Toxicology I PHTX 831

Spring 2023

Mechanism of Toxicity I

Tutorial 3
1
Course ILOs

2
 Tutorial Intended learning outcomes

➢ Discuss the potential stages in the development of toxicity.

➢ Differentiate between different pathways that lead to
accumulation of toxicants and the factors needed to oppose
toxication.
➢ Explain the toxic mechanism of action of various compounds
and their interaction on a molecular level.
➢ Interpret and review evidence based information needed in
toxicity assessment.

3
 Tutorial Outline

➢ Potential stages in the development of toxicity after chemical exposure

Step 1: Delivery: from the site of exposure to the target

❖ Absorption/ Reabsorption
❖ Distribution toward target / Distribution away from target
❖ Reabsorption/Excretion
❖ Toxication/ Detoxication

Step 2: Reaction of the ultimate toxicant with the target molecule

4
Potential stages in the development of toxicity
after chemical exposure

➢ Step 1:Delivery: from the site of

exposure to the target
➢ Step 2:Reaction of the ultimate
toxicant with the target molecule
➢ Step 3: Cellular dysfunction and
resultant toxicities
➢ Step 4: Repair or Dysrepair

5
Q1. Match the following toxicants with the correct
group according to the type of the toxicant:
1. Acetaminophen 2. Hydroxyl radical 3. paraquate
4. Doxorubicin 5. Bungarotoxin 6. Tetrodotoxin
7. Chlorpromazine 8. Erabutoxin 9. Nitrofurantoin
10. Lead 11. Protein carbonyl
Q2. Examples of parent xenobiotics that act as
ultimate toxicants include all of the following except:
a. Lead
b. CCL4
c. Tetrodotoxin
d. A&C
Q3.Examples of xenobiotics whose metabolites act as
ultimate toxicants:
a. Acetaminophen
b. Doxorubicin
c. Nitrofurantoin
d. Lead
e. All except d
 Step 1: Delivery:
• Mechanisms opposing distribution:
1. Binding to plasma proteins
2. Specialized Barriers
3. Distribution to storage sites
4. Export from cells

• Mechanisms facilitating distribution:

1. Porosity of the capillary endothelium
2. Specialized transport across the plasma membrane
3. Accumulation in cell organelles
Q4. Mechanisms opposing distribution of a toxicant
to the target site include all of the following except:
a. Plasma protein binding
b. Placenta
c. Accumulation in the bones
d. Large fenestrae in the capillary endothelium
Q5. Complete the following toxication and
detoxication pathways GPO
H2O
.NO SOD
ONOO –
O2.- HOOH

CO2 Fe(II) H2O

CAT

ONOOCO2- HOOH-

NO2. CO3.- OH. OH-

 Q6. Complete the following toxicaion and
detoxication pathways

POD
Chlorpromazine (CPZ) CPZ.+

Detox

GSSG 2 GSH
Q7. Detoxication mechanisms may fail due to:

a. Toxicant overwhelms the detoxication processes.

b. Depletion of glutathione.
c. Reactive toxicant inactivates a detoxicating enzyme.
d. Sometimes detoxication generates potentially
harmful product.
e. All of the above
Potential stages in the development of toxicity
after chemical exposure

➢ Step 1:Delivery: from the site of

exposure to the target

➢ Step 2:Reaction of the ultimate

toxicant with the target molecule

17
Q8. Major target molecules for toxicants
include all of the following except:
a. Ca2+ channels
b. Vitamins
c. RNA
d. Thyroperoxidase
Q9. Rearrange the following steps:

1. Hyperthermia & seizures

2. Mitochondrial dysfunction
3. Entering of 2,4 dinitrophenol in the mitochondrial
matrix space
4. Collapse of the proton gradient across the
membrane
Correct arrangement:
3 →4 → 2 →1
Q10. According to the below sentence arrange the
following toxicants:
The reaction of the ultimate toxicant with the target molecule can
be in the form of; direct interaction with the target molecule or
alteration of the biological environment.
A. Tetrodotoxin
B. Toxicant that changes the pH
C. 2,4 dinitrophenol
D. Precipitation of the toxicant in the kidney tubules
E. Formation of lipid peroxyl radicals by carbonate anion radical.
Toxicants that interact with the target molecule
A and E
Toxicants that alter the biological environment
B, C, and D
Q11. Mention the type of the reaction of
the toxicant:
1. Reversible binding of strychnine to glycine receptor on motor
neuron in spinal cord
Non-Covalent binding
2. Irreversible binding of toxicant with an intracellular protein
Covalent binding
3. Conversion of hemoglobin to methemoglobin by nitrites
Electron transfer
4. Lipid peroxidation
Hydrogen abstraction
5. Paralysis by botulinium toxin
Enzymatic reaction
6. Destruction of biomolecules by snake venoms
Enzymatic reaction
Q12. Match each toxicant with the correct
enzyme

1. O2-. B a. Peroxidase

2. H2O2 C b. Superoxide dismutase

3. Chlorpromazine A c. Catalase
d. Thioredoxin
4. Erabutoxin D