Oxidative Tissue Damage Flashcards
Why is oxygen the ideal electron acceptor for biological catalysis?
Convenient redox potential (readily accepts electrons from hydrogen) - produces energy
Plentiful
What are some endogenous sources of ROS?
Oxidative phosphorylation (electron leak) NADPH oxidases peroxisomes xanthine oxidase free metals (Fe and Cu)
What are some environmental sources of ROS?
Cigarette smoke Radiation Drugs/pesticides Pollutants Ozone
Define oxidative stress
Imbalance between oxidants and antioxidant defenses in favor of oxidants
Leads to disruption of redox control/signaling and to cell and molecular damage
What are reactive nitrogen species and why is it important for ROS?
RNS
Products of NO synthases
RNS interact with ROS to produce strong oxidants (peroxynitrite)
Define oxidative tissue damage
chemical disruption of cellular/tissue structure and function by the oxidation of specific macromolecules
How can reperfusion cause oxidative tissue injury?
Reintroducing oxygen can generate free radicals due to the fact that several cells are already damaged
What are two possible etiologies of oxidative tissue injury?
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)
What is a free radical?
A chemically-reactive atom or molecule with an unpaired or free electron
What is the relative half-life of free radicals?
Very short lived
What are the biochemical modifications and result of free radical damage to lipids?
Peroxidation
Nitration
Membrane damage
What are the biochemical modifications and result of free radical damage to proteins?
Oxidation
Nitration
Carbonylation
Enzyme Inactivation
What are the biochemical modifications and result of free radical damage to nucleic acids?
Hydroxylation
Nitration
Adduct formation
Mutagenesis
Esp. G
What can be the effects of protein oxidation?
Reversible
- disulfide
- exploited by body for signaling
Irreversible
- Tyr nitration
- Protein carbonylation
- Damages and affects functions
What are consequences of DNA oxidation and adduct formation?
Mutation, decreased replication, structural damage
What are three main DNA oxidation repair mechanisms?
Base Excision
Nucleotide excision
DNA mismatch repair
How can oxidative injury be prevented?
Use the O2
Control tissue pO2 (limited)
Maintain anti-oxidant defense systems
Sequester reactive transition metals (Fe, Cu) in unreactive forms
How are antioxidant enzymes regulated?
Both constitutive and inducible
Increased expression relies on redox-sensitive kinases, phosphates, TFs (Nrf2)
Where are antioxidant enzymes typically localized?
Sites of ROS generation
What are three critical factors for small molecule and dietary antioxidants?
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
How does ascorbate act as an antioxidant?
donates e- and H+ to quench a radial
becomes a radical itself, but is stabilized through resonance
enzymatically reduced back to ascorbate
