neurotoxicity and pulomonary toxicity Flashcards
what is MPTP
meperidine;
synthesised as an anticholinergic
potent analgesic problems due to mu opioid receptor agonism
mainly used for childbirth
normeperidine produced by N-demethylation via CYP2B6 and 3A4 is neurotoxic
how can opioid drug taking lead to neurotoxicity
production of MPPP, an opioid analgesic which can be used recreationally, can contain MPTP contamination
a C-O bond in MPPP is not particularly stable and breaks at higher temperatures forming MPTP, which is a pro-toxicant, it is also lipophillic so crosses the blood brain barrier easily where it is taken up by astrocytes
astrocytes express MAO-B which oxidises MPTP to MPDP+ which then disporportionates to MPP+
MPP+ is a substrate for high affinity DAT (dopamine transporter), expression of DAT correlates with neurone loss, DAT KO mice are resistant to MPTP toxicity and blocking DAT with cocaine reduces toxicity
MPP+
also undergoes high affinity uptake by VMAT2 and is
predominantly found in catecholaminergic vesicles (rather than
mitochondria), Mice overexpressing VMAT2 are more resistant to MPP+
toxicity, VMAT2 KO mice show increased susceptibility to MPTP/MPP+
toxicity
describe how MPP+ relates to mitochondrial respiration
Mitochondrial complex I (NADH:ubiquinone
oxidoreductase or NADH dehydrogenase)
– couples the transfer of electrons from NADH to ubiquinone
(to NAD+
and ubiquinol)
– Electrons are transferred to flavin mononucleotide, then
through a series of iron-sulphur groups and moves H+
across the membrane
MPP+ is actively accumulated in the mitochondria
and inhibits complex I of the electron transport chain
(only respiration linked to pyruvate, glutamate and
β–hydroxybutyrate are affected)
– Prevents passage of efrom Fe-S clusters to ubiquinone
could dopamine toxicity be a mechanism of MPP+ toxicity
MPP+
redistributes dopamine from vesicles to the cytoplasm more dopamine
released from neurones
• Excessive autoxidation of dopamine forms cytotoxic quinone derivatives and
highly reactive •OH
• Time wise, formation of hydroxyl radicals
appears to occur alongside dopamine
release and possibly before
mitochondrial dysfunction
how does MPTP induced neurotoxicity vary with species
Humans and monkeys are highly susceptible to MPTP-induced
neurotoxicity
• Guinea pigs are also susceptible but rodents are more resistant
(rats more resistant than mice, susceptibility varies between
species)
• Rats have high expression of MAO-B in
cerebral microvessels
• Infusion of MPTP directly into the substantia
nigra of rats leads to toxicity, but peripheral
administration does not seems that MAO
in the vasculature has a protective effect
Few species have neuromelanin in the brain.
Humans have more than NHP (though it is
structurally similar).
• It is completely absent from the dopaminergic
and noradrenergic neurons of rodent brain.
The more neuromelanin, the higher the decrease in TH+
neurones, apart from the locus coeruleus since lower binding of MPP+ to neuromelanin here since more densley packed terminals take up the MPP+ from astrocutes so less is accumulated in each neurone
how do calcium binding proteins effect MPTP toxicity
Calbindin (CB) is a calcium-binding protein that can buffer intracellular free calcium levels, thus
protecting them from toxicity
• There is evidence that MPTP increases Ca2+ levels and this might contribute to it’s toxicity
• Neurones containing CB are selectively spared after MPTP administration
how does route of administration effect MPTP toxicity
MPTP taken orally results in low concentrations of MPP+
in the brain
as it undergoes extensive first-pass metabolism
• It is biotransformed via hepatic N-demethylation to PTP (4-phenyl1,2,3,6-tetrahydropyridine).
– this is at least partially mediated by CYP2D6
– there appears to be some evidence that deficiency in this enzyme results in
increased risk of PD: a study with 229 patients and 720 controls found that
poor metabolisers with a defect in this gene had a 2.54 fold increased risk of
having PD, compared to those with the normal enzyme
what is a link between pesticides and parkinsonism
Epidemiological studies point to a link between exposure to
certain pesticides, and the risk of developing PD
• Rotenone is an insecticide and piscicide
• It is lipophilic and crosses the BBB and into brain cells
• It inhibits complex I in the same way to MPP+ (prevents
transfer of electrons to the Fe-S groups) – leads to ROS production which causes oxidative damage
• Causes a Parkinsonian syndrome characterised by rigidity,
tremors and bradykinesia
describe paraquat and its link to parkinsonism
structurally very similar to MPTP
it is very hydrophillic and so does not cross plasma membrane easily, however it can cross the BBB via the neurtral amino acid transporter, uptake into brain increases with age
MPTP and paraquat cause nigrostriatal neurone loss in mice, this is also associated with significant decrease in ambulatory activity
paraquat is now banned in many countries due to its high toxicity and mortality rate following both accidental occupational exposure and intentional poisoning
percutaneously it causes skin irritation and damage but there is limited percutaneous absorption and toxicity usually results from oral exposure
there is limited absorption (1.5% in humans) but this happens quickly by carrier mediated transport in the small intestine
main target organ is the lungs
what are symptoms of paraquat poisoning
after ingestion of a toxic dose (20-40mg/kg): abdominal pain, vomiting and diarrhoea due to GIT irritation/ local corrosive action of PQ
pulmonary haemorrhage 1-2 days after ingestion
pulmonary fibrosis 1-2 weeks after ingestion, which is what most likely causes death
after ingestion of fatal dose (over 40mg/kg):
usually death within hours
alveolar inflammation and pulmonary oedema
multiple organ failure
what organ system is paraquat toxicity relatively selective for
pulmonary toxicity
following exposure, lung conc is approx 6 times higher than plasma conc
target cells are type 1 and 2 alveolar epithelial cells and bronchiolar clara cells
this is due to expression of a polyamine uptake system (PUS) in these cells that usually moves putrescine, spermine and spermidine
affinity of this transporter for the polyamines is 7 times higher than for PQ, due to increased steric hindrance of the nitrogens by the ring structures
what is PQs mechanism for pulmonary toxicity
once inside the type 1 and 2 alveolar epithelial cells and bronchiolar clara cells PQ causes toxicity through production of ROS, this causes:
depletion of NADPH
depletion of glutathione
oxadative damage; DNA damage, alterations in membrane structure/lipid peroxidation leading to possible increase in calcium permeability, inactivation of enzymes
there is evidence of oxidative stress in PQ factory workers (increased lipid peroxidation, reduced antioxidant levels and SH groups)
how is PQ poisoning treated
activated charcoal limits further absorption, however must be done almost immediately
oxygen restriction
glucocorticoids and cyclophosphamide
