Toxic responses

Question 1

Which categories are toxic responses divided in?

Answer 1

Toxic responses can be categorized as follows according to the manifestation of the toxic effect:

1. Direct toxic action: tissue lesions
2. Pharmacological, physiological, and biochemical effects
3. Teratogenesis
4. Immunotoxicity
5. Mutagenesis
6. Carcinogenesis

Question 2

What are the stages following exposure to a toxic compound in 1) Direct Toxic Action: Tissue Lesions?

Answer 2

Primary, secondary, and tertiary events

Question 3

What are the major primary events in 1) Direct Toxic Action: Tissue Lesions?

Answer 3

• lipid peroxidation
• covalent binding to macromolecules
• changes in thiol status
• enzyme inhibition
• ischemia

Question 4

What are the major secondary events in 1) Direct Toxic Action: Tissue Lesions?

Answer 4

These are the changes that may occur in cells exposed to toxic compounds following the primary events.

The major secondary events are changes in:
* Membrane structure
* Permeability changes in the cytoskeleton
* Mitochondrial damage
* Depletion of ATP and other cofactors
* Changes in Ca2+ concentration
* DNA damage and poly ADP-ribosylation
* Lysosomal destabilization
* Stimulation of apoptosis
* Damage to endoplasmic reticulum (ER)

Question 5

What are the major tertiary events in 1) Direct Toxic Action: Tissue Lesions?

Answer 5

These are the final, observable manifestations of exposure to a toxic compound. Several may occur together, or they may occur sequentially.

The major tertiary events are as follows:
* Steatosis/fatty change
* Hydropic degeneration
* Blebbing
* Apoptosis
* Necrosis

Question 6

Which toxic effects are caused by oxygen species?

Answer 6

Lipid peroxidation

• Sulfydryl-containing enzymes are particularly susceptible to inhibition by lipid peroxidation
• can also cause cross linking of proteins

Question 7

What characterizes oxidative stress?

Answer 7

Oxidative stress is the production of excess active oxygen species, which may lead to a cycle of oxidation and reduction (redox cycle) with electrons being donated to oxygen to yield superoxide (O2- ·)

Question 8

What are the consequences of excess superoxide?

Answer 8

• Reduced GSH
• Depleted NADPH
• Formation of hydroxyl radicals and singlet oxygen

ROS will cause lipid peroxidation, but will also cause DNA damage and damage to proteins.

Question 9

Which detoxifying mechanism exists for superoxide (O2- ·)?

Answer 9

• Superoxide dismutase (major) –> converts O2- · to H2O2 + O2
• GSH peroxidase (glutahione peroxidase) –> converts H2O2 to 2H2O with the co-factor GSH
• Catalase –> converts H2O2 to H2O + O2

Question 10

What is lipid peroxidation?

Answer 10

Chain reaction of oxidative degradation of lipids which result in cellular damage

Question 11

Which drug causes oxidative stress and leads to lipid peroxidase and what is the mechanism?

Answer 11

Paraquat

1) Initial reaction between paraquat and an electron donor (e.g. NADPH) followed by readily acceptation of an electron
2) Acception of an electron leads to stable radical cation
3) Under aerobic conditions the e- is transferred to O2 giving rise to superoxide

As there is a lot of oxygen in the lungs, the process is repeated, and a redox cycle is set up.
NADPH is depleted leading to less recovery of GSH and thereby cell damage by oxygen radicals.

Question 12

Which general mechanisms are used in detoxification?

Answer 12

• Electrophiles: general mechanism of detoxication is conjugation with GSH
• Reactive aldehydes and ketones: reduction to alcohols by aldehyde dehydrogenase
• Metals: are bound by the small protein metallothionein and detoxified or detoxification by GSH
• Nucleophiles: conjugation at the nucleophilic group. Acetylation is the means of detoxifying amino (–NH2) or hydrazine (–NHNH2) or sulfonamido (–SO2NH2) groups
• Reactive intermediates: can also be detoxified by covalent reaction with noncritical proteins (such as plasma albumin).

Question 13

Which enzymes are especially important in detoxification?

Answer 13

• Superoxide dismutase (SOD)
• GSSH reductase
• GSH thiol transferase

Question 14

What can be used in repairing oxidation of protein sulfydryl groups after oxidative stress?

Answer 14

GSH and GSH thiol transferase

Question 15

What is the function of heat-shock proteins (hsps)?

Answer 15

They are proteins whose synthesis is up-regulated as a response to cell stress (from ROS and reactive metabolites).

They play a role in cell survival and serve a protective function by mending the structure of damaged proteins.

Question 16

What is the function of metallothioneins?

Answer 16

They bind potentially toxic metals such as cadmium, mercury, and lead, though binding with the sulfydryl groups. Consequently, the binding and removal of these metals are protective functions.

Question 17

Where is superoxide dismutase (SOD) located?

Answer 17

In the cytosol and mitochondria.

The location in the mitochondria is important because ROS are often produced there, and one form of SOD is inducible, as a result of oxidative stress.

Question 18

What is the protective mechanism of vitamin E?

Answer 18

Vitamin E neutralize lipid radicals and other radicals via reduction

Question 19

How can damage to macromolecules (proteins, lipids, DNA) be repaired?

Answer 19

• Oxidation of SH groups in proteins can be repaired by reduction using the enzyme thioredoxin (GSH and thioltransferase can also be used)
• P-SS-G (GSH protein adducts) can be repaired by reduction, using the enzyme glutaredoxin – GSH and NADPH are required
• Damaged protein structure may be repaired by hsps (heat shock proteins)
• As well as reduction by vitamin E as described, lipids damaged by oxidation to peroxides can be broken down by phospholipase A2 and the fatty acid peroxide replaced
• Although nuclear DNA is well protected by histones, there are a number of repair systems for DNA