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PMCOL 303 > 3- toxicity mechanism > Flashcards

3- toxicity mechanism Flashcards

1
Q

what is the deal with glutathione (GSH)

A

it is the most abundant low molecular weight thiol

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2
Q

what makes up glutathione

A

glutamate, cystein and glycine

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3
Q

how does glutathione act is an antioxidant

A

the thiol groups of the cysteine can donate a hydrogen to reduce other targets and itself become oxidized

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4
Q

what happens once glutathione donates a hydrogen

A

two of them conjugate to form GSSG (glutathione disulfide)

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5
Q

what can happen to glutathione disulfide

A

it can be reduced back to GSH by glutathione reductase

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6
Q

what is glutathione reductase

A

an enzyme that can convert glutathione disulfide back into glutathione

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7
Q

why is glutathione a good antioxidant

A

it donates hydrogens to other things so they are less likely to interact with other substances

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8
Q

how can some cancer cells protect themselves against anti-cancer drugs

A

they upregulate glutathione synthesis and glutamate-cysteine ligase (enzyme that is used to make GSH)

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9
Q

what is a way that we can increase effectiveness of some chemo agents

A

by inhibiting GSH synthesis (Cause they make more GSH to combat the anti cancer drugs)

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10
Q

what are 2 enzymes that are involved in glutathione synthesis

A

glutamate-cysteine ligase and glutathione synthetase

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11
Q

what does glutamate-cysteine ligase do

A

uses ATP to join glutamate and cysteine

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12
Q

what does glutathione synthetase do

A

uses ATP to add glycine (to glutamate-cysteine) to make glutathione

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13
Q

what do glutathione S-transferase enzymes do

A

conjugates glutathione with xenobiotics

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14
Q

how does glutathione conjugate with a xenobiotic (with help of S-transferase enzyme) (mechanism)

A

nucleophilic attack of the thiolate anion (GS-) with an electrophilic carbon, oxygen, nitrogen or sulfur

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15
Q

what happens to glutathione conjugates formed in the liver

A

they are transported into bile and excreted

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16
Q

where is most glutathione found in the body

A

in the liver

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17
Q

what does sequential cleavage of glutamic acid and glycine lead to

A

formation of mercapturic acids

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18
Q

what happens to glutathione levels in the cell when 4-HNE is added + why

A

glutathione levels drop (and so does 4-HNE levels)

because they conjugate with eachother

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19
Q

how does 4-HNE get detoxified (with GSH)

A

either spontaneous or glutathione-S-transferase mediated conjugation

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20
Q

what are 4 general ways that 4-HNE can be detoxified

A
  • with GSH
  • aldo-keto reductase
  • reduction by alcohol dehydrogenase
  • oxidation by aldehyde dehydrogenase
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21
Q

what happens to the 4-HNE metabolites

A

they are transported out of the cell

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22
Q

what is the breakdown product when GSH is broken down by aldehyde dehydrogenase

A

HNA

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23
Q

what is the breakdown product when GSH is broken down by alcohol dehydrogenase

A

DHN

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24
Q

what is another name for the antioxidant response elements (ARE)

A

the electrophile response element (EpRE)

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25
what is another name for the electrophile response element (EpRE)
antioxidant response elements (ARE)
26
what is the antioxidant response elements (ARE) / the electrophile response element (EpRE)
a DNA sequence that controls the proteins that can be up-regulated to combat oxidative stress
27
what controls the proteins that can be upregulated to combat oxidative stress
ARE / EpRE
28
what does Nrf2 do
it binds to ARE / EpRE in response to oxidative stress and activates downstream genes
29
what is Nrf2 (not function)
a nuclear factor, protein
30
what does Keap 1 do
binds to nrf2 and prevents its movement into the nucleus | and positions Cul3 in place to aid in ubiquitination
31
what does cul3 do
allows for interaction of ubiquitin ligase with nrf2
32
what composes the electrophile response pathway protein clump (# amounts too)
2 cul3 proteins 2 Keap 1 proteins 1 nrf2 protein (3 diff proteins, 5 in total)
33
what happens to nrf2 under basal conditions and no oxidative stress
nrf2 is targeted for proteasomal degradation (half life of 20 mins)
34
how is ubiquitin added to nrf2
added to the cysteine sulfhydryl groups by ubiquitin ligase
35
what does cul3 do
helps to position ubiquitin enzymes
36
how many cysteine residues does keap1 have
26
37
where is ubiquitin added to
cysteine sulfhydryl groups in nrf2 by ubiquitin ligase
38
does nrf2 have cysteine residues
yes
39
what 2 things can cause the modifications of sulfhydryl groups
- oxidation so that sulfhydryl groups form disulphides | - electrophilic attack of sulfhydryls resulting in covalent modifications (like by 4-HNE)
40
what happens once the sulfhydryl groups are modified (in that pathway thing)
Cul3 dissociates and ubiquitination no longer occurs, nrf2 is free to do its job and it targets the nucleus
41
what is sMaf
a transcription factor that pairs with Nrf2 to activate downstream genes (attached to electrophile response element)
42
what are 6 categories of responses via the electrophile stress response pathway
- xenobiotic detox - ROS detox (GSH) - iron sequestration (ferritin) - GSH synthesis - export - protein removal and repair think GRIPEX
43
what is the role of membrane transporters (general)
distribute things to and away from targets
44
what is the role of membrane transporters (toxins)
some accumulate toxins in cells, some pump them out
45
what are the 2 main families of membrane transporters
``` active transporters (ABC) facilitated transporters (SLC) ```
46
what does ABC stand for
ATP binding cassete
47
what is the defining feature of ABC transporters
use ATP to transport
48
what is the defining feature of SLC transporters
use electrochemical gradient to transport
49
what are the most abundant and important receptors in the SLC family (in humans)
OATP1A2 and OATP2B1
50
whats the big deal with OATP1A2 and OATP2B1
they are the most abundant and important receptors in the SLC family (in humans)
51
what is the deal with PEPT1 + which class
highly expressed in gut, uptake peptide and peptdie like drugs (antibiotics, like beta lactams) SLC
52
how do transporters vary around the gut
the relative abundance of transporters vary
53
where is MDR1 most + which class expressed
increasing from duodenum to colon (ABC)
54
where are most of the uptake transporters in the GIT
highest in duodenum and decrease towards the terminal ileum and colon
55
what type of transporter is MDR1
ABC transporter
56
which transporter increases expression from duodenum to colon
MDR1
57
what is a main mechanism that opposes the distribution to target
export from cells
58
what is an example of exporter away from cells
multidrug resistant proteins (mdr) are ATP dependent and pump chemicals out of cells
59
what is the typical structure of ABC family protein
1 single protein, 2 domains, 6 helices in each domain and 2 catalytic regions
60
how did the structure of the ABC transporter likely arise
via gene duplication events
61
what type of family is the OAT pumps
SLC
62
what is an allocrite
something that is transported from one side to another
63
what happens in step 1 of ABC transporter mechanism
allocrite binds to interior of cell (Resting state, open conformation)
64
what happens in step 2 of ABC transporter mechanism (3 in this one)
ATP binds to 2 domains, transporter clamps down (closes) and does a 90 degree turn, helices open to outside to release allocrite
65
what happens in step 3 of ABC transporter mechanism
ATP is hydrolyzed
66
what happens in step 4 of ABC transporter mechanism
Pi and ADP is released, transporter back to origional state
67
when is ATP needed in the ABC transporter mechanism
to return it to original state (not even needed to release the allocrite)
68
which family do DAT SERT and NET belong to
SLC6 family
69
how do SLC6 family transporters usually work
use an ion gradient to facilitate transporter (usually Na+, sometimes Cl-)
70
which family do OCT and OAT belong to (more specific)
SLC22
71
what does OCT stand for
organic cation transporter
72
what does OAT stand for
organic anion transporter
73
What is the structure of SLC family protein typically like
2 similar 5-helical domains, substrate binding domain with Na+ and Cl- associations
74
do all SLC family proteins have the same amount of helices
no, some have more and some have less
75
what is a weird structural thing about the SLC family proteins
they have a bendy bit, it seems to be an important HINGE
76
do the helices occur in order in SLC family proteins
no
77
what are the 3 known SLC mechanism models
- rocker switch (banana) - gated-pore - elevator
78
how does the rocker switch model work
the N and C halves of the transporter oscillate back and forth from an outward facing state to an inward facing state along the symmetry axis perpendicular to the membrane
79
what is step 1 of rocker switch
open to exterior to get allocrite
80
what is step 2 of rocker switch
occluded state, not open to inside or outside
81
what is step 3 of rocker switch
open to the interior to release allocrite
82
what is the structure of the gated-pore model like
the binding site of the transporter is enclosed by two gates
83
what are the 2 domains like in the gated-pore model
one domain is static and one domain does the moving
84
what is step 1 of gated pore model
opening of outward facing fate lets substrate bind
85
what is step 2 of gated pore model
it binds, closes outside facing gate
86
what is step 3 of gated pore model
the inward gate opens to face the cytosol, substrate releases
87
what is the extracellular gate in the gated-pore model
a salt bridge
88
what is the intracellular gate in the gated-pore model
TM1 (transmembrane 1)
89
do SLC family transporters require ATP
no
90
what is the elevator mechanism
the domain containing the binding site (transport domain) moves along axis to transport
91
what are the domains like in the elevator mechanism
transport domain moves along axis perpendicular to membrane, the oligomerization domain remains static
92
what is step 1 in the elevator mechanism
transport domain open to exterior, substraet binds
93
what is step 2 in the elevator mechanism
transport domain is closed to both sides
94
what is step 3 in the elevator mechanism
loop opens to exterior side to release the substrate
95
what is common in step 1 of all the SLC mechanisms
it is open to the exterior and the allocrite binds
96
what does the elevator likely form structurally
trimer
97
which SLC forms a trimer
the elevator model
98
what is common in step 2 of all the SLC mechanisms
it is closed off to the the interior and exterior
99
what is common in step 3 of all the SLC mechanisms
it is open to the exterior and releases the substrate
100
what is fibrosis
excessive deposition of extracellular matrix
101
what is the extracellular matrix
polysaccharides linked to proteins to form proteoglycans
102
what makes up the fibrosis scar tissue
type 1 collagen that replaces healthy tissue
103
what seems to be responsible for fibrosis + how
TGF B interacting with its cell surface receptor
104
where is TGF B stored
inactively in the ECM
105
what kind of things release TGF B
enzymatically by ROS
106
What are the 3 mechanisms that promote fibrogenesis (big)
- inhibit MMPs and increased TIMP - increase myofibroblast production - induction of matrix component gene transcription
107
what is MMP
matrix metalloproteases
108
what is TIMP
tissue inhibitor of metalloproteinase
109
what does TGF B do to matrix metalloproteases
inhibits
110
what does TGF B do to tissue inhibitor of metalloproteinase
increases its production
111
what does TGF B do to myofibroblast production
induction
112
what do myofibroblasts do
key in collagen production
113
what does TGF B do to matrix component gene transcription
induces it
114
what does TIMP do to MMP
inhibits
115
what does TGH B do to the ability to break down ECM
decreases
116
what do myofibroblasts product
collagen
117
simply put, what are 3 things that TGF B does
- Less degradation - Increase cells that make collagen - Increase in production of proteins we find in ECM
118
which family is mdr
ABC
119
which family is mrp
ABC
120
which family is oat
SLC
121
which family is pept
SLC
122
which family is bcrp
ABC
123
how to remember if its ABC or SLC
if theres a t in the name, its SLC. if not, then its ABC

PMCOL 303 (25 decks)

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