Oxidative stress Flashcards
Describe the production of superoxide radicals
- O2 is biradical
- superoxide O2.- produced by adding e to o2
How is OH. produced
- superoxide reacts with 2H+ and e to form H2O2
- reacts with e.g. Fe2+ to produce free radicals
- readily diffusible
- reacts with e.g. Fe2+ to produce free radicals
- H2O2 reacts with e and H+ to for water and OH.
- most reactive + damaging free radical
ROS (reactive oxygen species)
- H2O2
- OH.
- superoxide
RNS: reactive nitrogen species
- superoxide reacts with NO. to form peroxynitrite ONOO-
- powerful oxidant that damages cells
ROS damage to DNA
- reacts with base
- modified base lead to mispairing + mutation
- reacts with ribose/deoxyribose
- strand breaks + mutation on repair
ROS damage to proteins
- side chain
- modified amino acids
- change in protein structure
- protein degradation
- gain/loss of function
- change in protein structure
- modified amino acids
- backbone
- fragmentation
- protein degradation
- fragmentation
Disulphide bonds
formed between thiol groups of cysteine
ROS damage to lipids (mechanism)
- free radical extracts H atom from fatty acid
- lipid radical forms that reacts with O2 → lipid peroxyl radical
- chain reaction: radical extracts H
- hydrophobic environment disrupted
- membrane integrity fails
What happens during the reaction of ROS with lipids
lipid peroxidation
- significant in aetiology of atherosclerosis
Endogenous sources of biological oxidants
- electron transport chain
- nitric oxide synthases
- NADPH oxidases
Exogenous sources of biological oxidants
- radiation
- pollutants
- drugs
- toxins
• Outline defences against reactive oxygen species
- superoxide dismutase (SOD) - primary defence
- converts superoxide to H2O2 and O2
- catalase
- converts H2O2 to water and O2
- protects immune cells from oxidative burst
- converts H2O2 to water and O2
- free radical scavengers
Glutathione
- tripeptide
- antioxidant
- thiol donates an e to ROS, reacts with another GSH → disulphide bond (GSSG)
- catalysed by glutathione peroxidase
What is the role of an antioxidant
protection against oxidative damage
Selenium
required by glutathione peroxidase
What form is GSH
reduced
What form is GSSG
oxidised
- reduced back to GSH by glutathione reductase
Free radical scavengers (antioxidant)
- reduce free radical by donating H atom and its e to free radical in a nonenzymatic reaction
- vitamin e
- protects against lipid peroxidation
- vitamin c
- regenerating reduced form of vitamin e
- vitamin e
Identify types of Nitric oxide synthase (NOS)
- iNOS
- inducible NO synthase
- produce high NO conc in phagocytes for direct toxic effect
- converted to peroxynitrite radicals (inflammation)
- eNOS
- endothelial NOS (signalling)
- nNOS
- neuronal NOS (signalling)
Respiratory burst
- rapid production of a release of ROS by neutrophils and monocytes when stimulated
- cell + bacteria destroyed
NADPH oxidase
- present in cell membrane of phagosome
- transfers e from NADPH to couple to O2
- generates superoxide radicals
- important in atherosclerosis
Chronic granulomatous disease
- genetic defect in NADPH oxidase complex
- causes enhanced susceptibility to bacterial infections
Describe the mechanism behind a paracetamol overdose.
- over ~10g paracetamol, NAPQI produced
- covalent binds with hepatic proteins
- conjugates with glutathione
- depletes level: oxidative stress
- extremely toxic effect
Paracetamol overdose treatment
acetylcysteine within 8hrs
- good prognosis
replenishes glutathione
- liver can safely metabolise NAPQI
