Tox Damage Flashcards
How can a cell be damaged/injured?
Damage arrises when the limits of adaptation are exceeded. May be reversible, if irreversible leads to cell death
List the causes of cell injury
Hypoxia Physical agents chemical agents infectious agents immunologic agents genetic derangements nutritional imbalances ageing
List the common mechanisms of cell injury
.defects in membrane permeability (e.g. MAC)
.restrictions to glycolysis, citric acid cycle, oxidative phosphorylation - can measure ATP levels
.irreversible mitochondrial damage: leakage of CYTOCHROME C triggering apoptotic death
.oxygen and oxygen-derived free radicals/reactive oxygen species - respiratory burst (NADPH oxidase - catalyses the transfer of an electron from NADPH to O2 to form superoxide)
.dysregulation of intracellular calcium homeostasis (activates phospholipases, proteases, ATPases)
How are ROS produced endogenously?
Natural byproduct of cell metabolism. Also produced by hypoxia, apoptosis, pro-inflammatory cytokines and oncogenic cancer intermediates (e.g. RAS)
How are ROS produced exogenously?
Formed through sources such as ionising radiation (UV light, smoking, airpollution)
What can ROS do?
mitochondrial attack, protein oxidation/nitration, lipid peroxidation, DNA damage
Chemical Injury: what does mercuric chloride do?
Binds sulfhydryl groups of proteins
Chemical Injury: what does cyanide do?
Poisons mitochondrial cytochrome oxidase
Chemical Injury: What does CCl4 do?
Conversion to free radical CCl3 - causing lipid peroxidation
Chemical Injury: What does acetaminophen do?
P450 catalysed oxidation to toxic metabolite
Define excitotoxicity
pathological process by which neurons are damaged and killed by overreaction of receptors for excitatory neurotransmitter glutamate, such as the NMDA receptor and AMPA receptors - causes increase in cytosolic Ca 2+ and free radicals
Define stroke
reduced cerebral blood flow interrupts oxidative phosphorylation by mitochondria, reduces cellular ATP production - decr ATP levels cause inhibition of ATPase pump leading to loss of cellular membrane ionic gradient, cellular membrane depolarisation, incr in Ca 2+ - excessive glutamate release –> EXCITOTOXICITY
What does excitotoxicity cause?
mitochondrial damage, cell membrance disruption, production of free radicals, cytoskeletal breakdown, DNA fragmentation –>apoptosis or necrosis
Define genotoxicity
agents that damage DNA
What do DNA damage and repair mismatch repair enzymes do?
repair oxidative damage - catalyses thioredoxin-dependent reduction of oxidised methionine (MetO) back to methionine