Chapter 6 lecture 9 -10 Organ-selective toxicity Flashcards
(42 cards)
What are the 2 main sites when xenobiotics first contact with the body?
Respiratory + Oral
They are then absorbed and distributed
What is organtropic toxicity?
Toxicity targeting specific organ
What are the organs at higher risk of damage?
- Lungs (predisposed to xenobiotics)
- GI tracts (predisposed to xenobiotics)
- Kidney (High conc excreted drug metabolites)
- Liver
What are the organs at higher risk of damage?
- Lungs (predisposed to xenobiotics)
- GI tracts (predisposed to xenobiotics)
- Kidney (High conc excreted drug metabolites)
- Liver
What is Molecular homology
how a xenobiotic mimics the characteristics and behavior of an endogenous compound.
Why molecular homology is harmful?
Due to structural similarity, it can make use of physiological pathways for essential cell function, resulting in tissue-selective cellular uptake and possible accumulation.
What is the difference between inorganic and organic mercury?
Inorganic: Causes nephrotoxicity
Organic: Causes neurotoxicity
What is special about methyl-mercury?
- CNS-Selective Toxicity
- In environment, inorganic mercury can be transformed by bacteria plankton to MeHg
- MeHg accumulates in seafood/shells
- large predatory fish are more likely to have high levels of mercury (bioaccumulation)
- Intake through ingestion
Compare MeHg with inorganic Hg
MeHg showed 17 to 35 times
faster absorption than
inorganic mercury.
Can Hg directly be absorbed into blood?
q
No, need cysteine
How can Hg be absorbed into blood?
MeHg combines with cysteine
(MeHg-Cys) in the
duodenum.
What brings MeHg to red blood cells?
- organic anion transporters (OAT) brings MeHg to RBC
- binding to cysteine residues of α and β chains of haemoglobin
Besides binding to RBC, how can Me-Hg be transported?
- by several plasma proteins
- serum albumin (Alb)
- covalently binds through sulfhydryl groups
- MeHg-Alb conjugate
Besides binding to RBC, how can Me-Hg be transported?
- by several plasma proteins
- serum albumin (Alb)
- covalently binds through sulfhydryl groups
- MeHg-Alb conjugate
CNS is protected by blood brain barrier, can MeHg pass through?
Yes
* MeHg-Cys mimics amino acid methionine
* moves across BBB
* Get into CNS by LAT1
What is the primary health effect of MeHg?
impairing
neurological development.
MeHg crosses the placental barrier with the cross rate 10 times higher than other mercury compounds. T/F?
True
MeHg accumulates in fetal brain more easier than mother, T/F?
True
MeHg accumulates in fetal brain more easier than mother, T/F?
True
HOW does MeHg do damage to us?
- MeHg inhibits glutamate (Glu) uptake
- Enhance glu release
- over-activation of glutamate receptor, synapse over active
- Increase Ca2+ influx to postsynaptic neuron
- ROS keeps on being produced
- mitochondrial dysfunction
Affect e- transport chain -> increase ROS production
The formation of MeHg-SR complexes with endogenous thiol-containing biomolecules may _?
- increase its lipophilicity
- distribution of the metal into hydrophobic
compartments in brain cells
mitochondria, lysosome, nucleus and other organelles
Suggest some damages of MeHg can do
excitotoxicity, DNA damage,
alterations in neurogenesis, Ca2+
dyshomeostasis, exacerbation of
neuroinflammation, and cell death
mechanisms.
Other than alb and hb, what can MeHg bind?
- MeHg conjugates with sulfhydryl-containing molecules glutathione (GSH) to form MeHg-SG
- distributed to various tissues and organs
through the blood vessels.
Other than alb and hb, what can MeHg bind?
- MeHg conjugates with sulfhydryl-containing molecules glutathione (GSH) to form MeHg-SG
- distributed to various tissues and organs
through the blood vessels.
