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
What does the protein isoaspartylmethyltransferase (PIMT)
repairs age damage in proteins
What enzymes and vitamins defend against unwanted ROS?
Cellular defence enzymes - catalyse, superoxide dismutase (anti-oxidants), glutathione peroxidase
Cofactors - glutathione
Vitamins - Vit A, C and E
What is mitophagy?
Mitophagy is the selective degradation of mitochondria by autophagy
What is necrosis and what does it involve?
Severe cell swelling or cell rupture, denaturation and coagulation of cytoplasmic proteins and breakdown of cell organelles for lethally injured cell - increased eosinophilia, karyolysis (nuclear pallor), pyknosis (nuclear shrinkage), karyorrhexis (nuclear fragmentation)
What is apoptosis and what does it involve?
Programmed cell death - cel shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, phagocytosis by macrophages - DOES NOT IELICIT INFLAMMATION
- Protein cleavage
- Protein cross linkage
- DNA breakdown
- Phagocytic recognition
Describe the differences between apoptosis and necrosis
Apoptosis
- single cells
- no inflammation
- cell shrinkage
- membrane blebbing but integrity maintained
- increased mito membrane permeability, formation of apoptotic bodies (necrosis - organelle swelling and lysosomal leakage)
- chromatin condensation and non-random DNA fragmentation
- apoptotic bodies ingested by neighbouring cells (necrosis - lysed cells ingested by macrophages)
What is autophagy?
Increased quantity of autophagosomes formation Atg proteins participation
PRODUCES NO INFLAMMATORY RESPONSE
What does the intrinsic pathway involve - for cellular stress
BCL-2 proteins –> caspases 3 and 7 activation for cell death
What does the extrinsic pathway involve - for death receptors
death receptor ligation, procaspase 8 recruitment and activation –> caspases 3 and 7 activation for cell death
