2- toxicity mechanism Flashcards by Emily Liu

what are 3 importants attributes of target (of toxicity)

reactivity, accessibility, critical function

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what is important about target reactivity

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

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what is important about target accessibility

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

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what is important about target critical function

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

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what are 5 reaction types with ultimate toxicant and target

noncovalent binding
covalent binding
hydrogen abstraction
electron transfer
enzymatic reaction

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what is important about noncovalent binding

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

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what is important about covalent binding

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

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what is important about hydrogen abstraction

its lipid peroxidation

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what is important about electron transfer

fenton or redox cycle reactions, shuffle of electrons

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what is important about enzymatic reaction

enzymatic modifications of g proteins, like cholera

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what are 3 outcomes after interaction ultimate toxicant and target

dysfunction
destruction
neoantigen formation

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what is neoantigen formation

recognizes it as a new and foreign thing

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what are 3 things that the ultimate toxicant should do

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

mitochondrial stress

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what are 3 major causes of xenobiotic induced cell death

ATP depletion
calcium overload
overproduction of ROS RNS

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what 2 things can cause ROS and RNS overproduction

xenobiotics directly producing it or secondary to elevated calcium levels

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what plays a central role in all causes of cell death

mitochondria

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what are 2 main consequences of ATP depletion

accumulation of ADP and its breakdown products

- ATP requiring ion pumps shut down

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what happens with rapid ADP and ATP hydrolysis

accumulation of phosphoric acid from phosphate groups

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what happens with phosphoric acid accumulation

it produces acidosis

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is acidosis good or bad? what does it cause

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

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what is bad about ATP requiring pumps shutting down

loss of ionic and volume regulation control

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what are 3 ways that toxicants can elevate calcium levels

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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what is a major issue with elevated calcium

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

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how can elevated calcium cause increased ROS production

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

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

dissociation of microfilaments

how does elevated calcium cause dissociation of microfilaments

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

what happens once calcium cause dissociation of microfilaments

disrupt cytoskeleton, blebbing, membrane rupture

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

Ca++ dependent hydrolytic enzymes

name 3 Ca++ dependent hydrolytic enzymes

- calpains - phospholipases - endonucleases

what are calpains

Ca++ activated proteases with many targets

what are phospholipases

modification of membrane phospholipases

what are endonucleases

fragments of DNA

what is necrosis

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

what causes necrosis

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

what is apoptosis

programmed cell death

what is invovled in apoptosis

a cascade of calcium dependent proteases - the caspases

what is caspase 3 and what does it do

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

what happens structurally during apoptosis

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

does apoptosis require ATP

yes

does necrosis require ATP

does apoptosis cause inflammation

does necrosis cause inflammation

yes

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

you go into necrosis

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

apoptosis

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

apoptosis

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

necrosis (it can incapacitate apoptotic machinery)

how does the cell react to DNA damage

do apoptosis to prevent cancer

what is MPT (just acronym meaning)

mitochondria permeability transition

what is a main deciding factor for apoptosis or necrosis?

the number of mitochondria undergoing mitochondrial permeability transition

what is the mitochondria permeability transition

mechanism of mitochondrial membrane permeabilization

what is the role of mitochondria permeability transition

reversible cell injury, apoptosis and necrosis

what mediates mitochondria permeability transition

the mitochondria permeability transition pore (MPTP)

what is the MPTP (mitochondria permeability transition pore)

pore than spans the inner and outer mitochondrial membranes

when does the MPTP open

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

what are 2 main consequences of MPTP opening

inner membrane permeabilization, depolarization

what 4 things happen once MPTP oppens

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

what composes the MPTP

nobody knows

what does bcl 2 generally do

anti apoptosis

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

the release of cytochrome c

what does the release of cytochrome c from the mitochondria signal

apoptosis

what does bcl2 do to cyt c release

inhibits

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

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

what happens once cyt c is released

it joins other proteins to make the apoptosome

what dies pc-9 stand for

procaspase 9

what are the 4 components of the apoptosome

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

how is PC-9 activated and released from the apoptosome

using ATP as energy

what happens once PC-9 is released from the apoptosome

it becomes caspase 9, the active form

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

the initiator caspase, because it activates other caspases

when does C-9 cleave in the apoptosis pathway

PC-3 to become C-3

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

the effector caspase, which can act on many targets

what is p53

protein that senses DNA damage

what does p53 do

upregulates Bax and Fas protein production

what does Bax do

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

what does fas do

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

what are 2 death receptors

FAS and TNF

what are fas and tnf bound to

PC-8

how do fas and tnf lead to cell death and stuff

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

what happens once fas and tnf are interacted with

PC 8 gets cleaved into C 8

what does C8 do

cleaves bid to become t bid also it can activate PC-3 into C-3

what does t bid do

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

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

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

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

autophagy of mitochondria and cell survival

what happens if cyt c release is lots of mitochondria

caspase activation and apoptosis

what happens if cyt c release is in ALL mitochondria

ATP depletion and necrosis

what happens with death receptor stimulation

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

what happens with DNA damage

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

what happens with mitochondrial insults

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