Exercises Flashcards
How can you get in contact with carbon monoxide and why is it toxic?
Incomplete combustion, photochemical reactions in troposphere,
metabolism of hemoglobin, metabolism of xenobiotics
(dichloromethane)
It binds to hemoglobin and blocks the oxygen transfer
How can you get in contact with cyanides and why is it toxic?
ccidentally uptake of cyanide salts, e.g., NaCN or KCN.
Metabolism of nitriles (Bitter almond, crushed flax seeds, improperly
cooked cassava)
It binds to the heme group of cytochrome c oxidase in mitochondria,
and thus blocks the energy transfer (respiration chain)
How can you get in contact with hydrogen sulfide and why is it toxic?
Microbial degradation of organic matters under anaerobic conditions,
swamps and sewers.
Volcano gases, natural gas, thermal springs, human metabolism
Similar as HCN, it binds to the heme group of cytochrome c oxidase
in mitochondria, and thus blocks the energy transfer
What is the toxicity mechanism of 4-fluorobutyl acetate?
It metabolizes into fluoroacetic acid, which then blocks the citric acid
cycle
What is the toxicity mechanism of 1-chloroprop-2-yl butyrate?
The major risk comes from the metabolized α-chloroketone, which is a
strong alkylating agent/electrophile.
How does Dinoseb disturb the cell’s energy production?
It’s an uncoupler, which blocks the production of ATP.
Where do you find nitrite? How can it give rise to toxic effects?
Processed meats, bacons, sausages, fish
Bacterial conversion from nitrate
It can react with amines in the stomach to form carcinogenic N-
nitrosamines
It can oxidize Fe(II) to Fe(III) in the hemoglobin to cause
methemoglobinemia (can be used to treat cyanide poisoning)
Describe the mechanism for how aromatic amines give rise to
methaemoglobinemia.
It can be metabolized into hydroxyamines, which can then oxidize
Fe(II) to Fe(III) in the hemoglobin to cause methemoglobinemia
Hydroxylamines can also generate radicals and electrophilic species
after further metabolism.
What are base pair substitutions, frame-shift mutations, and chromosome
mutations?
What are the downsides of antioxidants?
Phenolics can stabilise radicals but sometimes can act as prooxidants. Some can decrease our bodyguard glutathione, decrease glutathione S transferase activity
What downside of oxidation can happen, and when using p450?
Generating ROS
What are the four types of oxidation?
Alkenes and aromatics (double bonds) can be epoxides
Carbon hydroxylation (not all carbons can be)
Heteroatom oxidation
Oxidation of alcohol and aldehydes
Which enzyme used to oxidise double bond ?
p450 (FeV centre in enzyme)
If you see a double bond what should you think?
Epoxidation
This course we can assume that if it is possible then it will happen, we don’t have to think about what’s more likely
That’s right
Epoxides are…
electrophilic
What is metabolic activation
That’s the molecule becomes toxic when metabolised
benzene can be epoxidised and then be oxidised to
phenol
Not all CH bonds can undergo hydroxylation, which ones can?
Using P450
- allylic hydrogen, the CH bond is connected to a double bond (next to unsaturation)
- next to heteroatom (alfa hydroxylation)
Carbon bound to heteroatom on either side is called a
hemiacetal
Hemiacetal (carbon bound to two heteroatoms) is unstable and will form two products, which?
aldehyde and alcohol/amine/thiol/HCl
What is oxidative dehydrohalogenation?
Carbon hydroxylation when carbon bound to Cl and O
What is oxidative dealkylation?
Carbon hydroxylation when carbon bound to oxygen and oxygen/sulfur/nitrogen, the hydroxylation forms a hemiacetal which is unstable and forms aldehyde and alcohol/amine/tiol
In oxidative dehydrohalogenation, what happens to primary, secondary and tertiary halides?
primary forms alcohol and HCl
secondary forms ketone and HCl
tertiary has no Alfa carbon so no reaction
chloroform can be metabolised into
phosgene
there is a synergistic effect between chloroform and which compound?
ethanol
Some groups behave like halogens, what are they?
acetonitrile forms formaldehyde and hydrogen cyanide
methane thiol
beta oxidation of fatty acids
beta carbon to carboxylic acid is oxidised and fatty acid is cleaved into acetic acid and a shorter acid (this is primary metabolism)
in which oxidation do we chop fatty acids, two off every time?
beta oxidation of fatty acids
which products do beta oxidation of fatty acids form?
acetic acid and a shorter acid
where do we make use of acetic acid?
in the citric acid cycle
whenever you see a fatty acid what should you do?
chop off acetic acid (two carbons) and two more untill you only have carboxylic acid left (which can undergo further reactions)
beta hydroxylation will chop off how many carbons?
two
Fenton and Haber Weiss reactions generate what?
ROS
What can lipid peroxidations form?
can generate metabolites that are electrophilic (Michael acceptors)
What can vitamin E do?
quench radicals
which heteroatoms do we talk about in heteroatom oxidation?
nitrogen and sulfur
imine is not stable, it will form …
formaldehyde and amine
allylamine can be metabolised to …
acrolein
Why are aromatic amines so toxic?
hydroxylamine can be both a strong electrophile and form ROS
which of the four forms of amine/nitro is the most toxic?
hydroxylamine
the line with X means whatever structure
hydroxylamine can be conjugated with
sulfate, creates a very good leaving group
whenever a leaving group is connected to a heteroatom, it’s leaving ability becomes much …
stronger
hydrogen in hydroxylamine can be easily abstracted by peroxidase and form …
ROS
a minor pathway of hydroxylamine is a …
Michael acceptor
what are the four electrophilic types
good leaving group
cyclic esters cyclic ethers
Michael acceptor
acid chloride
aromatic amines are very bad because they form three out of four … and …
three out of four electrophiles: good leaving group, Michael acceptor, cyclic ether and radical oxygen species
acylated aromatic amine can also form an electrophile because…
the acyl group can move to oxygen instead of sitting on N and then it forms a very good leaving group. acetate is only a good leaving group because connected to a heteroatom
which enzymes perform oxidation of alcohol and aldehyde?
alcohol dehydrogenase (NAD+ needed) and aldehyde dehydrogenase
in our bodies we have a … concentration of NAD+ and a … concentration of NADH
high NAD+
low NADH
secondary alcohol metabolism reversible and determined by NAD+ levels and forms
ketones
aldehyde can be reduced, but can acid be reduced?
no
what is the major metabolite of DDT?
DDA can be excreted in kidneys
DDT is very lipophilic, no polar groups and what does this mean for uptake?
it doesn’t not dissolve in stomach and that is why you can eat it without much problem
hydrolysis of epoxides, water can open epoxide to form a …
dihydroximolecule
epoxide hydrolase is an enzyme that opens up …
epoxides. there are certain substrates that do not fit the enzyme and therefore travel through our body as epoxides.
hydrolysis of esters form two products, which?
acetic acid and alcohol
COOR means?
Ester bond
what does ester become when cleaved?
carboxylic acid and alcohol
amide can be …
cleaved
what is an amide?
like ester but with nitrogen and double bound oxygen
what is the phase 2 reaction for electrophile?
glutathione GSH
cysteine is part of our body guard…
glutathione GSH
GSH glutathione is not very effective with acrolein because
acrolein can be regenerated in the kidneys which prolongs circulation time of acrolein
conjugation with sulphate is primarily for…
alcohol and phenol
what is PAPS?
an activated sulphate. used to conjugate to phenol
what are alcohols, phenols, carboxylic acid, aromatic amines, sulfonamide conjugated with?
glucoronic acid (already fairly large above 200 molecular weight)
if molecular weight larger than 500 the molecule is excreted in…
liver
conjugation with amino acids is primarily for
carboxylic acid
carboxylic acid can be conjugated with
glucoronic acid and with amino acid (glycine)
glucoronic acid can bind with a lot, what is the downside?
it’s slow
when you get rid of urine and CO2, do you get rid of acid and increase pH?
yes
ester, amides, alcohol and aldehydes can be metabolised to acids in the body which can lead to…
acidosis. they are masked acids.
what is feeling drunk actually?
non specific effect on CNS. molecules trapped in cell membranes and disturbs signals to nerve cells.
why is methanol toxic?
metabolised into formic acid and formaldehyde. can cause acidosis. but slowly metabolised because so hydrophilic.
Respiratory chain is blocked when HCN or H2S bind to …
the heme group of enzyme complex IV
the uncoupling effect of the respiratory chain can likened to what in a car?
adding gas while the clutch is down
signal within a nerve cell is … and the signals between nerve cells (at synapsis) are …
electrical and chemical
lipophilic molecules below molecular weight …. can pass membrane of cells
1000
why can ions not pass cell membranes?
they are not alone, usually complexed with water
what does asbestos do in the lungs?
stimulate cell growth and create a thick layer which does not allow blood gas exchange
what molecules can pass bbb, their molecular weight must be below … to be efficient and below
.. to pass at all, their log p value must be above …
300 and 400 and 1.5
some molecules can be trapped after the BBB because they are … into a form that does not pass
transformed/metabolised
