Tox Damage

Question 1

How can a cell be damaged/injured?

Answer 1

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

Question 2

List the causes of cell injury

Answer 2

Hypoxia 
Physical agents 
chemical agents
infectious agents
immunologic agents
genetic derangements
nutritional imbalances 
ageing

Question 3

List the common mechanisms of cell injury

Answer 3

.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)

Question 4

How are ROS produced endogenously?

Answer 4

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

Question 5

How are ROS produced exogenously?

Answer 5

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

Question 6

What can ROS do?

Answer 6

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

Question 7

Chemical Injury: what does mercuric chloride do?

Answer 7

Binds sulfhydryl groups of proteins

Question 8

Chemical Injury: what does cyanide do?

Answer 8

Poisons mitochondrial cytochrome oxidase

Question 9

Chemical Injury: What does CCl4 do?

Answer 9

Conversion to free radical CCl3 - causing lipid peroxidation

Question 10

Chemical Injury: What does acetaminophen do?

Answer 10

P450 catalysed oxidation to toxic metabolite

Question 11

Define excitotoxicity

Answer 11

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

Question 12

Define stroke

Answer 12

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

Question 13

What does excitotoxicity cause?

Answer 13

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

Question 14

Define genotoxicity

Answer 14

agents that damage DNA

Question 15

What do DNA damage and repair mismatch repair enzymes do?

Answer 15

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

Question 16

What does the protein isoaspartylmethyltransferase (PIMT)

Answer 16

repairs age damage in proteins

Question 17

What enzymes and vitamins defend against unwanted ROS?

Answer 17

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

Question 18

What is mitophagy?

Answer 18

Mitophagy is the selective degradation of mitochondria by autophagy

Question 19

What is necrosis and what does it involve?

Answer 19

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)

Question 20

What is apoptosis and what does it involve?

Answer 20

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

Question 21

Describe the differences between apoptosis and necrosis

Answer 21

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)

Question 22

What is autophagy?

Answer 22

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

Question 23

What does the intrinsic pathway involve - for cellular stress

Answer 23

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

Question 24

What does the extrinsic pathway involve - for death receptors

Answer 24

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