Multiple choice part Flashcards
Oxidative stress is counteracted by
Antioxidants such as vitamin E
Dioxin is toxic for mammals because
…it leads to alterations in gene transciption
Are initiators genotoxic?
Yes
Are promotors genotoxic?
No
What is a frameshift mutation?
Insertion or deletion of base pairs (not multiples of 3) into a gene sequence that means the gene is read differently, codons change.
Why is carbon monoxide toxic?
It binds to FeII in hemoglobin and blocks oxygen transport
Why is fluoroacetic acid toxic?
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
What is an antagonistic effect?
Antagonism is when one compound counteracts the
bilogical response (eg toxicity) of another
compound
What does teratogenic mean?
A compound that has effect on the reproductive system
and/or embryonic development
Explain how a small molecule can be allergenic. Give one example of such a compound.
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
One special chemical reactivity is associated with most genotoxic carcinogens. Which?
Electrophilicity (Electrophiles react with nucleophilic N in DNA bases.)
Give two different examples of compounds having electrophilic reactivity
Methyl iodide (primary halide), acrolein (Michael acceptor), hydroxyl amine conjugated with OSO3.
What structural features do you associate with anti-oxidant properties?
Phenolic OH
Why do phenols have antioxidant properties?
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)
What is BBB?
Blood brain barrier. Molecules of medium polarity can cross BBB but very slowly.
What is the purpose of metabolism?
increase water-
solubility and facilitate excretion via the kidney, hence possibly lowering toxic effects.
Are epoxides electrophiles
Yes
Is sulphated hydroxyl amine an electrophile?
Yes
How do we write glucuronidation for short?
GA
How do we write glutathione for short?
GSH
Phase II reactions
glucuronidation (GIA)
sulfation (OSO3)
amino acid conjugation (NH2CH2COOH)
What is plasma?
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.
Sulfated hydroxylamines are …
… electrophiles and often carcinogenic
NO2 groups on benzene gets reduced to…
nitroso —> hydroxylamines —> amines
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
What is methaemoglobinemia?
haemoglobin Fe(II) is oxidized to Fe(III) and cannot transport O2 anymore
What does a hemiacetal spontaneously fragment into?
an aldehyde and an alcohol leading to cleavage into two parts
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
What is an epigenetic carcinogen?
Something that is carcinogenic, but does not chemically change DNA and instead act via other mechanisms
What is a metabolic activation?
A metabolic transformation that makes a compound more toxic
Why is carbon monoxide toxic?
Binds strongly to Fe2+ in hemoglobin and blocks oxygen transport
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.
What is HBA?
Hydrogen bond acceptor
What is HBD
Hydrogen bond donor
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
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
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
Give an example of a compound that can NOT be absorbed into the cells by diffusion
NaCl
Ethanol can bind to GABAA receptor (an inhibitory neurotransmitter) in CNS, which may cause muscle
paralysis. This phenomenon is
specific toxicity
The meaning of LD10 is
the dose where 10% of the tested subjects die.
Phenols with electron withdrawing groups can cause death because they can
inhibit of the ATP production
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
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
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
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
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
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
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
Which of the following compounds is the most toxic?
a) Benzyl chloride
b) Benzyl bromide
c) Benzyl iodide
d) Chlorobenzene
Benzyl iodide
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
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.
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
What happens in nucleophilic substitution?
A good leaving group gets replaced by a nucleophile
General rule of leaving groups
The weaker base (corresponding to a strong acid) the leaving group is, the better!
The rate of SN2 reactions depends on:
The leaving group
The steric hindrance of electrophile
The nucleophile
The conditions for the reaction (pH, temperature…)
What is a Michael acceptor?
Unsaturation conjugated with an electron-withdrawing group
that is polarised and has a positive charge on the β-carbon
Michael acceptors can be…
Nitro NO2
Nitroso N=O
Nitril
Sulfoxid
A carboxylic acid halide is an…
electrophile
Important factors for reactivity;
Electronic factors – Inductive – Resonance Steric factors Chemical environment Metabolism
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
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
Which areas should we focus on in absorption of chemicals?
Lungs
Intestinal tract
Skin
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)
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
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
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
Which three excretion routes should we focus on?
Via the kidneys
Via the liver
Via the lungs
The major excretion routes for
hydrophilic, small molecules is…
via the kidney
What extends the time that an exogenous chemical stays in the body?
Enterohepatic circulation
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)
Metabolism of xenobiotics is also called…
Biotransformation, detoxification
What is the goal of metabolism?
To make use of a compound or to facilitate its excretion
What is an important enzyme in metabolism phase I
Cytochrome P450
In an oxidation, does P450 make use of NADPH+ + H+ ?
Yes
Enzymes (and vitamins) to degrade ROS
Catalse Superoxide dismutase Glutathione peroxidase G-SH Vitamine C Vitamine E
Phase I oxidations
- Epoxidation of alkenes and aromatics
- Carbon hydroxylation
- Heteroatom oxidation
- Oxidation of alcohols and aldehydes
Can epoxidations of alkenes be classified as a metabolic activation?
Yes, it becomes an electrophile
Carbon hydroxylations can happen next to…
1) unsaturations
2) heteroatoms (alfa hydroxylation)
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)
Can nitriles and thiols behave like halogens, and be metabolized in a
similar fashion as “oxidative dehydrohalogenation”?
Yes
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)
Phase I reductions:
- Reduction of ketones and aldehydes
- Reduction of oxidised heteroatoms
- Reductive dehalogenation
Phase I hydrolyses
Hydrolysis of epoxides
Hydrolysis of esters and amides
Hydrolysis of esters uses … and produces …
esterase and produces carboxylic acid and alcohol (cleaves bond)
Hydrolysis of amide uses … and produces …
amidase and produces carboxylic acid and amine
Phase II reactions
Conjugation with glutathione
Conjugation with sulphate
Conjugation with glucuronic acid
Conjugation with amino acids
Conjugation with glutathione is for…
electrophiles
Conjugation with sulphate is mostly for
- Primarily for alcohols and phenols
* Fast, but low capacity
Conjugation with glucuronic acid (GA) for…
Conjugation with alcohols, phenols, carboxylic acids,
hydroxyamines, aromatic amines, sulfonamides
Conjugation with amino acids
Primarily for carboxylic acids (with glycine forms hippuric acid)
Ethylene glycol can be metabolised to
oxalic acid
How are minor pH-variations are handled
buffers in blood (HCO3–, HPO42–, H+)
increased CO2 exhalation
increased acid excretion via urine
Which toxicity mechanisms exist?
Lipid peroxidation Acidosis Energy production in cells Nerve toxic compounds Allergy causing compounds Teratogenic compounds Genotoxic compounds Carcinogens
Toxicity related to energy production in cell, inhibition of any of the following processes:
Respiratory chain
Oxygen transport
Citric acid cycle
Oxidative phosphorylation
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
Uncouplers target…
production of ATP
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
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
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
What are oncogenes?
individual genes that, when introduces
in healthy cells, make the cell loose control over cell
division
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.
What are antioncogenes?
genes coding for proteins inhibiting
cell division.
What is a growth factor?
Proteins stimulating cell division (normally expressed
e.g. platelets in injured tissue)
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
What are oncogenes’ proteins called?
Protein kinases and growth factors
Cancer can form when…
protooncogenes are activated or antioncogenes are inactivated
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
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
What are PAHs?
Polycyclic aromatic hydrocarbons
Examples of fuels and exhausts
Petrol Diesel Methane Ozone Nitrogen oxides Sulfur oxides Carbon monoxide Carbon dioxide (Hydrogen cyanide, Hydrogen sulfide)
Examples of pesticides and humanicides
Moth balls DDT Aldrin/dieldrin Hexachlorobenzene Phenoxy acids Disulfiram/tiram
What are moth balls made of?
Naphthalene
What is the toxicity of hydroquinone?
It is a Michael acceptor and can bind to DNA
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.
What are dioxins?
Dioxins are polychlorinated dibensofurans (PCDFs) and
dibensodioxins (PCDDs)
They are formed by pyrolysis of chlorinated organic
materials.
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
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.
What is nicotine?
Nicotine is a nerve poison, a stimulant in low concentrations but deadly in higher. It is nitrosated to carcinogenic nitroso- amines.
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
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.
