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BIOL3207 Toxicology > Chapter 6 lecture 9 -10 Organ-selective toxicity > Flashcards

Chapter 6 lecture 9 -10 Organ-selective toxicity Flashcards

1
Q

What are the 2 main sites when xenobiotics first contact with the body?

A

Respiratory + Oral

They are then absorbed and distributed

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2
Q

What is organtropic toxicity?

A

Toxicity targeting specific organ

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3
Q

What are the organs at higher risk of damage?

A
  • Lungs (predisposed to xenobiotics)
  • GI tracts (predisposed to xenobiotics)
  • Kidney (High conc excreted drug metabolites)
  • Liver
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3
Q

What are the organs at higher risk of damage?

A
  • Lungs (predisposed to xenobiotics)
  • GI tracts (predisposed to xenobiotics)
  • Kidney (High conc excreted drug metabolites)
  • Liver
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4
Q

What is Molecular homology

A

how a xenobiotic mimics the characteristics and behavior of an endogenous compound.

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5
Q

Why molecular homology is harmful?

A

Due to structural similarity, it can make use of physiological pathways for essential cell function, resulting in tissue-selective cellular uptake and possible accumulation.

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6
Q

What is the difference between inorganic and organic mercury?

A

Inorganic: Causes nephrotoxicity
Organic: Causes neurotoxicity

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7
Q

What is special about methyl-mercury?

A
  • 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
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8
Q

Compare MeHg with inorganic Hg

A

MeHg showed 17 to 35 times
faster absorption than
inorganic mercury.

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9
Q

Can Hg directly be absorbed into blood?

q

A

No, need cysteine

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10
Q

How can Hg be absorbed into blood?

A

MeHg combines with cysteine
(MeHg-Cys) in the
duodenum.

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11
Q

What brings MeHg to red blood cells?

A
  • organic anion transporters (OAT) brings MeHg to RBC
  • binding to cysteine residues of α and β chains of haemoglobin
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12
Q

Besides binding to RBC, how can Me-Hg be transported?

A
  • by several plasma proteins
  • serum albumin (Alb)
  • covalently binds through sulfhydryl groups
  • MeHg-Alb conjugate
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13
Q

Besides binding to RBC, how can Me-Hg be transported?

A
  • by several plasma proteins
  • serum albumin (Alb)
  • covalently binds through sulfhydryl groups
  • MeHg-Alb conjugate
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14
Q

CNS is protected by blood brain barrier, can MeHg pass through?

A

Yes
* MeHg-Cys mimics amino acid methionine
* moves across BBB
* Get into CNS by LAT1

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15
Q

What is the primary health effect of MeHg?

A

impairing
neurological development.

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16
Q

MeHg crosses the placental barrier with the cross rate 10 times higher than other mercury compounds. T/F?

A

True

17
Q

MeHg accumulates in fetal brain more easier than mother, T/F?

A

True

17
Q

MeHg accumulates in fetal brain more easier than mother, T/F?

A

True

18
Q

HOW does MeHg do damage to us?

A
  1. MeHg inhibits glutamate (Glu) uptake
  2. Enhance glu release
  3. over-activation of glutamate receptor, synapse over active
  4. Increase Ca2+ influx to postsynaptic neuron
  5. ROS keeps on being produced
  6. mitochondrial dysfunction

Affect e- transport chain -> increase ROS production

19
Q

The formation of MeHg-SR complexes with endogenous thiol-containing biomolecules may _?

A
  • increase its lipophilicity
  • distribution of the metal into hydrophobic
    compartments in brain cells

mitochondria, lysosome, nucleus and other organelles

20
Q

Suggest some damages of MeHg can do

A

excitotoxicity, DNA damage,
alterations in neurogenesis, Ca2+
dyshomeostasis, exacerbation of
neuroinflammation, and cell death
mechanisms.

21
Q

Other than alb and hb, what can MeHg bind?

A
  • MeHg conjugates with sulfhydryl-containing molecules glutathione (GSH) to form MeHg-SG
  • distributed to various tissues and organs
    through the blood vessels.
22
Q

Other than alb and hb, what can MeHg bind?

A
  • MeHg conjugates with sulfhydryl-containing molecules glutathione (GSH) to form MeHg-SG
  • distributed to various tissues and organs
    through the blood vessels.
23
Q

What is special about MeHg-SG

A
  • 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
24
Q

What are some damages MeHg does to kidney?

A

changes in DNA methylation and repair, inflammation, mitochondrial
injury and oxidative stress.

25
Q

What do chelating agents do to MeHg?

A
  • Chelating agents have -SH group
  • form complexes with MeHg which are excreted faster than the complexes with GSH or cysteine.
    *
26
Q

What are the disadvantages using chelating agent to treat MeHg?

A

the chelating agents cannot reach the
subcellular environment
tBut it is the majority of the MeHg is located

27
Q

What is DES (Diethylstilbestrol)

A

a potent synthetic estrogen

28
Q

How was DES originally used?

A
  • prostate cancer in men
  • pregnant women prevent miscarriage and premature delivery in women.
29
Q

The adverse effect of DES has gone with the generation of the pragnent woman, T/F?

A

False

Children and grandchild also have

30
Q

How can DES reach fetal circulation?

A

cross the placenta

31
Q

What are the adverse effects for the daughter generation of DES?

A

rare forms of cervical,
vaginal and breast cancers.

32
Q

is DES classified as carcinogen?

A

YES

33
Q

Are the steroid receptors on the cell surface

A

No they are in the nucleus

34
Q

How estrogen receptors regulate gene expression?

A

They are transcription factors to regulate the expression of specific genes

through its binding to DNA sequences called estrogen response elements (EREs).

35
Q

How does DES relate to ER?

A

an endocrine-disrupting chemical (EDC)
* DES binds to ERα with an affinity 5 times greater than estradiol

36
Q

ER is already expressed in the mouse fetus before sexual differentiation is terminated, T/F?

A

TRUE

37
Q

EDCs modulate the epigenetic profile of the cell. T/F?

A

True

38
Q

How can EDC promote cancer growth?

A

Estrogenic EDCs can promote the proliferation and epithelial-mesenchymal Transition (EMT) through RACK1 in the prostate and breast cancer cells.

39
Q

How many genes can DES induce expression?

A

Over 200

40
Q

How can DES induce epigenetic alterations?

A

DES -> doubling expression of EZH2( histone methyltransferase)
Increases methylation
Decreased miRNA expression
increase of the expression of DNA methyltransferases and histone deacetylases

BIOL3207 Toxicology (7 decks)

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