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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
Q

what is another name for the electrophile response element (EpRE)

A

antioxidant response elements (ARE)

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26
Q

what is the antioxidant response elements (ARE) / the electrophile response element (EpRE)

A

a DNA sequence that controls the proteins that can be up-regulated to combat oxidative stress

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27
Q

what controls the proteins that can be upregulated to combat oxidative stress

A

ARE / EpRE

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28
Q

what does Nrf2 do

A

it binds to ARE / EpRE in response to oxidative stress and activates downstream genes

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29
Q

what is Nrf2 (not function)

A

a nuclear factor, protein

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30
Q

what does Keap 1 do

A

binds to nrf2 and prevents its movement into the nucleus

and positions Cul3 in place to aid in ubiquitination

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31
Q

what does cul3 do

A

allows for interaction of ubiquitin ligase with nrf2

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32
Q

what composes the electrophile response pathway protein clump (# amounts too)

A

2 cul3 proteins
2 Keap 1 proteins
1 nrf2 protein
(3 diff proteins, 5 in total)

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33
Q

what happens to nrf2 under basal conditions and no oxidative stress

A

nrf2 is targeted for proteasomal degradation (half life of 20 mins)

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34
Q

how is ubiquitin added to nrf2

A

added to the cysteine sulfhydryl groups by ubiquitin ligase

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35
Q

what does cul3 do

A

helps to position ubiquitin enzymes

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36
Q

how many cysteine residues does keap1 have

A

26

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37
Q

where is ubiquitin added to

A

cysteine sulfhydryl groups in nrf2 by ubiquitin ligase

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38
Q

does nrf2 have cysteine residues

A

yes

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39
Q

what 2 things can cause the modifications of sulfhydryl groups

A
  • oxidation so that sulfhydryl groups form disulphides

- electrophilic attack of sulfhydryls resulting in covalent modifications (like by 4-HNE)

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40
Q

what happens once the sulfhydryl groups are modified (in that pathway thing)

A

Cul3 dissociates and ubiquitination no longer occurs, nrf2 is free to do its job and it targets the nucleus

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41
Q

what is sMaf

A

a transcription factor that pairs with Nrf2 to activate downstream genes (attached to electrophile response element)

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42
Q

what are 6 categories of responses via the electrophile stress response pathway

A
  • xenobiotic detox
  • ROS detox (GSH)
  • iron sequestration (ferritin)
  • GSH synthesis
  • export
  • protein removal and repair

think GRIPEX

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43
Q

what is the role of membrane transporters (general)

A

distribute things to and away from targets

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44
Q

what is the role of membrane transporters (toxins)

A

some accumulate toxins in cells, some pump them out

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45
Q

what are the 2 main families of membrane transporters

A 
active transporters (ABC)
facilitated transporters (SLC)
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46
Q

what does ABC stand for

A

ATP binding cassete

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47
Q

what is the defining feature of ABC transporters

A

use ATP to transport

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48
Q

what is the defining feature of SLC transporters

A

use electrochemical gradient to transport

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49
Q

what are the most abundant and important receptors in the SLC family (in humans)

A

OATP1A2 and OATP2B1

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50
Q

whats the big deal with OATP1A2 and OATP2B1

A

they are the most abundant and important receptors in the SLC family (in humans)

51
Q

what is the deal with PEPT1 + which class

A

highly expressed in gut, uptake peptide and peptdie like drugs (antibiotics, like beta lactams)

SLC

52
Q

how do transporters vary around the gut

A

the relative abundance of transporters vary

53
Q

where is MDR1 most + which class expressed

A

increasing from duodenum to colon (ABC)

54
Q

where are most of the uptake transporters in the GIT

A

highest in duodenum and decrease towards the terminal ileum and colon

55
Q

what type of transporter is MDR1

A

ABC transporter

56
Q

which transporter increases expression from duodenum to colon

A

MDR1

57
Q

what is a main mechanism that opposes the distribution to target

A

export from cells

58
Q

what is an example of exporter away from cells

A

multidrug resistant proteins (mdr) are ATP dependent and pump chemicals out of cells

59
Q

what is the typical structure of ABC family protein

A

1 single protein, 2 domains, 6 helices in each domain and 2 catalytic regions

60
Q

how did the structure of the ABC transporter likely arise

A

via gene duplication events

61
Q

what type of family is the OAT pumps

A

SLC

62
Q

what is an allocrite

A

something that is transported from one side to another

63
Q

what happens in step 1 of ABC transporter mechanism

A

allocrite binds to interior of cell (Resting state, open conformation)

64
Q

what happens in step 2 of ABC transporter mechanism (3 in this one)

A

ATP binds to 2 domains, transporter clamps down (closes) and does a 90 degree turn, helices open to outside to release allocrite

65
Q

what happens in step 3 of ABC transporter mechanism

A

ATP is hydrolyzed

66
Q

what happens in step 4 of ABC transporter mechanism

A

Pi and ADP is released, transporter back to origional state

67
Q

when is ATP needed in the ABC transporter mechanism

A

to return it to original state (not even needed to release the allocrite)

68
Q

which family do DAT SERT and NET belong to

A

SLC6 family

69
Q

how do SLC6 family transporters usually work

A

use an ion gradient to facilitate transporter (usually Na+, sometimes Cl-)

70
Q

which family do OCT and OAT belong to (more specific)

A

SLC22

71
Q

what does OCT stand for

A

organic cation transporter

72
Q

what does OAT stand for

A

organic anion transporter

73
Q

What is the structure of SLC family protein typically like

A

2 similar 5-helical domains, substrate binding domain with Na+ and Cl- associations

74
Q

do all SLC family proteins have the same amount of helices

A

no, some have more and some have less

75
Q

what is a weird structural thing about the SLC family proteins

A

they have a bendy bit, it seems to be an important HINGE

76
Q

do the helices occur in order in SLC family proteins

A

no

77
Q

what are the 3 known SLC mechanism models

A
  • rocker switch (banana)
  • gated-pore
  • elevator
78
Q

how does the rocker switch model work

A

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
Q

what is step 1 of rocker switch

A

open to exterior to get allocrite

80
Q

what is step 2 of rocker switch

A

occluded state, not open to inside or outside

81
Q

what is step 3 of rocker switch

A

open to the interior to release allocrite

82
Q

what is the structure of the gated-pore model like

A

the binding site of the transporter is enclosed by two gates

83
Q

what are the 2 domains like in the gated-pore model

A

one domain is static and one domain does the moving

84
Q

what is step 1 of gated pore model

A

opening of outward facing fate lets substrate bind

85
Q

what is step 2 of gated pore model

A

it binds, closes outside facing gate

86
Q

what is step 3 of gated pore model

A

the inward gate opens to face the cytosol, substrate releases

87
Q

what is the extracellular gate in the gated-pore model

A

a salt bridge

88
Q

what is the intracellular gate in the gated-pore model

A

TM1 (transmembrane 1)

89
Q

do SLC family transporters require ATP

A

no

90
Q

what is the elevator mechanism

A

the domain containing the binding site (transport domain) moves along axis to transport

91
Q

what are the domains like in the elevator mechanism

A

transport domain moves along axis perpendicular to membrane, the oligomerization domain remains static

92
Q

what is step 1 in the elevator mechanism

A

transport domain open to exterior, substraet binds

93
Q

what is step 2 in the elevator mechanism

A

transport domain is closed to both sides

94
Q

what is step 3 in the elevator mechanism

A

loop opens to exterior side to release the substrate

95
Q

what is common in step 1 of all the SLC mechanisms

A

it is open to the exterior and the allocrite binds

96
Q

what does the elevator likely form structurally

A

trimer

97
Q

which SLC forms a trimer

A

the elevator model

98
Q

what is common in step 2 of all the SLC mechanisms

A

it is closed off to the the interior and exterior

99
Q

what is common in step 3 of all the SLC mechanisms

A

it is open to the exterior and releases the substrate

100
Q

what is fibrosis

A

excessive deposition of extracellular matrix

101
Q

what is the extracellular matrix

A

polysaccharides linked to proteins to form proteoglycans

102
Q

what makes up the fibrosis scar tissue

A

type 1 collagen that replaces healthy tissue

103
Q

what seems to be responsible for fibrosis + how

A

TGF B interacting with its cell surface receptor

104
Q

where is TGF B stored

A

inactively in the ECM

105
Q

what kind of things release TGF B

A

enzymatically by ROS

106
Q

What are the 3 mechanisms that promote fibrogenesis (big)

A
  • inhibit MMPs and increased TIMP
  • increase myofibroblast production
  • induction of matrix component gene transcription
107
Q

what is MMP

A

matrix metalloproteases

108
Q

what is TIMP

A

tissue inhibitor of metalloproteinase

109
Q

what does TGF B do to matrix metalloproteases

A

inhibits

110
Q

what does TGF B do to tissue inhibitor of metalloproteinase

A

increases its production

111
Q

what does TGF B do to myofibroblast production

A

induction

112
Q

what do myofibroblasts do

A

key in collagen production

113
Q

what does TGF B do to matrix component gene transcription

A

induces it

114
Q

what does TIMP do to MMP

A

inhibits

115
Q

what does TGH B do to the ability to break down ECM

A

decreases

116
Q

what do myofibroblasts product

A

collagen

117
Q

simply put, what are 3 things that TGF B does

A
  • Less degradation
  • Increase cells that make collagen
  • Increase in production of proteins we find in ECM
118
Q

which family is mdr

A

ABC

119
Q

which family is mrp

A

ABC

120
Q

which family is oat

A

SLC

121
Q

which family is pept

A

SLC

122
Q

which family is bcrp

A

ABC

123
Q

how to remember if its ABC or SLC

A

if theres a t in the name, its SLC. if not, then its ABC

PMCOL 303 (25 decks)

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