poisoning:
Mitochondrial cytochrome oxidase is poisoned by
Cyanide.
It inhibits oxidation phosphorylation
18. Conversion to toxic metabolic :
Most toxic chemicals are not biologically
toxic