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Toxicology Summary
- Vak
- Toxicology
- Instelling
- Radboud Universiteit Nijmegen (RU)
Toxicology Summary Bachelor Medical Biology Radboud University
[Meer zien]Voorbeeld 4 van de 35 pagina's
Voorbeeld 4 van de 35 pagina's
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VolgenVoorbeeld van de inhoud
HC IntroductionToxicology= The study of adverse effects of chemicals on health.
Phosphate group= nerve agent (Sarin, VX) → very specific, don’t need a lot of them
Examples:
- Excessive exposure to fluoride causes an arthritic bone disease called skeletal fluorosis → it
was in the water of these people → when they made this water source they didn’t check the
water quality
- Atropine in Nachtschade (used to dilate pupils in women) → so toxicity and therapeutic
function (increases function of heart and intestinal tract)
- Warfarin (dicumarol): when coumarin (from a plant) is changed into warfarin like compound by
a mold → hereby it became quit toxic, found to poison livestock after eating this moldy sweet
clover → can also be used therapeutic, as an anticoagulant → due to toxicity can also be used
as (rat) poison
Take home message: toxic compounds can also have beneficial effects, quit often
Dose that determines whether something is toxic, everything is toxic at some dose → just as water
Toxic compounds used in terrorism as chemical weapons
Botox contains botulinum toxin, a toxic compound which could kill the entire Dutch population with 5
gram.. → botox contains very little amount of this → you need to inject this toxin, otherwise it doesn’t
work, so hard to use as a chemical weapon → so normally not considered a chemical weapon
- Botox can also be used as a therapeutic agent, as it inhibits muscle movement → so people
with trembling muscles can benefit from this
Nature and severity of intoxication is determined by:
- The toxicity of the substance
- Exposure (route, type, size, duration, frequency)
- The organism (species, strain, sex, age, hormonal and nutritional status, illness)
- Interactions: physical (temperature, pressure), environmental and social factors, simultaneous
or successive exposure
Many dyes used in clothes are toxic, azodyes → these contain benzidine which is
a carcinogenic component → can bind to DNA and cause cancer - mutations
The people who made the clothes were exposed to much more danger
Doses phases
1. Exposition phase= Behavior of a substance in the environment, changes in the application
form, available for uptake.
2. Toxicokinetic phase (what our body does with the drug): Absorption, distribution,
biotransformation (toxification, detoxification), excretion.
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, 3. Toxicodynamics phase (what the drug does to our body): Interactions with receptors or other
(macro) molecules at the site of the operation
Required information
a. Which substances are involved
b. What is the structure/ what are the physico-chemical properties?
c. What is known of the toxicity?
d. What is known from the exposure?
e. What is known about the dose response relationship?
f. What is known of the mechanism?
HC Biotransformation
Biotransformation is more applicable to foreign compounds which are taken up by the body, changed
and after biotransformation are excreted again.
Toxic compound → taken up by enterocytes in the gut → these can excrete it again or take it up
(pharmacokinetics) → once it comes into the portal vein it goes to the liver which is major organ for
biotransformation (contains a lot of enzymes) → only when it passes the liver (so when it is not
excreted into the bile) or when it is not changed due to biotransformation then it gets into the general
circulation
Biotransformation is a way for the body to inactivate compounds, make them more water soluble, to
excrete them → sometimes also side effects, the compound becomes more toxic after
biotransformation
Biotransformation occur mainly in the liver but theoretically it can happen in all cells → as long as they
have biotransformation enzymes → for example in the enterocytes (intestine), kidney
Biotransformation= metabolism of xenobiotics
Effect of drug metabolism on excretion
- Lipophilic drug → glomerulus → excreted → but can be retained again by membranes
(because it is this lipophilic) → are taken up
- Hydrophilic drug → can stay in the urine and leave the body more easily
Same for liver/ bile
The biotransformation process → the general principle of biotransformation is to make the compound
more water soluble
1. Phase 1 reactions: making the product more polar
- Oxidation, reduction, hydrolysis
- This is done to introduce of a functional group (-OH, -NH2 , -SH or –COOH)→ mostly an
oxygen group which will become hydroxyl group
2
,Oxidation is the most important phase I reaction → The cytochrome P450 (CYP) system
- Family of enzymes with an iron in its center → large family of isoforms
- Changes molecules and adds oxygen atoms to the molecule to be removed
- Depending on which isoform they have different substrates/ functions
- Discovered at 450 nm, that’s why the name
CYP reactions - oxidation ( → electrophilic), reduction, hydrolysis ( → both nucleophilic):
- Hydroxylation of aromatic carbon
- Hydroxylation of aliphatic carbon → if they enzyme can chose, it always
chooses for the aliphatic carbon → because the aromatic rings are quit
stable which will take more energy to change something here → it’s more
easy to change the side chain→ more accessible
- N-, O-, and S-dealkylation
- S-oxydation
- IMPORTANT: epoxidation → when the question is to draw a 2-3 epoxide,
you should be able to draw this
The epox side is very unstable → will be changed into a hydroxyl group
- Activation of benzo[a]pyrene→ very well known toxic compound →
present in cigarette smoke → best studied carcinogenic is cigarette
smoke
Bay region in benzo(a)pyrene → epoxide on the lower side → unstable so
hydrolyzed very quickly → now you get an epoxide in the Bay region which is
more stable → because it is more stable it has time to go to the nucleus and
react with the DNA (picture) and other molecules
The same compound can be activated by different (CYP) enzymes → most
important ones in humans are CYP2D6 and CYP3A4
2. Phase 2 reactions: making the compound more hydrophilic
Conjugation with endogenous substrate → so adding of large groups to make the compound more
water soluble → Examples:
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, - Sulfate
- Glucuronic acid: sugarlike compound → sugar dissolves
in water quit easily (lot of oxygen → polar groups) →
oxygen doesn’t only make the compound more water
soluble but it also makes it more likely to be transported
by transport proteins
Done by glucuronosyl transferase
- Glutathione → can react with the epoxide group → then
the enzyme glutathione S transferase is involved: adds
glutathione to this epoxide and thereby inactivated the
toxic epoxide
Epoxide groups can be removed different ways: spontaneously go into hydroxyl groups, it can use
epoxide hydrolase or react with glutathione
- Acetate
- Water
- Glycine
- Methyl → exception is the methyl group, this doesn’t make the compound more water soluble
but still is often seen is phase 2
All reactions performed by transferases except for glycine (conjugation acyl CoA synthetase)
3. Phase 3: excreting/ transport → goes more easily when the compound is connected to a
glucuronide or a glutathione molecule
Phase I and II reactions: species differences →like amphetamine or paracetamol (has a toxic
intermediate phase which we can transform very quickly, only risk is overdosing)→ when you want to
test a certain compound you need to pick your test animal properly → often dogs are used because
they have similar biotransformation systems (rats and mice have different ones)
Factors that influence biotransformation
- Environment: alcohol, grapefruit juice
- Disease: when you feel sick you might have more/ less biotransformation enzymes
- Genetics: for example fast and slow acetylators → for example the frequency of TB differs a
lot among countries
There is a lot of genetic variability (polymorphisms) (between different ethnic groups)
There are also CYP inducers (like in cigarette smoke or sometimes even in food) → example is
CYP3A4-induction
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