L16 Target Organ Toxicity Flashcards
Local toxicity
Toxic effects occur at the site of first contact due to extreme physicochemical properties of toxicants. EG=.g skin, eyes and lungs
Systemic toxicity
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
Target organ toxicity
Toxicants cause damage to particular organs
hepatotoxicity
Toxic liver disease is damage to your liver
nephrotoxicity
rapid deterioration in the kidney function due to toxic effect of medications and chemicals.
Direct-acting toxicant
Electrophiles highly reactive and form adducts with proteins and DNA. E.g alpha and beta unsaturated carbonyls
Bioactivation-dependent toxicant
Electrophile metabolite is formed following metabolism (by Cytochrome P450) E.g NAPQI from paracetamol
Drug-induced liver injury (DILI)
the unexpected harm to the liver caused by drugs (mainly lipophilic drugs). Remember that the liver is where most drug metabolising enzymes are.
The liver is susceptible to toxicity bc:
- 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
Intrinsic DILI classification
Frequency: common
Predictability: predictable
Dose-related: Yes
Reproducible in animal models: Yes
Example: paracetamol
Idiosyncratic DILI classification
Frequency: rare
Predictability: unpredictable
Dose-related: No
Reproducible in animal models: No
Example: NSAIDs
Hepatic drug uptake and metabolism
- transporter-mediated uptake of drugs into hepatocytes on the basolateral membrane (SLC transporters)
- drug metabolism - can lead to the formation of reactive metabolites
Molecular mechanisms of DILI (cell stress and injury) drug-protein adduct do what.
- 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.
Molecular mechanisms of DILI (BSEP and bile acid-induced stress)
- 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
Intrinsic DILI - paracetamol
excessive use or overdose is a major cause of acute liver failure
Paracetamol metabolism
CYP2E1-mediated NAPQI formation
↓
hepatotoxicity
glutathione conjugation
↓
NAPQI detoxification
Paracetamol hepatotoxicity - mechanism
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
____ = acetaminophen (APAP)
paracetamol = acetaminophen (APAP)
Liver-on-a-chip to study hepatotoxicity
- recreate 3D organ microenvironment
- multicellular environment; fluid flow, vascular perfusion
- inter-species differences
paracetamol-mediated depletion of ____ (GSH) and inhibition
of ___ synthesis
glutathione and ATP
Paracetamol increased reactive____ species formation
oxygen
* enhanced in the presence of BSO (buthionine sulfoximine, a GSH-
depleting agent)
Idiosyncratic DILI - NSAIDs
NSAIDs (non-steroidal anti-inflammatory drugs)
* widely used non-opioid analgesics
* cause idiosyncratic DILI (aspirin is of exception - intrinsic DILI)
Diclofenac
- reactive metabolites cause mitochondrial injury and oxidative stress
- drug-protein adducts act as neoantigens to trigger immune response
- forms reactive metabolites
Diclofenac Metabolites
diclofenac-1’,4’-quinone imine
diclofenac-2,5-quinone imine
diclofenac acyl glucuronide
Drug-induced nephrotoxicity
The kidneys are the major organ for drug excretion the patient factors as well as drug and kidney factors can lead to DIN
NSAID-induced nephrotoxicity
Cyclooxygenase (COX) and the synthesis and functions of (prostaglandin E2) PGE2
NSAID causes inhibition of COX.
PGE2 is a pain mediator
COX-1 (Cyclooxygenase)
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)
NSAID-induces acute renal function
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.
Acute kidney injury
- acute renal dysfunction - ↓ renal blood flow
- related to the mechanism of action of NSAIDs (i.e., COX inhibitors)
- acute interstitial nephritis - delayed hypersensitivity reactions
When small amounts of NAPQI is in body what detoxifies it
Glutathione
When glutathione decreases and NAPQI increases
damage and hepatotoxicity
NAPQI is an electrophile or nucleophile metabolite
electrophile
Bioactivation and direct acting toxicants explain what happens
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.
BSEP name
[bile salt export pump]
Which NSAID does not cause idiosyncratic DILI
Aspirin
acute interstitial nephritis
delayed hypersensitivity reactions
drug-protein adducts
(complexes formed between a drug or its metabolite and cellular proteins)
