Lecture 1

Question 1

What are the 4 principle steps of toxicity?

Answer 1

Delivery, interaction with target molecule or biological environment, induce cellular dysfunction/injury, inappropriate repair/adaptation

Question 2

what is toxicokinetics

Answer 2

What the body does to the toxicant (how it reaches the target)

Question 3

What is type 2a toxicity?

Answer 3

specific interaction (ie. tetradotoxin)
inhibits Na+ channels and leads to paralysis

Question 4

What is type 2b toxicity?

Answer 4

Non specific interaction (ie. dinitrophenol)

uncouples the oxidative phosphorylation chain by reducing the proton gradient across the inner mitochondrial membrane

Question 5

What are the most common routes of toxicant delivery?

Answer 5

GI tract, lungs and skin

Question 6

Is metabolism a positive or negative effect?

Answer 6

Depends on the substance. It could detoxify a toxicant or create a toxic metabolite from a otherwise non toxic substance.

Question 7

What are enterocytes?

Answer 7

Epithelial cells in the intestine

Question 8

How do enterocytes transport drugs?

Answer 8

Through drug trasporters on both the lumen and the basolateral (blood) side.

Question 9

What are hepatocytes? What are their key features?

Answer 9

The parenchymal cells of the liver. They uptake toxicants through the blood and excrete into the bile or liver veins. They also metabolize drugs.

Question 10

What is the BBB? what can be transported?

Answer 10

a function of the endothelial cells in the brain. Only small water soluble or lipophilic substances can enter by diffusion. other molecules have to be transported.

Question 11

Can lipophilic compounds be renally excreted? Does the kidney excrete large compounds? What can reabsorption do?

Answer 11

No, they prefer small molecules (<330da) and reaborption could retain toxicants.

Question 12

What is phase 1 metbolism?

Answer 12

Usually oxidation (to create electrophiles) or reduction (to create nucleophiles)

Question 13

What is phase 2 metabolism?

Answer 13

Usually conjugation reactions. Electrophiles undergo glutathione conjugation and nucleophiles under either sulfation, acetylation or glucuronidation.

Question 14

What are the 3 principle methods of free radical formation?

Answer 14

Acceptance of electrons by CYP reductase, removal of electrons by peroxidases and homolytic fission of a covalent bond (ie. fenton reaction).

Question 15

What are the 4 types of binding with a target?

Answer 15

Reversible (non-covalent, ie warfarin), Irreversible (covalent), Hydrogen abstraction and electron transfer

Question 16

What are the 4 types of effects with a target?

Answer 16

Activation (morphine activating opiod receptor), inactivation (S-S bonds inactive proteins), destruction (lipid peroxidation) and neoantigen formation (haptens and prohaptens).

Question 17

What is repair and adaptation in terms of toxicology?

Answer 17

Repair refers to fixing the damage done to the cell and adaptation is the cell learning to cope better to toxicants

Question 18

How are oxidised proteins (prot-S-S-prot etc.) repaired?

Answer 18

Thioredoxin pathway can reduce these bonds

Question 19

How are denatured proteins repaired?

Answer 19

Disaggregation possible by heat-shock proteins and these proteins can also assist with ubiquitination and proteasomal degradation

Question 20

How are lipids repaired?

Answer 20

When fatty acid radicals are produced they are converted to peroxides (dependent on tocopherol, ascorbate and NADPH) which is then excised and reduced by glutathione peroxidase

Question 21

How is DNA repaired?

Answer 21

DNA is initially protected by histones along with repair mechanisms. They can be repaired directly (no base excision), by excision repaire and also homo/non homologous recombination

Question 22

What is TP53 and what is its role in DNA regulation?

Answer 22

TP53 is a transcription factor that stimulates important proteins (ie. p21) for the cell cycle. It can also stop the cell cycle to allow time for DNA repair

Question 23

What is the basics of cellular repair processes?

Answer 23

Apoptosis, necrosis, mitophagy (elimination of mitochondria).

Question 24

When is cell deletion used?

Answer 24

During the tissue repair process and its used by cells with the ability to multiply. Deletion achieved either by apoptosis or necrosis

Question 25

What process usually follows cell deletion and how does it work?

Answer 25

Cell multiplication occurs after cell injury and usually after cell deletion. It is controlled by cyclins and use to reach regular cell number again

Question 26

What are common mediators of the tissue repair cycle?

Answer 26

Macrophages degrade dying cells and in the process secrete TNF-alpha and Growth factors (ie. TGF-beta) which promote cell proliferation

Question 27

What are side effects of tissue repair?

Answer 27

Inflammation when necrosis dominates (TNF-alpha and IL-1) and production of ROS and RNS (NADPH oxidase in macrophages)

Question 28

What are mechanisms of adaptation?

Answer 28

Decreased delivery to the target, increased compensation and or defense mechanisms and increased repair capacity

Question 29

What is an example of antioxidative defense?

Answer 29

Nrf2 is normally attached to Keap1 and degraded. When cells undergo oxidative stress Keap1 is phosphorylated and Nrf2 can enter the nucleus and active important antioxidative genes.

Question 30

What are examples of increased repair responses?

Answer 30

Electrophile response (thioredoxin system), Heat-shock response (HSF1 transcription factor release into cytosol), ER stress response, DNA damage response and proliferative response

Question 31

What happens when repair/adaptation fail?

Answer 31

Consequences include fibrosis or carcinogenesis