Oxidative Tissue Damage

Question 1

Why is oxygen the ideal electron acceptor for biological catalysis?

Answer 1

Convenient redox potential (readily accepts electrons from hydrogen) - produces energy
Plentiful

Question 2

What are some endogenous sources of ROS?

Answer 2

Oxidative phosphorylation (electron leak)
NADPH oxidases
peroxisomes
xanthine oxidase
free metals (Fe and Cu)

Question 3

What are some environmental sources of ROS?

Answer 3

Cigarette smoke
Radiation
Drugs/pesticides
Pollutants 
Ozone

Question 4

Define oxidative stress

Answer 4

Imbalance between oxidants and antioxidant defenses in favor of oxidants
Leads to disruption of redox control/signaling and to cell and molecular damage

Question 5

What are reactive nitrogen species and why is it important for ROS?

Answer 5

RNS
Products of NO synthases
RNS interact with ROS to produce strong oxidants (peroxynitrite)

Question 6

Define oxidative tissue damage

Answer 6

chemical disruption of cellular/tissue structure and function by the oxidation of specific macromolecules

Question 7

How can reperfusion cause oxidative tissue injury?

Answer 7

Reintroducing oxygen can generate free radicals due to the fact that several cells are already damaged

Question 8

What are two possible etiologies of oxidative tissue injury?

Answer 8

Insufficient antioxidant defense

• consumption (overwhelmed)
• impaired upregulation (defects in tc control of AOE genes)

Increased production of ROS

• chronic inflammation
• free rad. generators (free metals)

Question 9

What is a free radical?

Answer 9

A chemically-reactive atom or molecule with an unpaired or free electron

Question 10

What is the relative half-life of free radicals?

Answer 10

Very short lived

Question 11

What are the biochemical modifications and result of free radical damage to lipids?

Answer 11

Peroxidation
Nitration

Membrane damage

Question 12

What are the biochemical modifications and result of free radical damage to proteins?

Answer 12

Oxidation
Nitration
Carbonylation

Enzyme Inactivation

Question 13

What are the biochemical modifications and result of free radical damage to nucleic acids?

Answer 13

Hydroxylation
Nitration
Adduct formation

Mutagenesis
Esp. G

Question 14

What can be the effects of protein oxidation?

Answer 14

Reversible

• disulfide
• exploited by body for signaling

Irreversible

• Tyr nitration
• Protein carbonylation
• Damages and affects functions

Question 15

What are consequences of DNA oxidation and adduct formation?

Answer 15

Mutation, decreased replication, structural damage

Question 16

What are three main DNA oxidation repair mechanisms?

Answer 16

Base Excision
Nucleotide excision
DNA mismatch repair

Question 17

How can oxidative injury be prevented?

Answer 17

Use the O2
Control tissue pO2 (limited)
Maintain anti-oxidant defense systems
Sequester reactive transition metals (Fe, Cu) in unreactive forms

Question 18

How are antioxidant enzymes regulated?

Answer 18

Both constitutive and inducible

Increased expression relies on redox-sensitive kinases, phosphates, TFs (Nrf2)

Question 19

Where are antioxidant enzymes typically localized?

Answer 19

Sites of ROS generation

Question 20

What are three critical factors for small molecule and dietary antioxidants?

Answer 20

Bioavailability for reaction
Local conc. of antioxidants
Kinetics of rxn.

Initial detoxification rate = k [Antioxidant] [Oxidant]

[Antiox] and k must be high enough to prevent oxidant from reacting with the the substrate that the antiox. is there to protect

Question 21

How does ascorbate act as an antioxidant?

Answer 21

donates e- and H+ to quench a radial
becomes a radical itself, but is stabilized through resonance
enzymatically reduced back to ascorbate