L16 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. EG=.g skin, eyes and lungs

Question 2

Systemic toxicity

Answer 2

Toxic effects occur at internal organs following absorption of toxicants into the bloodstream. e.g liver, kidneys, brain and heart

Can lead to target organ toxicity

Question 3

Target organ toxicity

Answer 3

Toxicants cause damage to particular organs

Question 4

hepatotoxicity

Answer 4

Toxic liver disease is damage to your liver

Question 5

nephrotoxicity

Answer 5

rapid deterioration in the kidney function due to toxic effect of medications and chemicals.

Question 6

Direct-acting toxicant

Answer 6

Electrophiles highly reactive and form adducts with proteins and DNA. E.g alpha and beta unsaturated carbonyls

Question 7

Bioactivation-dependent toxicant

Answer 7

Electrophile metabolite is formed following metabolism (by Cytochrome P450) E.g NAPQI from paracetamol

Question 8

Drug-induced liver injury (DILI)

Answer 8

the unexpected harm to the liver caused by drugs (mainly lipophilic drugs). Remember that the liver is where most drug metabolising enzymes are.

Question 9

The liver is susceptible to toxicity bc:

Answer 9

• 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 10

Intrinsic DILI classification

Answer 10

Frequency: common
Predictability: predictable
Dose-related: Yes
Reproducible in animal models: Yes
Example: paracetamol

Question 11

Idiosyncratic DILI classification

Answer 11

Frequency: rare
Predictability: unpredictable
Dose-related: No
Reproducible in animal models: No
Example: NSAIDs

Question 12

Hepatic drug uptake and metabolism

Answer 12

• transporter-mediated uptake of drugs into hepatocytes on the basolateral membrane (SLC transporters)
• drug metabolism - can lead to the formation of reactive metabolites

Question 13

Molecular mechanisms of DILI (cell stress and injury) drug-protein adduct do what.

Answer 13

• drug-protein adduct inhibits protein functions causes cell stress, e.g., mitochondria (lead to formation of ROS)
• cell injury releases drug-protein adducts into extracellular environment → be seen as neoantigens to trigger immune response

The immune system may start attacking the liver cells that contain or release these adducts, leading to further liver damage and inflammation.

Question 14

Molecular mechanisms of DILI (BSEP and bile acid-induced stress)

Answer 14

• drug metabolites inhibit efflux transporters (e.g., BSEP [bile salt export pump]) on the apical membrane of hepatocytes increase intracellular bile acid mitochondrial damage
• bile acid-induced stress sensitise the cell to ligand-induced apoptosis and necrosis

Question 15

Intrinsic DILI - paracetamol

Answer 15

excessive use or overdose is a major cause of acute liver failure

Question 16

Paracetamol metabolism

Answer 16

CYP2E1-mediated NAPQI formation
↓
hepatotoxicity

glutathione conjugation
↓
NAPQI detoxification

Question 17

Paracetamol hepatotoxicity - mechanism

Answer 17

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 18

____ = acetaminophen (APAP)

Answer 18

paracetamol = acetaminophen (APAP)

Question 19

Liver-on-a-chip to study hepatotoxicity

Answer 19

• recreate 3D organ microenvironment
• multicellular environment; fluid flow, vascular perfusion
• inter-species differences

Question 20

paracetamol-mediated depletion of ____ (GSH) and inhibition
of ___ synthesis

Answer 20

glutathione and ATP

Question 21

Paracetamol increased reactive____ species formation

Answer 21

oxygen
* enhanced in the presence of BSO (buthionine sulfoximine, a GSH-
depleting agent)

Question 22

Idiosyncratic DILI - NSAIDs

Answer 22

NSAIDs (non-steroidal anti-inflammatory drugs)
* widely used non-opioid analgesics
* cause idiosyncratic DILI (aspirin is of exception - intrinsic DILI)

Question 23

Diclofenac

Answer 23

• reactive metabolites cause mitochondrial injury and oxidative stress
• drug-protein adducts act as neoantigens to trigger immune response
• forms reactive metabolites

Question 24

Diclofenac Metabolites

Answer 24

diclofenac-1’,4’-quinone imine
diclofenac-2,5-quinone imine
diclofenac acyl glucuronide

Question 25

Drug-induced nephrotoxicity

Answer 25

The kidneys are the major organ for drug excretion the patient factors as well as drug and kidney factors can lead to DIN

Question 26

NSAID-induced nephrotoxicity

Answer 26

Cyclooxygenase (COX) and the synthesis and functions of (prostaglandin E2) PGE2
NSAID causes inhibition of COX.
PGE2 is a pain mediator

Question 27

COX-1 (Cyclooxygenase)

Answer 27

COX-1 (constitutively active)
* involved in production of prostaglandin E2 that maintains renal blood flow of compromised kidneys
- e.g., vasodilation (relaxation of blood vessels)

Question 28

NSAID-induces acute renal function

Answer 28

NSAID inhibits the function of COX1 leading to reduced formation of PGE2 (which widens BV in compromised kidneys) leading to reduce blood flow in the kidneys and resulting in acute renal dysfunction.

Question 29

Acute kidney injury

Answer 29

• acute renal dysfunction - ↓ renal blood flow
• related to the mechanism of action of NSAIDs (i.e., COX inhibitors)
• acute interstitial nephritis - delayed hypersensitivity reactions

Question 30

When small amounts of NAPQI is in body what detoxifies it

Answer 30

Glutathione

Question 31

When glutathione decreases and NAPQI increases

Answer 31

damage and hepatotoxicity

Question 32

NAPQI is an electrophile or nucleophile metabolite

Answer 32

electrophile

Question 33

Bioactivation and direct acting toxicants explain what happens

Answer 33

A drug is bioactivated (metabolised) into an electrophilic metabolite that forms an adduct with proteins and DNA which goes on to cause damage and cell death.

Question 34

BSEP name

Answer 34

[bile salt export pump]

Question 35

Which NSAID does not cause idiosyncratic DILI

Answer 35

Aspirin

Question 36

acute interstitial nephritis

Answer 36

delayed hypersensitivity reactions

Question 37

drug-protein adducts

Answer 37

(complexes formed between a drug or its metabolite and cellular proteins)