Tox Damage Flashcards

1
Q

How can a cell be damaged/injured?

A

Damage arrises when the limits of adaptation are exceeded. May be reversible, if irreversible leads to cell death

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2
Q

List the causes of cell injury

A
Hypoxia 
Physical agents 
chemical agents
infectious agents
immunologic agents
genetic derangements
nutritional imbalances 
ageing
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3
Q

List the common mechanisms of cell injury

A

.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)

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4
Q

How are ROS produced endogenously?

A

Natural byproduct of cell metabolism. Also produced by hypoxia, apoptosis, pro-inflammatory cytokines and oncogenic cancer intermediates (e.g. RAS)

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5
Q

How are ROS produced exogenously?

A

Formed through sources such as ionising radiation (UV light, smoking, airpollution)

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6
Q

What can ROS do?

A

mitochondrial attack, protein oxidation/nitration, lipid peroxidation, DNA damage

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7
Q

Chemical Injury: what does mercuric chloride do?

A

Binds sulfhydryl groups of proteins

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8
Q

Chemical Injury: what does cyanide do?

A

Poisons mitochondrial cytochrome oxidase

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9
Q

Chemical Injury: What does CCl4 do?

A

Conversion to free radical CCl3 - causing lipid peroxidation

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10
Q

Chemical Injury: What does acetaminophen do?

A

P450 catalysed oxidation to toxic metabolite

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11
Q

Define excitotoxicity

A

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

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12
Q

Define stroke

A

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

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13
Q

What does excitotoxicity cause?

A

mitochondrial damage, cell membrance disruption, production of free radicals, cytoskeletal breakdown, DNA fragmentation –>apoptosis or necrosis

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14
Q

Define genotoxicity

A

agents that damage DNA

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15
Q

What do DNA damage and repair mismatch repair enzymes do?

A

repair oxidative damage - catalyses thioredoxin-dependent reduction of oxidised methionine (MetO) back to methionine

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16
Q

What does the protein isoaspartylmethyltransferase (PIMT)

A

repairs age damage in proteins

17
Q

What enzymes and vitamins defend against unwanted ROS?

A

Cellular defence enzymes - catalyse, superoxide dismutase (anti-oxidants), glutathione peroxidase
Cofactors - glutathione
Vitamins - Vit A, C and E

18
Q

What is mitophagy?

A

Mitophagy is the selective degradation of mitochondria by autophagy

19
Q

What is necrosis and what does it involve?

A

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)

20
Q

What is apoptosis and what does it involve?

A

Programmed cell death - cel shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, phagocytosis by macrophages - DOES NOT IELICIT INFLAMMATION

  1. Protein cleavage
  2. Protein cross linkage
  3. DNA breakdown
  4. Phagocytic recognition
21
Q

Describe the differences between apoptosis and necrosis

A

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)
22
Q

What is autophagy?

A

Increased quantity of autophagosomes formation Atg proteins participation
PRODUCES NO INFLAMMATORY RESPONSE

23
Q

What does the intrinsic pathway involve - for cellular stress

A

BCL-2 proteins –> caspases 3 and 7 activation for cell death

24
Q

What does the extrinsic pathway involve - for death receptors

A

death receptor ligation, procaspase 8 recruitment and activation –> caspases 3 and 7 activation for cell death