Transcript toxic oxygen - Hatzalah of Miami-Dade

T
O
X Y G E N
X
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There is no reading assignment for this section
Woman’s Day, 9/1/02 page 26
Why do we care about toxic oxygen?
Because it is formed and disposed of at a very high rate and
because it can form and propagate free radicals that cause
tissue damage and can cause cancer and
there is a recently elucidated syndrome called
“Post-ischemic Reperfusion Injury” that we shall discuss
A memory jog on free radicals
RH
R+ H
Initiation
here
is
Propagation
(1)
+ The
RH + under
R
RH material
for information only.
Propagation
(2)
Do not panic.
There will
be
R-C-C
R + -C=Cno questions on it. This is what happens
In lipid peroxidation
R
R +R
R-R
Termination
This is how superoxide
dismutase works
Oxygen
O2
Oxygen + 1 electron
O2 superoxide
Oxygen + 2 electrons
H2O2 peroxide
Oxygen + 3 electrons
Oxygen + 4 electrons
OH + OHhydroxyl and hydroxide
radical
anion
2H2O
water
How do we get each type of reduced oxygen?
Superoxide anion O2This is formed by leakage of electrons from the
mitochondrial or the microsomal (cytochrome
P-450 for example) electron transport chains.
Approximately 10% of electrons in the
mitochondrial chain leak this way.
Superoxide dismutase metabolizes superoxide to
hydrogen peroxide
2O2- + 2H+
superoxide
R +R
H2O2 + O2
hydrogen peroxide
R-R
Termination
This is how superoxide
dismutase works
Catalase metabolizes hydrogen peroxide
2H2O2
2H2O + O2
hydrogen peroxide
Note: catalase has the highest turnover number
of any known enzyme
Why is it so important to get rid of superoxide anion
and peroxide?
H2O2 + O2-
OH- + OH
The “very bad” oxygen
OH +
R-C=C-
R-C-C + O2
R-C-C
R-C-C-O-O
An oxidized unsaturated lipid
R + -C=C-
R-C-C
Refer back to
“radical reminder” slide
OH +
R-C=C-
R-C-C + O2
R-C-C
R-C-C-O-O
This can
abstract H
from another
carbon and
cause a chain
reaction
The hydroxyl radical can also cause depurination
and strand breaks in DNA, as well as protein
denaturation
There are two other enzymes that metabolize
peroxides
Peroxidase
ROOH + HXOH
XO + ROH + H2O
HOOH + HOOH
O2 + H2O +H2O
Note: peroxidase can metabolize hydrogen
peroxide, but catalase cannot metabolize organic
peroxides
Glutathione peroxidase
2GSH + H2O2
Remember its role in
protecting RBC’s from
oxidative damage. It is
the enzyme with
selenocysteine
GSSG + 2H2O
The GSSG is reduced back to GSH by glutathione
reductase, an NADPH-dependent enzyme
Remember G6PDH deficiency?
Can reduced oxygen molecules travel?
Peroxide can move between cells
Superoxide can move, but only within the cell
The hydroxyl radical reacts immediately
Rarely is anything all bad. Oxygen free radicals
play an important role in microbial killing by
phagocytic cells such as neutrophils and
macrophages
Post-ischemic Reperfusion Injury
This phenomenon is the cause of much of
the damage that results from strokes. It also
provides a good example of the integration of
material you have/will learn in medical school
Here are the parts of the story that we need:
None of it should be new to you.
Let’s go back to proteolysis and enzymes. You
were told about proteolytic enzymes (such as
trypsin and chymotrypsin.)
Later you learned that enzymes have different
mechanisms (for instance some proteases are
serine proteases and others have different
mechanisms.) Some proteases require Ca++
for activity .
And you certainly know that Ca++ is required in
the diet.
You also know about ATP, and its role in
cellular integrity and the maintenance of gradients
(pumps)
Electron transport can only occur in mammals
in the presence of oxygen
You know that ATP goes to ADP and AMP and
adenine in the absence electron transport
Adenine is metabolized to hypoxanthine and
xanthine. A key enzyme is xanthine oxidase.
Let’s put it all together
A clot cuts off oxygen to the brain
No ATP can be made by electron transport
Cell membranes lose ability to control passage of
molecules into cells
Ca++ floods into the cell
Calcium-dependent proteases are activated
The proteases clip off a small sequence from some
xanthine oxidases
Remember!
truncated
xanthine oxidase
Adenine is metabolized to hypoxanthine and
xanthine. A key enzyme is xanthine oxidase.
xanthine oxidase
hypoxanthine (or xanthine)
truncated
xanthine oxidase
hypoxanthine (or xanthine)
H2O2
xanthine (or uric acid)
O2-
xanthine (or uric acid)
xanthine oxidase
H2O2
hypoxanthine (or xanthine)
truncated
xanthine oxidase
xanthine (or uric acid)
O2-
hypoxanthine (or xanthine)
+
xanthine (or uric acid)
OH