Chapter 6 lecture 9 -10 Organ-selective toxicity Flashcards
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.
What is special about MeHg-SG
- MeHg-SG reaches the kidney and easily pass through the glomerular filtration barrier.
- GSH is enzymatically cleaved to form dicysteinyl–Hg
complex (Cys–Hg–Cys), mimics the endogenous compound, cystine (Cys–Cys) - Free ticket to proximal tubular epithelia, cannot be distinguished
What are some damages MeHg does to kidney?
changes in DNA methylation and repair, inflammation, mitochondrial
injury and oxidative stress.
What do chelating agents do to MeHg?
- Chelating agents have -SH group
- form complexes with MeHg which are excreted faster than the complexes with GSH or cysteine.
*
What are the disadvantages using chelating agent to treat MeHg?
the chelating agents cannot reach the
subcellular environment
tBut it is the majority of the MeHg is located
What is DES (Diethylstilbestrol)
a potent synthetic estrogen
How was DES originally used?
- prostate cancer in men
- pregnant women prevent miscarriage and premature delivery in women.
The adverse effect of DES has gone with the generation of the pragnent woman, T/F?
False
Children and grandchild also have
How can DES reach fetal circulation?
cross the placenta
What are the adverse effects for the daughter generation of DES?
rare forms of cervical,
vaginal and breast cancers.
is DES classified as carcinogen?
YES
Are the steroid receptors on the cell surface
No they are in the nucleus
How estrogen receptors regulate gene expression?
They are transcription factors to regulate the expression of specific genes
through its binding to DNA sequences called estrogen response elements (EREs).
How does DES relate to ER?
an endocrine-disrupting chemical (EDC)
* DES binds to ERα with an affinity 5 times greater than estradiol
ER is already expressed in the mouse fetus before sexual differentiation is terminated, T/F?
TRUE
EDCs modulate the epigenetic profile of the cell. T/F?
True
How can EDC promote cancer growth?
Estrogenic EDCs can promote the proliferation and epithelial-mesenchymal Transition (EMT) through RACK1 in the prostate and breast cancer cells.
How many genes can DES induce expression?
Over 200
How can DES induce epigenetic alterations?
DES -> doubling expression of EZH2( histone methyltransferase)
Increases methylation
Decreased miRNA expression
increase of the expression of DNA methyltransferases and histone deacetylases
