Hepatotoxicity Flashcards
What is the main function of the liver?
Responsible for filtering blood and making bile.
Supports proper function of virtually all organs and tissues.
What are the four sources from which the liver receives blood?
The liver receives blood from four sources.
What is the main type of metabolism involved with the addition/removal of components to the blood and bile?
Protein metabolism.
Breakdown product of RBCs (heme) metabolism tints urine color and gives it a smell.
What is a lobule?
The functional unit of the liver, consisting of a bunch of hepatocytes.
What is the most common model of hepatic micro architecture?
Lobular model.
What is an alternative type of liver model?
Acinar model.
What is a Kupffer cell?
A macrophage in the liver that clears particulates.
What is a hepatocyte?
A parenchymal liver cell that performs all functions ascribed to the liver.
What is a dendritic cell?
A specialized type of monocyte that displays antigens on its cell surface.
What is a stellate cell?
A neuron characterized by a radial, star-like distribution of dendrites, found in the space of Disse.
What are cholangiocytes?
Epithelial cells of hepatic ductules that modify the composition of bile.
What can cause stress and lead to toxicity in the liver?
Modulations/disruptions in liver function.
What can alcohol abuse lead to in terms of liver function?
Alcohol abuse leads to deposition of collagen and differentiation of myofibroblasts in the space of Disse.
What is the space of Disse?
The space between sinusoids and hepatocytes.
What cell types are activated under liver stress?
Kupffer cells and stellate cells.
What are functional liver units called?
Acini (acinus).
How are functional liver units subdivided?
Into three zones: zone 1 (peri-lobular), zone 2 (mid-lobular), and zone 3 (centri-lobular).
What is a sinusoid?
Cellular borders of blood that mix the blood.
What specializes hepatocyte function along zones?
Differential enzyme expression.
What are different areas of the acinus susceptible to?
Different toxins due to different cellular characteristics.
What are inducers of zone 1 necrosis?
Allyl alcohol and phosphorus.
What is zone 1 necrosis characterized by?
High levels of glutathione and oxygen, leading to O2 free radical induced necrosis.
What are inducers of zone 3 necrosis?
Alpha-amanitin, acetaminophen, CCl3, chloroform, halothane.
What is zone 3 necrosis characterized by?
High CYP2E1, high alcohol dehydrogenase, and low oxygen.
Which zone is the most susceptible to damage?
Zone 3.
Why is zone 3 most susceptible?
Due to increased risk of ATP depletion.
What transporters do hepatocytes express?
OATPs, BSEP, MRP2, BCRP, MDR.
What are bile acids?
Cholesterol derivatives.
How much bile does the liver synthesize daily?
600-1000 mg.
What is the total bile pool?
~3g, stored in the gallbladder.
What is canalicular cholestasis?
Disruption in the production of biliary secretion.
How can canalicular cholestasis be detected?
Through bloodwork for enzymes.
What are clinical symptoms of canalicular cholestasis?
Jaundice and inflammation.
What is jaundice?
Failure to break down bilirubin from hemoglobin.
What hormones inhibit BSEP from the canalicular side?
Estrogen and progesterone.
What drugs can inhibit BSEP?
Troglitazone and rifampicin.
What triggers inflammatory/stress gene expression and liver damage?
Build-up of salt.
What is apoptosis mediated cell death largely dependent on?
Death receptor dependent (extrinsic apoptotic pathway).
What causes swelling of the liver?
Blockage of sinusoids, especially in zone 3.
What happens when liver function declines?
Poor blood filtration.
What can cause liver function decline?
Cytoskeletal changes in endothelium and collapse of space of Disse.
What is veno-occlusive disease?
Cytoskeletal changes in endothelium and collapse of space of Disse.
What can indicate early liver toxicity?
Cholangiocyte swelling.
What is bile duct damage?
Ducts carry bile acids to the GI tract, lined by cholangiocytes.
What is a sign of toxicity?
Initial cholangiocyte swelling.
What chronic toxicity causes?
Biliary proliferation and fibrosis.
What is vanishing bile duct syndrome?
Progressive destruction of intrahepatic bile ducts.
What can cause vanishing bile duct syndrome?
Some antibiotics, anabolic steroids, contraceptive steroids, and carbamazepine.
What do stressed cells activate?
Apoptotic or necrotic death pathways.
What are the two bile-induced death pathways?
- Mito-caspase 8-caspase 3-Bcl2 family proteins-cytochrome c release.
- Fas-dependent classical (FADD)-DISC-cFLIP-caspase cascade.
How do hydrophilic acids oppose homeostatic disturbances?
Using cAMP, PI3K, MAPK.
How do hydrophobic acids induce apoptosis?
By cytokine storm followed by cell surface death-receptor mediated signaling.
What are microcystin characteristics?
Cyanobacteria and environmental blooms.
What is the pharmacokinetics of microcystin?
Taken up by OATPs, conjugated by glutathione.
What does microcystin cause?
Phosphorylation of cytoskeletal proteins, leading to hepatocyte deformation.
What happens at low doses of microcystin?
Inhibition of dynein motor protein affecting sub-cellular trafficking.
What is acetaminophen (APAP) known for?
The most common cause of liver injury in Canada, USA, and UK.
What does APAP cause?
Hepatotoxicity via cell death and fibrosis.
What happens at therapeutic doses of APAP?
90% is conjugated and non-toxic.
What causes APAP toxicity?
Saturation of glucuronidation and sulfation pathways at high doses.
What does NAPQI facilitate?
Redox cycling and free radical generation.
What happens once GSH is depleted?
Free radicals cause damage.
What does NAC1 provide?
Sulfur for the PST reaction.
What does NAC2 provide?
Cysteine to regenerate GSH.
What does NAC3 do?
Substitutes for GSH.
What does NAC4 prevent?
NAPQI toxicity.
What does NAPQI covalently modify?
Proteins, especially in the mitochondria.
What happens when MPTP opens?
Mitochondrial dysfunction occurs.
What does mitochondrial dysfunction from APAP toxicity cause?
Apoptosis or necrosis depending on kinetics.
What continues to spread injury to adjacent cells?
Release of DNAse 1 and calpains from ruptured cells.
How can APAP toxicity be treated?
With n-acetylcysteine (NAC).
What is chloroform?
Not an ultimate poison; can be reduced or oxidized.
What does the oxidative pathway of chloroform involve?
Dechlorination to trichloromethanol and then to phosgene.
What is phosgene?
Highly reactive and acetylates proteins, carbohydrates, and lipids.
What does phosgene deplete?
GSH stores, inducing severe oxidative stress.
What is steatosis?
Fat in stool, indicating liver failure.
What does the reductive pathway of chloroform involve?
Dichloromethyl free radical labeling enzymes and phospholipids.
What are the three stages of alcoholic liver disease?
- Development of fatty liver.
- Alcoholic hepatitis.
- Cirrhosis.
How does liver function decrease?
Through stages of alcoholic liver disease.
What happens to excess acetate?
Converted to acetyl-CoA by thiokinase.
