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pmcol 303 > 1- toxicity mechanism > Flashcards

1- toxicity mechanism Flashcards

1
Q

what are 2 things that happen after delivery and before cellular dysfunction and injury

A

interaction with target molecule and alteration of biological environment

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2
Q

what happens after a toxicant does interaction with target molecule and alteration of biological environment

A

it causes cellular dysfunction and injury

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3
Q

what can cellular dysfunction and injury lead to (2)

A

inappropriate repair and adaptation, toxicity

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4
Q

what does inappropriate repair and adaptation lead to

A

toxicity

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5
Q

what 4 things are important in the delivery of the toxicant

A

absorption, distribution toward target, reabsorption (tubules), toxication

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6
Q

what is toxication

A

when some molecules become more toxic by bodily processes

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7
Q

what are 4 things that reduce delivery of the toxicant

A

presynaptic elimination, distribution away from target, excretion, detoxication

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8
Q

what is detoxication

A

when your body tries to make something less toxic and remove it

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9
Q

what is the ultimate toxicant

A

chemical that reacts with an endogenous molecule or alters the biological environment resulting in toxicity, may be a metabolite or byproduct of the primary toxicant to which the organism is exposed

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10
Q

what are the 4 main steps of toxicity

A

1-delivery
2-interaction with target molecule
3-cellular dysfunction, injury
4-inappropriate tissue repair and adaptation, non functionality of organ

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11
Q

is the consumed toxicant the same as the one that interacts with the body

A

sometimes, but they can be different

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12
Q

what is toxication

A

biotransformation into a harmful product

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13
Q

what are electrophiles

A

usually positively charged (full or partial), attracted to negative charges, electron deficient

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14
Q

what happens to chemical reactivity with toxication

A

increased

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15
Q

what are nucleophiles

A

electron rich, donate electron pair, can be negatively charged

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16
Q

what are ROS RNS

A

oxygen/nitrogen containing things with one or more unpaired electrons in outer orbital

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17
Q

what is detoxication

A

biotransformation that eliminates ultimate toxicant or prevents its formation

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18
Q

what are 3 things that are made with toxication

A

electrophiles, ROS/RNS, nucleophiles (more uncommon)

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19
Q

which is the relatively uncommon toxication pathway

A

nucleophiles

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20
Q

how are electrophiles usually produced and what does it make (2 production ways, 3 products)

A

when an oxygen is inserted resulting in a ketone, aldehyde or epoxide, or due to heterolytic cleavae (uneven distribution of electrons that formed the bond)

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21
Q

what is the charge of the carbon in ketones, aldehydes and epoxides

A

usually partially + cause of electron withdrawal

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22
Q

what are electrophiles

A

molecules containing an electron-deficient atom with a full or partial charge

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23
Q

what happens once an oxygen is inserted resulting in a ketone/aldehyde/epoxide?

A

it produces an electrophile

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24
Q

what is produced if there is heterolytic cleavage in which there is an uneven distribution fo the electrons that form the bond

A

electrophiles

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25
Q

what is a reactive oxygen species

A

a molecule containing oxygen that contains one or more unpaired electrons in its outer orbital

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26
Q

what is so bad about ROS

A

they are highly reaction, and like to interct with proteins DNA lipids

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27
Q

where are ROS most found

A

in mitochondria via ETC (normal)

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28
Q

Are ROS found naturally in the body and where

A

yes, esp in in mitochondria via ETC

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29
Q

if ROS is found naturally, why dont we die earlier

A

because the body has a healthy balance between production and destruction of ROS but this can change when cells are stressed

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30
Q

what can cause a change in the healthy balance between production and destruction of ROS

A

cells are stressed

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31
Q

what are 3 examples of ROS

A 
superoxide anion (O2*-)
hydroxyl radical (OH*)
hydrogen peroxide is kinda (H2O2)
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32
Q

what is the deal with superoxide anion (O2*-) (when does it occur, what happens once its formed)

A

it happens when rxns are incomplete, produce ETC, can travel far and last long

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33
Q

what is the deal with hydrogen peroxide (H2O2) (what happens once its formed)

A

powerful oxidizer, feeds into pathways that generates ROS. it is not a ROS itself (check)

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34
Q

what is the deal with hydroxyl radical (OH*)

) (what happens once its formed)

A

very reactive with a short half life, significant local damage, doesnt travel far

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35
Q

which ROS travels far

A

superoxide anion (O2*-)

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36
Q

which ROS doesn’t travels far

A

hydroxyl radical (OH*)

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37
Q

what are 3 major sources of ROS

A
  • mitochondrial reduction of oxygen during ATP production
  • reduction of H2O2 by transition metal ions (fenton)
  • redox cycling
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38
Q

why can mitochondrial reduction of oxygen during ATP production lead to ROS production? what is supposed to happen

A

it usually ends up in H2O but a small % ends up as ROS

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39
Q

what is the fenton reaction (Definition)

A

reduction of H2O2 by transition metal ions

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40
Q

what is redox cycling

A

quinones and bipyridyls contributing to a never ending process of ROS production

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41
Q

what is the specific reaction i the Fenton reaction

A

HOOH + transition state metal (Fe Cu Mn Cr Ni) –> HOOH- –> OH* + OH-

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42
Q

what does superoxide dismutase do

A

turn superoxide anion (O2*-) into hydrogen peroxide

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43
Q

what happens if superoxide anion (O2-) and NO join

A

it forms peroxynitrite (ONOO-)

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44
Q

what can happen to peroxynitrite (ONOO-)

A

spontaneous rxn with CO2 to form nitrosoperoxy carbonate (ONOOCO-2)

45
Q

what happens to nitrosoperoxy carbonate (ONOOCO-2)

A

spontaneous cleavage into NO2* and CO3* (both damaging)

46
Q

what happens after the fenton reaction to HOOH-

A

homolytic cleavage into OH* (damaging) and OH- (not reactive)

47
Q

what are 2 example of toxification paths from O2*-

A

fenton reaction to OH* then the peroxynitrite side to make NO2* and CO3-*

48
Q

what does redox cycling generate

A

free radicals

49
Q

how do drugs contribute to redox cycling (paraquat, doxorubicin, nitrofurantoin)

A

they pick up electron from cofactor then donate it to oxygen

50
Q

what are 2 things that contribute to toxicity in redox cycling

A

the creation of ROS but also the running out of cofactors (like NADPH)

51
Q

what enzyme helps out in redox cycling

A

P450 reductase

52
Q

what is an example reaction of what P450 reductase can do

A

NADH + H+ –> NAD+

53
Q

what are 3 drug examples that create redox cycling

A

paraquat, doxorubicin, nitrofurantoin

54
Q

what is paraquat

A

a herbicide

55
Q

what kind of bad thing does paraquat do

A

redox cycling

56
Q

what are 3 targets of ROS

A

lipids proteins DNA

57
Q

what does ROS do to lipids (1 word)

A

peroxidation

58
Q

what is peroxidation (general)

A

breakdown of lipids into small and reactive fragments

59
Q

what are 3 things that ROS can do to proteins

A

protein carboneyls, crosslnks, fragmentation

60
Q

what are protein carbonyls

A

aldehydes and ketone formation as a result of modification by lipid fragments

61
Q

what are 3 things that ROS can do to DNA

A

oxidation of nucleobases, single strand breaks, crosslinks

62
Q

what is peptide fragmentation

A

when the backbone of peptide is attacked

63
Q

what are the main product name formed with lipid peroxidation

A

α,β-unsaturated aldehydes

64
Q

what are 2 examples of α,β-unsaturated aldehydes

A

4-ONE and 4-HNE

65
Q

peroxidation of what causes the formation of 4-ONE and 4-HNE

A

omega-6 polyunsaturated fats, linoleic acid and arachidonic acid

66
Q

What do 4-ONE and 4-HNE do in cell and why (simple)

A

damage a lot because they are reactive electrophiles

67
Q

why are 4-ONE and 4-HNE electrophiles (structurally, where in molecule is the electrophilicity)

A

carbonyl group + hydroxy or ketone results in electron poor environment centered around the 2-3 double bond (C3 become strongly electrophilic)

68
Q

what often happens to C3 in reactive aldehydes and by who

A

nucleophilic attack by the side chains of cysteine, lysine, histidine from the nucleophile N/S

69
Q

why are cysteine, lysine, histidine able to do nucleophilic attack on C3

A

because of their nitrogens and sulfers

70
Q

what produces 4-ONE and 4-HNE (generally)

A

lipid peroxidation

71
Q

are 4-ONE and 4-HNE reactive

A

highly yes

72
Q

can 4-ONE and 4-HNE act at a distance and why

A

yes because they are amphiphilic so can cross lipid bilayers and attack cytoplasmic proteins at site distant from origin

73
Q

can adjacent cells not involved in lipid peroxidation be damaged by 4-ONE and 4-HNE

A

yes because they are amphiphilic so can travel (cross bilayers)

74
Q

what is the main detoxification pathway for 4-ONE and 4-HNE

A

conjugation with glutathione

75
Q

do 4-ONE and 4-HNE have formal charges

A

no, they are amphililic

76
Q

what are the main amino acid targets for covalent bonding of lipid aldehyde

A

cysteine, lysine, histitine

77
Q

what results in 4-ONE or 4-HNE binding to a protein

A

introduction of a free carbonyl group

78
Q

what is michael addition

A

conjugation of α,β-unsaturated aldehydes to cysteine, lysine or histidine via nucleophilic attack on C3 of the unsaturation aldehyde

79
Q

what is a schiff base

A

conjugation of α,β-unsaturated aldehydes to lysine residues in proteins via nucleophilic attack by amino group of lysine on the aldehyde carbon of α,β-unsaturated aldehydes

80
Q

where does the nucleophilic attack happen in michael addition

A

C3 of α,β-unsaturated aldehyde

81
Q

where does the nucleophilic attack happen in schiff base

A

aldehyde carbon of α,β-unsaturated aldehyde

82
Q

which amino acids are involved in michael addition

A

cyteine, lysine or histidine

83
Q

which amino acids are involved in schiff base

A

lysine

84
Q

what happens with a schiff base formation with lysine (like what forms)

A

pyrrole ring! carbons 1 and 2 fold in on themselves and cyclize

85
Q

what can form with michael addition

A

a lactol if it cyclizes

86
Q

what % of all carbonyl adducts does michael adduction account for

A

80%

87
Q

what % of all carbonyl adducts does schiff base adduction account for

A

20%

88
Q

how can a cyclized michael adduct cause protein crosslinking

A

the hydroxyl group is reactive so it can react again, like with a nitrogen on lysine and cause crosslinking

89
Q

what are the 2 pathways to crosslinking of 4-HNE modification of protein

A
  • no cyclization michael adduct + schiff base

- 4-HNE followed by michael cyclization then crosslink

90
Q

how does the non cyclized michael protein crosslink happen (3 steps)

A
  • 2 nucleophilic residues to start with
  • one gets michael adduct (not cycled)
  • schiff base crosslink
91
Q

how does the cyclized Michael protein crosslink happen (1 step, name reaction and how product forms)

A
  • cyclized michael adduct, add Lys

- then the OH groups reacts and crosslinks with new protein

92
Q

what is the net result of protein crosslinking (simple)

A

dysfunctional proteins

93
Q

what functional groups seem to be especially sensitive to reactive aldehyde modification and why

A

sulfhydryl groups (SH) because the microenvironment of some active sites appear to make them so sensitive (and they are numerous in many active sites of enzymes)

94
Q

what does 4-HNE and 4-ONE do to cell life (which is more toxic)

A

it causes cell death, with ONE seeming more toxic

95
Q

what is apoptosis

A

a type of cell death characterized by an ordered, programmed process

96
Q

how does 4-HNE do to apoptosis

A

induce the process by interfereing with a protein that normallyinhibits apoptosis

97
Q

where does bcl-2 reside

A

in mitochondrial membrane

98
Q

what is the normal role of bcl-2

A

anti-apoptosis

99
Q

how dies bcl-2 prevent apoptosis

A

inhibits the opening of a mitochondrial channel that releases proteins into the cytoplasm which are a signal for apoptosis to commence

100
Q

what controlls bcl-2 gene expression

A

transcription factor NF-KB

101
Q

what are p50 and p65

A

part of NF-KB

102
Q

what holds NF-KB in the cytoplasm

A

IBK (inhibitor of KB)

103
Q

how does 4-HNE effect NF-KB pathway

A

it inhibits IKB degradation, keeping NF-KB bound and inactive (doesnt go to nucleus and do anti-apoptotic stuff)

104
Q

how does 4-HNE also effect bcl-2 (last point on slide)

A

inactivation by increasing ability of IKK to phosphorylate BCL-2

105
Q

what does IKK do

A

phosphorylates Bcl-2 (to inactivate it)

106
Q

what happens when Bcl-2 is phosphorylated

A

it becomes inactive

107
Q

if 4-HNE increases apoptosis, why is it linked to cancer?

A

4-HNE has pro or anti cancer effects depending on cell type and the modified targets (sometimes 4-HNE suppresses tumour suppressor proteins)

108
Q

what does linoleic acid peroxidation form

A

4-ONE

109
Q

what does arachidonic acid peroxidation form

A

4-HNE

pmcol 303 (25 decks)

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