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PMCOL 303 > 2- toxicity mechanism > Flashcards

2- toxicity mechanism Flashcards

1
Q

what are 3 importants attributes of target (of toxicity)

A

reactivity, accessibility, critical function

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2
Q

what is important about target reactivity

A

some toxins interact directly with target, some become more reactive after modifications

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3
Q

what is important about target accessibility

A

if poison doesnt get into general circulation or BBB, the target may not be affective

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4
Q

what is important about target critical function

A

some toxins may just bind to proteins in blood and not do anything

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5
Q

what are 5 reaction types with ultimate toxicant and target

A 
noncovalent binding
covalent binding
hydrogen abstraction
electron transfer
enzymatic reaction
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6
Q

what is important about noncovalent binding

A

you dont have to make new proteins to restore function because it is reversible

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7
Q

what is important about covalent binding

A

not reversible, you have to make new proteins (like schiff base stuff)

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8
Q

what is important about hydrogen abstraction

A

its lipid peroxidation

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9
Q

what is important about electron transfer

A

fenton or redox cycle reactions, shuffle of electrons

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10
Q

what is important about enzymatic reaction

A

enzymatic modifications of g proteins, like cholera

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11
Q

what are 3 outcomes after interaction ultimate toxicant and target

A
  • dysfunction
  • destruction
  • neoantigen formation
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12
Q

what is neoantigen formation

A

recognizes it as a new and foreign thing

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13
Q

what are 3 things that the ultimate toxicant should do

A
  • react with target and adversely affect function
  • reach effective concentration at target site
  • alter target in a way that is mechanistically consistent with toxicity (like apoptosis)
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14
Q

what is a common theme that causes cell injury, dysfunction and death

A

mitochondrial stress

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15
Q

what are 3 major causes of xenobiotic induced cell death

A
  • ATP depletion
  • calcium overload
  • overproduction of ROS RNS
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16
Q

what 2 things can cause ROS and RNS overproduction

A

xenobiotics directly producing it or secondary to elevated calcium levels

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17
Q

what plays a central role in all causes of cell death

A

mitochondria

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18
Q

what are 2 main consequences of ATP depletion

A
  • accumulation of ADP and its breakdown products

- ATP requiring ion pumps shut down

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19
Q

what happens with rapid ADP and ATP hydrolysis

A

accumulation of phosphoric acid from phosphate groups

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20
Q

what happens with phosphoric acid accumulation

A

it produces acidosis

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21
Q

is acidosis good or bad? what does it cause

A

initially beneficial cause forms insoluble calcium phosphate (less free calcium) and inhibits phospholipases

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22
Q

what is bad about ATP requiring pumps shutting down

A

loss of ionic and volume regulation control

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23
Q

what are 3 ways that toxicants can elevate calcium levels

A
  • increased opening of ion channels or LGICs
  • increased leakage from mitochondria or ER
  • decreased calcium efflux by transporters or depletion of their driving force
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24
Q

what is a major issue with elevated calcium

A

increase Ca++ uptake in mitochondria pissipating the membrane potential and halting ATP synthesis (proton gradient needed to make ATP)

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25
Q

how can elevated calcium cause increased ROS production

A

increase activity of ETC (cause less ATP is made) and increase ROS production

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26
Q

what is a structural thing that happens with elevated cytosolic Ca++

A

dissociation of microfilaments

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27
Q

how does elevated calcium cause dissociation of microfilaments

A

elevated Ca++ causes dissociation of actin from proteins involved in anchoring to the plasma membrane

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28
Q

what happens once calcium cause dissociation of microfilaments

A

disrupt cytoskeleton, blebbing, membrane rupture

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29
Q

what kind of enzymes may be activated with elevated cytosolic Ca++

A

Ca++ dependent hydrolytic enzymes

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30
Q

name 3 Ca++ dependent hydrolytic enzymes

A
  • calpains
  • phospholipases
  • endonucleases
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31
Q

what are calpains

A

Ca++ activated proteases with many targets

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32
Q

what are phospholipases

A

modification of membrane phospholipases

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33
Q

what are endonucleases

A

fragments of DNA

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34
Q

what is necrosis

A

cell swelling, vacuolization and lysis, spilling of contents into surrounding tissue, inflammatory response

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35
Q

what causes necrosis

A

calcium overload ! all mitochondria is damaged, no ATP can be made

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36
Q

what is apoptosis

A

programmed cell death

37
Q

what is invovled in apoptosis

A

a cascade of calcium dependent proteases - the caspases

38
Q

what is caspase 3 and what does it do

A

effector caspase that starts a pathway to cleave cellular components such as DNA and cytoskeleton

39
Q

what happens structurally during apoptosis

A

the cell is reduces to a cluster of membrane bound sacs (apoptotic bodies) that are engulfed by macrophages

40
Q

does apoptosis require ATP

A

yes

41
Q

does necrosis require ATP

A

no

42
Q

does apoptosis cause inflammation

A

no

43
Q

does necrosis cause inflammation

A

yes

44
Q

what happens if you are doing apoptosis then you run out of ATP

A

you go into necrosis

45
Q

what usually happens (necrosis or apoptosis) with low exposure toxicant levels

A

apoptosis

46
Q

what usually happens (necrosis or apoptosis) with early exposure to high toxicant levels

A

apoptosis

47
Q

what usually happens (necrosis or apoptosis) with high concentration of toxicant

A

necrosis (it can incapacitate apoptotic machinery)

48
Q

how does the cell react to DNA damage

A

do apoptosis to prevent cancer

49
Q

what is MPT (just acronym meaning)

A

mitochondria permeability transition

50
Q

what is a main deciding factor for apoptosis or necrosis?

A

the number of mitochondria undergoing mitochondrial permeability transition

51
Q

what is the mitochondria permeability transition

A

mechanism of mitochondrial membrane permeabilization

52
Q

what is the role of mitochondria permeability transition

A

reversible cell injury, apoptosis and necrosis

53
Q

what mediates mitochondria permeability transition

A

the mitochondria permeability transition pore (MPTP)

54
Q

what is the MPTP (mitochondria permeability transition pore)

A

pore than spans the inner and outer mitochondrial membranes

55
Q

when does the MPTP open

A

in response to excess Ca++ uptake, decreased membrane potential, generation of ROS and RNS, depletion of ATP

56
Q

what are 2 main consequences of MPTP opening

A

inner membrane permeabilization, depolarization

57
Q

what 4 things happen once MPTP oppens

A
  • entry of solutes (K+ Mg++ Ca++) and water
  • swelling of mitochondrial matrix
  • rupture of outer membrane
  • leakage of mitochondrial proteins and cytochrome into cytoplasm
58
Q

what composes the MPTP

A

nobody knows

59
Q

what does bcl 2 generally do

A

anti apoptosis

60
Q

what is the signal thing that the mitochondria can release to trigger something important in the cell

A

the release of cytochrome c

61
Q

what does the release of cytochrome c from the mitochondria signal

A

apoptosis

62
Q

what does bcl2 do to cyt c release

A

inhibits

63
Q

how does cyt c get released (how does it release when bcl 2 doesnt want it to)

A

when the mitochondria is insulted, MPTP is more active and outweighs influence of anti apoptotic proteins like bcl 2

64
Q

what happens once cyt c is released

A

it joins other proteins to make the apoptosome

65
Q

what dies pc-9 stand for

A

procaspase 9

66
Q

what are the 4 components of the apoptosome

A

Cyt C, ATP, PC-9, Apaf-1

67
Q

how is PC-9 activated and released from the apoptosome

A

using ATP as energy

68
Q

what happens once PC-9 is released from the apoptosome

A

it becomes caspase 9, the active form

69
Q

what do we call c-9 (caspase-9) and why

A

the initiator caspase, because it activates other caspases

70
Q

when does C-9 cleave in the apoptosis pathway

A

PC-3 to become C-3

71
Q

what do we call c-3 (caspase-9) and why

A

the effector caspase, which can act on many targets

72
Q

what is p53

A

protein that senses DNA damage

73
Q

what does p53 do

A

upregulates Bax and Fas protein production

74
Q

what does Bax do

A

inserts itself into the mitochondrial membrane to help release cyt c (pro-apoptotic)

75
Q

what does fas do

A

its a receptor that, when stimulated, leads to cell death

76
Q

what are 2 death receptors

A

FAS and TNF

77
Q

what are fas and tnf bound to

A

PC-8

78
Q

how do fas and tnf lead to cell death and stuff

A

more DNA damage upregulates its expression in the membrane, immune cells have ligands for these receptors in their membranes, then immune cells can target and kill it

79
Q

what happens once fas and tnf are interacted with

A

PC 8 gets cleaved into C 8

80
Q

what does C8 do

A

cleaves bid to become t bid

also it can activate PC-3 into C-3

81
Q

what does t bid do

A

it inserts into the membrane and enhances the whole apoptosome pathway (similar to bax)

it also is thought to counteract the anti apoptotic effects bcl2

82
Q

what is the main reason that elephants dont get as much cancer as humans

A

they have a lot more genes that help control for DNA damage (like p53) and much more caspase repair activity

83
Q

what happens if cyt c release is in just a few mitochondria

A

autophagy of mitochondria and cell survival

84
Q

what happens if cyt c release is lots of mitochondria

A

caspase activation and apoptosis

85
Q

what happens if cyt c release is in ALL mitochondria

A

ATP depletion and necrosis

86
Q

what happens with death receptor stimulation

A

caspase 8 activation, bid inhibits anti-apoptotic proteins, cyt c release…

87
Q

what happens with DNA damage

A

p53 stabilization (more active in nucleus), inhibit anti-apop proteins, cyt c release

88
Q

what happens with mitochondrial insults

A

less ATP more calcium, leading to more ROS and more RNS, then cyt c release

PMCOL 303 (25 decks)

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