Chapter 1.4 Free Radical Injury Flashcards
What is a free radical?
chemical species with unpaired electron in the outer orbit
How are free radicals generated physiologically?
oxidative phosphorylation
- cytochrome C oxidase transfers electrons to O2 during oxidative phosphorylation
- (O accepts 4 electrons, then water generated, if O partially reduced and doesnt receive all 4 electrons then free radicals can be generated)
- partial reduction yields O2 (radical), H2O2, OH- radicals
Why does generation of free radicals occur during oxidative phosphorylation?
If oxygen accepts 1 electron it becomes super-oxide , 2 then H2O2 (hydrogen peroxide), if 3 then OH- ion, if 4 then becomes H2O
-partial reduction yields O2 (radical), H2O2, OH radicals
How can free radicals be generated pathologically?
- ionizing radiation (OH… radiation hits water within tissues and then hydroxyl free radical can be generated)
- inflammation (oxygen dependent or independent, oxygen dep starts with oxidative burst, oxygen taken and acted on by enzyme NADPH oxidase)
- metals (copper and iron which are normally bound in body)
- drugs and chemicals (acetaminophen goes to liver, converted by hepatocytes/ p450 system and free radicals generated which can damage tissues)
Of all free radicals which is the most damaging?
hydroxyl radical
OH
What converts oxygen to super oxide?
How is bleach formed?
NADPH oxidase
acts on O2 and converts it to super oxide (a free radical), then super oxidase dismutase converts it to hydrogen peroxide and then that is converted by myloperoxidase to make bleach or HOCl.
How can iron generate free radicals? Which does it generate?
in an unbound state
fenton reaction
generates hydroxyl free radical
What happens when iron or copper build up?
What is underlying mechanism?
Excess iron- hemochromatosis results in free radicals that produce tissue damage (cirrhosis in liver)
Excess copper = Wilson’s disease, generates free radicals
If someone was exposed to dry cleaning industry presents with fatty liver change, describe the mechanism of what has occurred.
CCl4 (carbon tetrachloride) gets into blood and converted into CCl3 in p450 system of liver, once converted to CCl3 its a free radical and damages hepatocytes
key sign of reversible damage is cellular swelling (RER will swell and ribosomes pop off and protein synthesis is reduced
-key function of liver is to repackage fat and send it back out, repackaging of fat occurs by binding up molecules of chol. and lipids via apolipoproteins, lack of apo proteins, so fat gets into liver but can’t get out …so classical finding is FATTY CHANGE OF LIVER.
How can free radicals be eliminated? (Since they are created physiologically)
antioxidants (Vit A, Vit C, Vit E)
enzymes (SOD, Glutathione peroxidase, catalase)
metal carrier proteins (copper and iron can create free radicals … so transferrin in blood tightly binds iron to deliver it to macrophages or liver, then in liver its bound to ferratin)
Which 3 major enzymes are important for elimination of each of the free radicals?
- SOD (superoxide dismutate)
- Glutathione peroxidase (OH*)
- Catalase (H2O2)
(accepting an electron)
O2– O2–H2O2 –OH–H2O
Patient with MI, cardiac enzymes going up, taken to cardiac cath lab, artery opened, then cardiac enzymes continue to rise. Why?
free radical injury
reperfusion injury
when cut blood supply to an organ, coronary artery occluded, MI, tissue begins to die, once tissue dies, cell membrane damaged (hallmark of irreversible damage) enzymes leak into blood, troponins will leak out, as they leak they indicate that there has been irreversible injury to cell, if blood returned to the organ, artery opened and blood back to organ, now oxygen also returned to organ with inflammatory cells…combo of inflammatory cells with dead tissue and oxygen can generate free radicals and can further damage cardiac myocytes
enzymes continue to rise bc blood returned and contains oxygen and inflammatory cells, free radicals produced, continued injury to myocardium.
