2- toxicity mechanism Flashcards
what are 3 importants attributes of target (of toxicity)
reactivity, accessibility, critical function
what is important about target reactivity
some toxins interact directly with target, some become more reactive after modifications
what is important about target accessibility
if poison doesnt get into general circulation or BBB, the target may not be affective
what is important about target critical function
some toxins may just bind to proteins in blood and not do anything
what are 5 reaction types with ultimate toxicant and target
noncovalent binding covalent binding hydrogen abstraction electron transfer enzymatic reaction
what is important about noncovalent binding
you dont have to make new proteins to restore function because it is reversible
what is important about covalent binding
not reversible, you have to make new proteins (like schiff base stuff)
what is important about hydrogen abstraction
its lipid peroxidation
what is important about electron transfer
fenton or redox cycle reactions, shuffle of electrons
what is important about enzymatic reaction
enzymatic modifications of g proteins, like cholera
what are 3 outcomes after interaction ultimate toxicant and target
- dysfunction
- destruction
- neoantigen formation
what is neoantigen formation
recognizes it as a new and foreign thing
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)
what is a common theme that causes cell injury, dysfunction and death
mitochondrial stress
what are 3 major causes of xenobiotic induced cell death
- ATP depletion
- calcium overload
- overproduction of ROS RNS
what 2 things can cause ROS and RNS overproduction
xenobiotics directly producing it or secondary to elevated calcium levels
what plays a central role in all causes of cell death
mitochondria
what are 2 main consequences of ATP depletion
- accumulation of ADP and its breakdown products
- ATP requiring ion pumps shut down
what happens with rapid ADP and ATP hydrolysis
accumulation of phosphoric acid from phosphate groups
what happens with phosphoric acid accumulation
it produces acidosis
is acidosis good or bad? what does it cause
initially beneficial cause forms insoluble calcium phosphate (less free calcium) and inhibits phospholipases
what is bad about ATP requiring pumps shutting down
loss of ionic and volume regulation control
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
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)
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
no
does apoptosis cause inflammation
no
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
