Multiple choice part Flashcards
(120 cards)
1
Q
Oxidative stress is counteracted by
A
Antioxidants such as vitamin E
2
Q
Dioxin is toxic for mammals because
A
…it leads to alterations in gene transciption
3
Q
Are initiators genotoxic?
A
Yes
4
Q
Are promotors genotoxic?
A
No
5
Q
What is a frameshift mutation?
A
Insertion or deletion of base pairs (not multiples of 3) into a gene sequence that means the gene is read differently, codons change.
6
Q
Why is carbon monoxide toxic?
A
It binds to FeII in hemoglobin and blocks oxygen transport
7
Q
Why is fluoroacetic acid toxic?
A
It forms fluoroacetyl-CoA and enters the citric acid cycle, but when fluorocitric acid is formed this can not be further reacted and then acts as a citric acid cyle
inhibitor
8
Q
What is an antagonistic effect?
A
Antagonism is when one compound counteracts the
bilogical response (eg toxicity) of another
compound
9
Q
What does teratogenic mean?
A
A compound that has effect on the reproductive system
and/or embryonic development
10
Q
Explain how a small molecule can be allergenic. Give one example of such a compound.
A
A small molecule that reacts with a biomolecule (ie a protein) in such a way that the covalently modified protein is
recognized by the immune system as non-self. Example are phthalic anhydrides, formaldehyde, and isocyanates
11
Q
One special chemical reactivity is associated with most genotoxic carcinogens. Which?
A
Electrophilicity (Electrophiles react with nucleophilic N in DNA bases.)
12
Q
Give two different examples of compounds having electrophilic reactivity
A
Methyl iodide (primary halide), acrolein (Michael acceptor), hydroxyl amine conjugated with OSO3.
13
Q
What structural features do you associate with anti-oxidant properties?
A
Phenolic OH
14
Q
Why do phenols have antioxidant properties?
A
Phenols form relatively stable radicals upon loosing a H atom to a radical, because phenol radicals are
resonance stabilised (5p). Further conjugation of the phenol ring with for example alkenes increases the resonance
stabilization (as in Rosemarinic acid)
15
Q
What is BBB?
A
Blood brain barrier. Molecules of medium polarity can cross BBB but very slowly.
16
Q
What is the purpose of metabolism?
A
increase water-
solubility and facilitate excretion via the kidney, hence possibly lowering toxic effects.
17
Q
Are epoxides electrophiles
A
Yes
18
Q
Is sulphated hydroxyl amine an electrophile?
A
Yes
19
Q
How do we write glucuronidation for short?
A
GA
20
Q
How do we write glutathione for short?
A
GSH
21
Q
Phase II reactions
A
glucuronidation (GIA)
sulfation (OSO3)
amino acid conjugation (NH2CH2COOH)
22
Q
What is plasma?
A
Plasma is the largest part of your blood. It makes up more than half (about 55%) of its overall content. When separated from the rest of the blood, plasma is a light yellow liquid. Plasma carries water, salts and enzymes.
The main role of plasma is to take nutrients, hormones, and proteins to the parts of the body that need it. Cells also put their waste products into the plasma. The plasma then helps remove this waste from the body. Blood plasma also carries all parts of the blood through your circulatory system.
23
Q
Sulfated hydroxylamines are …
A
… electrophiles and often carcinogenic
24
Q
NO2 groups on benzene gets reduced to…
A
nitroso —> hydroxylamines —> amines
25
What can hydroxylamines be conjugated with and how does it affect excretion?
Hydroxylamines will likely be conjugated with sulfate and/orglucuronic acid, which will increase water solubility and
kidney excretion
26
What is methaemoglobinemia?
```
haemoglobin Fe(II) is oxidized to Fe(III) and cannot transport O2
anymore
```
27
What does a hemiacetal spontaneously fragment into?
an aldehyde and an alcohol leading to cleavage into two parts
28
Why is diethylene glycol toxic?
It can be metabolised (oxidation and cleavage) into two molecules of oxalic acid per molecule diethylene glycol. Oxalic acid causes acidosis which is fatal
29
What is an epigenetic carcinogen?
Something that is carcinogenic, but does not chemically change DNA and instead act via other mechanisms
30
What is a metabolic activation?
A metabolic transformation that makes a compound more toxic
31
Why is carbon monoxide toxic?
Binds strongly to Fe2+ in hemoglobin and blocks oxygen transport
32
What is logP?
P is Octanol/Water partition coefficient.
The partition coefficient measures how hydrophilic ("water-loving") or hydrophobic ("water-fearing") a chemical substance is. Partition coefficients are useful in estimating the distribution of drugs within the body. Hydrophobic drugs with high octanol-water partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells. Conversely, hydrophilic drugs (low octanol/water partition coefficients) are found primarily in aqueous regions such as blood serum.
33
What is HBA?
Hydrogen bond acceptor
34
What is HBD
Hydrogen bond donor
35
How does hydroxylamine cause methemoglobinemia?
The metabolized aromatic hydroxylamine can react with the O2 that binds to Fe(II) of hemoglobin, which generates
H2O2 that will further oxidize Fe(II) to Fe (III) so it will lose its ability to transport oxygen
36
Hydroxyamines (R-NH-OH) can be converted into an electrophile and thus cause damage to human bodies,
after being conjugated (Phase 2 reaction) with
sulfate
37
Which halogenated carboxylic acids cannot undergo oxidative dehydrohalogenation catalyzed by
cytochrome P450?
Tertiary halogenated carboxylic acid (carboxylic acid with three Cl as R group R-COOH
38
Give an example of a compound that can NOT be absorbed into the cells by diffusion
NaCl
39
Ethanol can bind to GABAA receptor (an inhibitory neurotransmitter) in CNS, which may cause muscle
paralysis. This phenomenon is
specific toxicity
40
The meaning of LD10 is
the dose where 10% of the tested subjects die.
41
Phenols with electron withdrawing groups can cause death because they can
inhibit of the ATP production
42
Which of the following is NOT commonly considered as genotoxic carcinogens?
a) Electrophiles
b) ROS (radicals)
c) Endocrine disruptors
d) Metal ions
c) Endocrine disruptors
43
```
In the table below, which compound has the highest possibility to pass the blood brain barrier? (Note, P is Octanol/Water partition coefficient)
Molecular weight (g/mol) / logP
(A) 130 / -0.95
(B) 221 / 0.06
(C) 249 / 2.69
(D) 657 / 2.80
```
(C) 249 / 2.69
| Small enough to be absorbed and still high P partition coefficient
44
The major toxic effect of hydrogen cyanide exposure is
a) lung damage
b) hemoglobin alteration
c) hemolysis of red blood cells
d) inhibition of mitochondrial respiration
e) acidosis
d) inhibition of mitochondrial respiration
45
Organophosphorus compounds (e.g. Sarin, Novichok) are toxic to nerve system, because they can
a) block the release or reabsorption of neurotransmitters
b) bind to the receptor and stimulate it (agonists)
c) bind to the receptor but not stimulate it (antagonists)
d) block the ion channels
e) inhibit the enzyme that can inactivate the neurotransmitters
e) inhibit the enzyme that can inactivate the neurotransmitters
46
The most important Phase 2 metabolic reactions of xenobiotics with epoxy groups is
a) conjugation with glucuronic acid
b) conjugation with glycine
c) conjugation with glutathione
d) conjugation with sulfate
c) conjugation with glutathione
47
Which of the following alkyl halides cannot undergo oxidative dehydrohalogenation catalyzed by cytochrome
P450?
a) Chloroethane (ethyl chloride)
b) Dichloromethane (methylene chloride)
c) Isopropyl chloride
d) tert-Butyl chloride
d) tert-Butyl chloride
48
Chronic exposure to which of the following hydrocarbons can irreversibly damage the proteins in the
peripheral nervous system and testicle tissues?
a) Pentane
b) Hexane
c) Heptane
d) Octane
Hexane
49
Which of the following compounds is the most toxic?
a) Benzyl chloride
b) Benzyl bromide
c) Benzyl iodide
d) Chlorobenzene
Benzyl iodide
50
Ligands binding to central nervous system (CNS) receptors belong to
a) Specific toxicity
b) Non-specific toxicity
c) Selective toxicity
d) Non-selective toxicity
Non-specific
51
It is recommended that fentanyl should not be taken together with ethanol. Please explain why
This is the cocktail effect (synergistic effect) of ethanol and fentanyl. Ethanol can induce the production of
P450, which is used for the metabolic activation of aromatic amines to hydroxyamines, and benzene to
benzene oxides.
52
An electrophile can have:
A good leaving group that the nucleophile can
replace
A strained ring with a polarised bond that the
nucleophile can attack
A polarised unsaturation conjugated with an
electron-withdrawing group (Michael acceptors)
A polarised unsaturation with leaving group on
the positively charged atom
53
What happens in nucleophilic substitution?
A good leaving group gets replaced by a nucleophile
54
General rule of leaving groups
The weaker base (corresponding to a strong acid) the leaving group is, the better!
55
The rate of SN2 reactions depends on:
The leaving group
The steric hindrance of electrophile
The nucleophile
The conditions for the reaction (pH, temperature…)
56
What is a Michael acceptor?
Unsaturation conjugated with an electron-withdrawing group
| that is polarised and has a positive charge on the β-carbon
57
Michael acceptors can be...
Nitro NO2
Nitroso N=O
Nitril
Sulfoxid
58
A carboxylic acid halide is an...
electrophile
59
Important factors for reactivity;
```
Electronic factors
– Inductive
– Resonance
Steric factors
Chemical environment
Metabolism
```
60
What can be transported by diffusion through cell membranes?
The efficiency depends on the size of the molecule:
• Small (H2O, MeOH) molecules can pass easily
• Large (M<1000) lipophilic molecules can pass
• Large hydrophilic molecules (e.g. glucose) cannot pass
• Ions cannot pass
61
What is facilitated diffusion?
• Facilitated diffusion is a process involving a membrane
protein and specific recognition
• Cannot concentrate a compound on one side
• Important for hydrophilic molecules that are not sufficiently
small
62
Which areas should we focus on in absorption of chemicals?
Lungs
Intestinal tract
Skin
63
Absorption in the lungs
Gases, small particles and droplets can reach alveoli, where there is no cilia
Quartz, asbestos will stimulate cell division, forming new cell layers, and hindering the
oxygen diffusion (silicosis, asbestosis)
64
Absorption in the gut/intestines
```
• The gastrointestinal tract is a tube that
transverses the body (appr. 8 m long!)
• Not many compounds can escape
• Small, hydrophobic molecules can be
absorbed by diffusion
• Hydrophilic molecules or ions can be
absorbed by facilitated diffusion or ion
channels
• Large molecules (e.g. proteins) can be
absorbed by endocytosis
• Insoluble molecules are poorly absorbed
```
65
Absorption through the skin
• The skin is a physical barrier that protects us and maintain our body fluid.
• The chemical must penetrate (by diffusion) the epidermis before reaching
the blood vessels in the dermis
• Small, nonpolar molecules can pass easily (e.g. MeOH, HgMe2)
• DMSO can increase the permeability of skin
66
Distribution of xenobiotics depends on...
Solubility
• Lipophilic compounds distributed to lipophilic tissues
• Hydrophilic compounds distributed to blood, eyeballs, muscles
• Pb, F can deposite in bones
```
Biological barriers (e.g. blood-brain barrier, “BBB”)
• Water, glucose can pass
• Small lipophilic molecules can pass
• Large, hydrohilic molecules or ions cannot pass
```
Transformations/Conversions
67
Which three excretion routes should we focus on?
Via the kidneys
Via the liver
Via the lungs
68
The major excretion routes for
| hydrophilic, small molecules is...
via the kidney
69
What extends the time that an exogenous chemical stays in the body?
Enterohepatic circulation
70
What can be excreted by the lungs?
Volatile compounds can go
from the blood to the air in the
lungs and be exhaled
* Diethyl ether (major route
* Ethanol (small portion)
71
Metabolism of xenobiotics is also called...
Biotransformation, detoxification
72
What is the goal of metabolism?
To make use of a compound or to facilitate its excretion
73
What is an important enzyme in metabolism phase I
Cytochrome P450
74
In an oxidation, does P450 make use of NADPH+ + H+ ?
Yes
75
Enzymes (and vitamins) to degrade ROS
```
Catalse
Superoxide dismutase
Glutathione peroxidase G-SH
Vitamine C
Vitamine E
```
76
Phase I oxidations
1. Epoxidation of alkenes and aromatics
2. Carbon hydroxylation
3. Heteroatom oxidation
4. Oxidation of alcohols and aldehydes
77
Can epoxidations of alkenes be classified as a metabolic activation?
Yes, it becomes an electrophile
78
Carbon hydroxylations can happen next to...
1) unsaturations
| 2) heteroatoms (alfa hydroxylation)
79
Oxidative dealkylation and oxidative dehydrohalogenation are examples of...
```
Carbon hydroxylations
(OH binds in next to heteroatom or halogen X and then it rearranges to a doublebound oxygen and RX leaves)
```
80
Can nitriles and thiols behave like halogens, and be metabolized in a
similar fashion as “oxidative dehydrohalogenation”?
Yes
81
Oxidation of primary, secondary and tertiary alcohol
Primary become aldehydes
Secondary become ketones
Tertiary alcohols cannot be oxidized to aldehydes or
ketones, but can be oxidize on the β carbon (Phase I), or
conjugation with glucuronic acid (Phase II)
82
Phase I reductions:
1. Reduction of ketones and aldehydes
2. Reduction of oxidised heteroatoms
3. Reductive dehalogenation
83
Phase I hydrolyses
Hydrolysis of epoxides
| Hydrolysis of esters and amides
84
Hydrolysis of esters uses ... and produces ...
esterase and produces carboxylic acid and alcohol (cleaves bond)
85
Hydrolysis of amide uses ... and produces ...
amidase and produces carboxylic acid and amine
86
Phase II reactions
Conjugation with glutathione
Conjugation with sulphate
Conjugation with glucuronic acid
Conjugation with amino acids
87
Conjugation with glutathione is for...
electrophiles
88
Conjugation with sulphate is mostly for
* Primarily for alcohols and phenols
| * Fast, but low capacity
89
Conjugation with glucuronic acid (GA) for...
Conjugation with alcohols, phenols, carboxylic acids,
| hydroxyamines, aromatic amines, sulfonamides
90
Conjugation with amino acids
Primarily for carboxylic acids (with glycine forms hippuric acid)
91
Ethylene glycol can be metabolised to
oxalic acid
92
How are minor pH-variations are handled
buffers in blood (HCO3–, HPO42–, H+)
increased CO2 exhalation
increased acid excretion via urine
93
Which toxicity mechanisms exist?
```
Lipid peroxidation
Acidosis
Energy production in cells
Nerve toxic compounds
Allergy causing compounds
Teratogenic compounds
Genotoxic compounds
Carcinogens
```
94
Toxicity related to energy production in cell, inhibition of any of the following processes:
Respiratory chain
Oxygen transport
Citric acid cycle
Oxidative phosphorylation
95
What makes flouracetic acid toxic?
Fluoroacetic acid resembles acetic acid and interferes with citric acid cycle. The enzyme converting citric acid into cis-actonic acid is blocked by flouracetic acid
96
Uncouplers target...
production of ATP
97
Toxic effects on nerve system
(1) Block the reuptake or reabsorption of neurotransmitters
(2) Bind to the receptor and stimulate it (agonists)
(3) Bind to the receptor but not stimulate it (antagonists)
(4) Block the ion channels
(5) Inhibit the enzyme that can inactivate the neurotransmitters
98
Allergy inducing compounds
• Antigens are big molecules (M>5000), but small molecules (called
haptens) can bind to endogenous molecules (e.g. proteins) to stimulate
the immune system.
• Electrophile (or pre-electrophiles), radical-generation molecules, metal
ions can be potential allergens
99
What is a teratogenic compound? Give an example
One that is tovic to reproductive system or embryo
Example:
thalidomide (neurosedyn) that blocks angiogenesis during day 23-38
100
What are oncogenes?
individual genes that, when introduces
in healthy cells, make the cell loose control over cell
division
101
What are protooncogenes?
exact (almost) copies of
oncogenes, present in all of our cells. They normally
carefully regulate and code for proteins stimulating cell
division.
102
What are antioncogenes?
genes coding for proteins inhibiting
| cell division.
103
What is a growth factor?
Proteins stimulating cell division (normally expressed
| e.g. platelets in injured tissue)
104
What are protein kinases?
• Enzymes that phosphorylates other proteins (e.g.
tyrosine), affecting the proteins’ functions.
• Human genome encodes 538 protein kinases, many of
which are associated cancer initiation and progression.
• Inhibitors of protein kinases as cancer treatment
105
What are oncogenes' proteins called?
Protein kinases and growth factors
106
Cancer can form when...
protooncogenes are activated or antioncogenes are inactivated
107
How are protooncogenes activated?
• Activation of the transcription/translation
• Point mutations in a protooncogene or in genes involved in
their regulation
• Chromosome mutations moving a protooncogene from an
inactive part to an active part of the genome
108
How are antioncogenes inactivated?
• Point mutations in an antioncogene or in genes regulating it
• Chromosome mutations moving an antioncogene from an
active to an inactive part of the genome
109
What are PAHs?
Polycyclic aromatic hydrocarbons
110
Examples of fuels and exhausts
```
Petrol
Diesel
Methane
Ozone
Nitrogen oxides
Sulfur oxides
Carbon monoxide
Carbon dioxide
(Hydrogen cyanide, Hydrogen sulfide)
```
111
Examples of pesticides and humanicides
```
Moth balls
DDT
Aldrin/dieldrin
Hexachlorobenzene
Phenoxy acids
Disulfiram/tiram
```
112
What are moth balls made of?
Naphthalene
113
What is the toxicity of hydroquinone?
It is a Michael acceptor and can bind to DNA
114
What makes DDT toxic?
DDT is a persistent nerve poison that very slowly is
metabolised in man. Major metabolites are DDD and DDE.
Structurally similar to DES, a synthetic hormone, and one of
the toxic effects is on the endocrine system.
115
What are dioxins?
Dioxins are polychlorinated dibensofurans (PCDFs) and
dibensodioxins (PCDDs)
They are formed by pyrolysis of chlorinated organic
materials.
116
What is carbaryl?
Carbaryl is an insecticide and a nerve poison, which acts by
blocking acetylcholine esterase. It is made in a reaction
involving methyl isocyanate
117
What is nitrite and how it is toxic?
Nitrite is a preservative that in high concentrations will damage
the blood. It can react with amines at pH 1 to yield potentially
carcinogenic nitrosamines.
118
What is nicotine?
```
Nicotine is a nerve poison,
a stimulant in low
concentrations but deadly
in higher. It is nitrosated to
carcinogenic nitroso-
amines.
```
119
What is acryl amide?
```
s toxic
to the nervous
system. It is also
weakly genotoxic, a
poor Michael
acceptor, but it can
be epoxidised to an
electrophilic
compound
```
120
Why is hexane toxic?
```
Hexane is only
slowly oxidised, and
the toxic metabolite
is the dione.
This reacts with
primary amines to
form pyrrole
derivatives, and
destroys peripheral
nerve cells.
```
