Samenvatting
Summary compounds toxicology (NWI-MOL054)
- Instelling
- Radboud Universiteit Nijmegen (RU)
Samenvatting van de stoffen die je moet kennen voor het vak toxicology.
[Meer zien]Voorbeeld 3 van de 18 pagina's
Voorbeeld 3 van de 18 pagina's
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Voorbeeld van de inhoud
Compounds in toxicologySpecific compounds
Cadmium
Cadmium tends to accumulate in the kidney as a complex with the metallothionein protein. This
complex is reabsorbed in the proximal tubule cells. In the lysosomes, the complex is broken down
and cadmium is released, which then damages the kidney cells. This damage can be determined by
measuring the glucose, amino acids and proteins in the urine. This kind of damage is an example of
an accumulation effect.
2-aminofluorene/acetylaminofluorene
Acetylaminofluorene is one of the
most widely studied carcinogens and a very potent mutagen. It causes tumors in the liver, bladder,
and kidney. Metabolism is important, hence, conjugates (sulfate and acetyl) of N-
hydroxyacetylaminofluorene are more potent carcinogens than the parent compound. These may
give rise to nitrenium and carbonium ions. Sulfate conjugation leads to cytotoxicity and
tumorigenicity and DNA adducts. Some species (guinea pig) are resistant because of lack of formation
of the N-hydroxy metabolite and low sulfotransferase activity.
The biotransformation of acetylaminofluorene leads to nitrenium ion, arylamidonium ion, carbonium
ion and nitrenium ion. These can all cause DNA adducts. However the pathways to these compounds
are intertwined and caused by different enzymes (or spontaneous).
Dimethylnitrosamine
Dimethylnitrosamine is a by product of various chemical reactions. Its
biotransformation and therefore activation is catalysed predominantly by
cytochrome p450 enzymes. Therefore, the damage of dimethylnitrosamine is
concentrated in the liver. The formation of formaldehyde leads to reduction to CO2
and methanol formation. Next to formaldehyde, methyldiazonium ions are formed,
,which are an alkylating agent. Therefore, it methylates proteins and DNA, therefore increasing the
risk of cancer. Dimethylnitrosamine causes oxidative stress, leading to liver necrosis and cirrhosis.
Carbon tetrachloride
CYP2E1-mediated metabolism of carbon tetrachloride in the liver produces trichloromethyl radicals.
Via chain reactions, resulting in the formation of aldehydes and fatty acid radicals that will disrupt
calcium homeostasis, these cause damage to the rough endoplasmatic reticulum. This also affects
the activating enzyme, CYP2E1, thereby preventing more radicals from forming. Tetra is an example
of a suicide substrate, because its metabolites ultimately prevent formation of more metabolites.
Chloroform
CYP-mediated cleavage of the C-H bond leads to formation of phosgene. Chloroform can
be detoxicated by conjugation with cysteine and glutathione.
Paraquat
Paraquat has a chemical structure similar to that of endogenous polyamines such
as putrescine and spermine, which are actively incorporated into alveolar epithelial
cells. Paraquat reacts with NADPH. This produces superoxides and NADPH and GSH
depletion occurs. This happens especially in the lungs because oxygen saturation of the tissues is very
high. Severe lung injury in the form of pulmonary fibrosis can’t be reversed.
Carbon monoxide
CO binds the heme moiety of hemoglobin molecules, thereby preventing the binding of oxygen. This
leads to headache, increased heart rate, fatigue or, in case of high exposure, death. Administration of
100% O2 can be used as a treatment. The concentration of carboxyhemoglobine in the blood is a
good biomarker for CO exposure.
Cyanide
Cyanide blocks the actions of cytochrome a3 and thereby stops the reduction of water and the
movement of electrons and protons in the mitochondrial electron transport chain. This causes ATP
production to stop and anoxia. These symptoms occur mostly in the brain and heart muscle, as with
CO poisoning. There is only a fivefold difference between the first symptoms and a lethal dose, so
cyanide is a very deadly poison. Furthermore, it can reversibly bind to hemoglobin, preventing
oxygen from binding. Often, co-poisoning with CO occurs during smoke inhalation.
NaNO2 used as a cyanide poisoning antidote, as it forms methaemoglobin to which cyanide binds
more avidly, therefore transporting it out of the tissues as cyanomethaemoglobin. Thiosulfate
administration facilitates the dissociation of cyanomethaemoglobin into cyanide and haemoglobin, of
which the cyanide is converted into thiocyanide. Thiocyanide is easily excreted into the urine.
Methanol
, Methanol can be biotransformed to formaldehyde, and consequently to formic acid. The protonation
of this compound, due to acidosis, leads to a faster absorption of formic acid in neurons. This leads to
depression of the central nervous system, including anesthesia of the respiratory center. This
enhances the formation of lactate acidosis, which again inspires. The first symptoms include absence
of any ocular reflex. Formic acid is involved in inhibition of cytochrome oxidases in the optic nerve. As
the optic nerve cells have few mitochondria, they are very susceptible to this histotoxic hypoxia.
Administration of alcohol, which acts as a competitive inhibitor of alcohol dehydrogenase, could
reduce the toxicity. Bicarbonate can combat the acidosis.
Benzo[a]pyrene
Benzo[a]pyrene is a genotoxic human carcinogen. It causes DNA-adduct-derived
mutations in cancer susceptibility genes (for example p53 in human long tumors).
Many potent PAHs act as complete carcinogens in mice. They induce the tumor
initiation and promotion phase. Benzo[a]pyrene is activated by the formation of an
epoxide by cytochrome P450 and further biotransformation by microsomal epoxide
hydrolase (mEH).
Isoniazid/acetylhydrazine
Isoniazid is broken down at different rates in the body, depending on the genotype. A
‘fast’ and ‘slow’ acetylator type can be distinguished. The rate of formation of the toxic
metabolite is influenced by this genotype. The metabolite acetylhydrazine, through
oxidative formation out of isoniazid, can damage the liver by formation of carbonium ion
radicals, which bind covalently to liver proteins. Further acetylation of acetylhydrazine to
diacetylhydrazine is considered a detoxification reaction. Overall, ‘slow’ acetylators are
more susceptible for the toxic effects of isoniazid. Alcohol, which enhances the function
of CYP2E1, leads to more reactive metabolite formation in the case of isoniazid. Hydrazine causes
hypertension.
Pyrazinamide
Rifampicin
Acetaminophen (paracetamol)
Paracetamol is transformed to NAPQI by CYP2E1-mediated hydrolysis and
rearrangement. This toxic metabolite reacts with proteins and nucleic acid in the
liver, leading to indirect cellular damage (centrilobular hepatic necrosis in zone
3). Detoxification occurs by glucuronidation. However, only 4% of paracetamol is
metabolized into the toxic compound NAPQI in the first place.
An antidote (of which the function is not completely known) against
acetaminophen intoxication is to administer N-acetyl cysteine as a
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