Target organ toxicity

Question 1

local toxicity

Answer 1

Toxic effects occur at the site of first contact due to
extreme physicochemical properties of toxicants

Question 2

systemic toxicity

Answer 2

Toxic effects occur at internal organs
following absorption of toxicants into the
bloodstream

Question 3

target organ toxicity

Answer 3

toxicants cause damages to particular organ(s)

Question 4

direct-acting toxicant

Answer 4

electrophiles (electron-loving) - highly reactive; form adducts with proteins and DNA

Question 5

bioactivation-dependent toxicant

Answer 5

electrophilic metabolite is formed following
metabolism (e.g., by cytochrome P450)

Question 6

why the liver is susceptible to toxicity

Answer 6

• rich blood supply (intestinal drug absorption → portal vein)
• SLC transporters on the basolateral membrane of hepatocytes - drug uptake and accumulation
• the most important organ for drug metabolism - detoxification and bioactivation

Question 7

compare the main characteristics of
intrinsic and idiosyncratic drug-induced liver injury

Answer 7

Intrinsic DILI:
- Frequency - common
- Predictability- predictable
- Dose related: Y
-Reproducible in animal models: Y
- e.g. paracetamol

Idiosyncratic DILI
- F: rare
- P: unpredictable
- DR: N
- R: N
- e.g. NSAIDs

Question 8

describe the molecular mechanisms of drug-induced liver injury

Answer 8

1. drug-protein adduct inhibits protein functions causes cell stress, e.g., mitochondria
2. cell injury releases drug-protein adducts → neoantigens to trigger immune response
3. drug metabolites inhibit efflux transporters (e.g., BSEP [bile salt export pump]) on the apical
   membrane of hepatocytes –> increase intracellular bile acid –> mitochondrial damage

2.bile acid-induced stress sensitise the cell to ligand-induced apoptosis and necrosis

Question 9

explain the molecular mechanism of paracetamol-induced hepatotoxicity

Answer 9

excessive NAPQI depletes glutathione and forms protein adducts –> glutathione depletion leads to mitochondrial oxidative stress –> c-Jun N-terminal kinase (JNK) is phosphorylated and translocated –> production of reactive species and protein modification in the mitochondria –> amplification of mitochondrial dysfunction
results in hepatocyte necrosis

Question 10

explain the molecular mechanism of diclofenac induced hepatoxicity

Answer 10

Idiosyncratic
- formation of reactive metabolites cause mitochondrial injury and oxidative stress
- formation drug-protein adducts act as neoantigens to trigger immune response

Question 11

explain the molecular mechanism of NSAID-induced nephrotoxicity

Answer 11

1. arachidonic acid is metabolised by cyclooxygenase to form Prostaglandin H2
2. Prostaglandin H2 forms three metabolites one of which is prostaglandin E2
3. prostaglandin E2 maintains renal blood flow of the compromised kidney

4.NSAIDS inhibit the action of cyclooxygenase, reducing pain and acute renal dysfunction - ↓ renal blood flow