TOPIC 1: MECHANISMS OF TOXICITY

Question 1

Toxicology

Answer 1

• The study of the adverse effects of chemicals on living organisms
• This involves the study of mechanisms, symptoms treatments and detection
  
  • Historically, a major driver in the development of toxicology has been the investigation of poisoning cases

Question 2

To maintain normal functioning, cells must:

and what happens when these are disrupted

Answer 2

• Maintain a stable intracellular environment
• Produce energy for operation
• Synthesise molecules
• Assemble macromolecules
• Assemble membranes
• Assemble cellular organelles

Disruption of these essential functions can lead to dysfunction and eventually necrosis

• The most problematic are disruption to energy generation and protein synthesis

Question 3

A key consequence of ATP depletion is the

Answer 3

• loss of control of ion gradients
• This is a positive feedback loop: as more Na+ and Ca2+ enter the cell, more voltage-gated channels open and more ions enter
• This causes loss of volume control: water influx, cell swelling

Eventually, the cell lyses: necrosis

Question 4

Ca2+ is involved in

Answer 4

• Activation of enzymes (e.g. TCA cycle)
• Cytoskeletal polymerisation
• Muscle contraction
• Neurotransmission
• Regulation of signal transduction and exocytosis
• Transporters

Question 5

Mechanisms of removal of Ca2+

Answer 5

1. Extracellular Ca2+ ATPase
2. Endoplasmic reticulum Ca2+ ATPase
3. Extracellular Na+/Ca2+ exchanger
4. Mitochondrial Ca2+ uniporter

Question 6

Narcosis

Answer 6

A reversible downstream effect, general depression of biological activity

Question 7

ROS and RNS can be generated directly by:

Answer 7

• Activation of foreign compounds (e.g. benzene)
• Redox cycling (e.g. paraquat)
• Transition metals
• Inhibition of mitochondrial electron transport

Question 8

ROS and RNS can be generated indirectly by:

Answer 8

• Activation of cytochrome P450
• Increased intracellular Ca2+

Question 9

Increased intracellular Ca2+ generates ROS/RNS:

Answer 9

1. Activation of dehydrogenases in the TCA cycle
   
   • Increases electron output via the electron transport chain, causing increased production of superoxide
2. Activation of Ca2+-dependent proteases
   
   • Convert xanthine dehydrogenase to xanthine oxidase, which also produces superoxide and hydrogen peroxide
3. Activation of constitutively-expressed nitric oxide synthases in neuronal and endothelial cells
   
   • Increases NO production, which reacts with superoxide to form highly reactive peroxynitrite

Question 10

First order vs zero order elimination

Answer 10

• First-order elimination (the most common) means the elimination rate of the substance is directly proportional to its concentration
  
  • In this model, the plasma concentration of the substance decreases exponentially over time
• Zero-order elimination means the elimination rate is independent of the concentration
• In this model, the plasma concentration of the substance decreases in a linear fashion over time

Question 11

Non-polar substances and those with low plasma protein binding activity have

Answer 11

the highest VD – most likely to go into tissues

Question 12

Liver or kidney failure can increase

Answer 12

VD – because they cannot metabolise as efficiently