Hepatotoxicology Flashcards
Liver overview
nutrients and substances from GIT delivered to the liver
Forms urea and glycogen synthesis/storage.
Synthesises bile acids and are secreted through OATs
Synthesises albumin, clotting factors, V-LDLP, triglycerides, bilirubin, haem, and recycles iron.
Metabolises and conjugates metabolites.
leaky gut causes bacterial lipopolysaccharides (LPS) to be present in liver
causes of liver failure
reactive metabolites causing necrosis and hepatocyte death, e.g., paracetamol
steatosis (fatty liver) from mitochondrial inhibition or fatty acid beta-oxidation inhibition.
cholestatic agents can inhibit bile acid secretion or disrupt bile flow
Vascular damage can cause liver damage.
Cancer
Liver biomarkers
alanine aminotransferase (ALT) shows damage to hepatocytes
aspartate aminotransferase (AST) shows damage to hepatocytes (also seen in heart damage
alkaline phosphatease (ALP) shows bile duct damage (also seen in renal and bone damage)
gamma glutamyl transpeptidase (GGT) indicates bile duct injury (or renal damage)
Bile salts, bilirubin or biliverdin in the blood indicate biliary damage.
mir-122 is a highly selective marker of liver damage
CYP enzymes in liver toxicity and examples and glutathione depletion
While they mostly detoxify, they can also cause the conversion of compounds into reactive metabolites.
Many drugs may also cause inhibition or induction of CYP enzymes leading to DDIs
Grapefruit juice causes inhibition of CYP3A4 - nifedipine interaction.
Pimozide can cause QT prolongation which is exacerbated by enzyme inhibition increasing its half-life.
glutathione depletion can lead to toxicity where the liver can no long conjugate drugs, e.g., NAPQI.
Methapyrilene toxicity mechanism
an antihistamine with some AChR antagonism. insomnia drug.
Depletes glutathione causing mitochondrial toxicity leading to staetosis and elevated ammonia. this can cause peri-portal necrosis. Occurs via histone methylation
Thioacetamide mechanism
causes centrilobular necrosis by reacting to amino groups (lysine residues)
N-nitrosodimethylamine mechanism
generated in food treated with nitrite (e.g., bacon) and found in cigs.
Ranitidine was withdrawn because it decomposes into this.
It is activated to ethanolamine by CYP, causing DNA adducts to form
Transporter mediated toxin accumulation in the liver example
microcrystin (Cyanobacteria) is found in blue green algae. OATP-1 mediated accumulation.
Inhibits protein phosphatase PP1 and PP2A causing apoptosis, liver failure and hepato-carinoma. rifampicin (OATP-1 inhibitor) useful for treating.
Mechanism of death cap toxicity
Contains amanitin and phalloidin.
Phalloidin enters liver through OATP1 causing cholestasis and haemorrhage necrosis. also binds actin filaments strongly.
Amanitin enters via OATPs (1B3) and causes necrosis and haemorrhage by inhibiting ribonucleic acid polymerase II blocking protein synthesis. also causes apoptosis, oxidative stress and lipid peroxidation.
diuretics, dialysis, antioxidants (NAC) and OATP1B3 inhibitors to treat
ragwort poisoning mechanism
can be present in milk and honey.
mediated by pyrrolizidine alkaloids which enters hepatocytes through OATP1 and is metabolised into an alkylating agent. causes intrahepatic haemorrhage and necrosis. can lead to cirrhosis and liver failure
It is metabolised into monocrotaline pyrrole which binds to glutathione, lysine residues and DNA.
The lung is also a secondary target.
Aflatoxins mechanism
found in fungal contaminated foods
potent carcinogens.
Metabolised by CYP into reactive metabolites - aflatoxin epoxide binds to guanine residues. other metabolites form lysine adducts.
Fatty liver/steatosis
caused by free fatty acids from diet which can become esterified with glycerol to form triglycerides. will conjugate VLDL which will transport them.
Steatosis can occur when drugs inhibit beta-oxidation of these free fatty acids, e.g., tamoxifen, valproic acid, and ethanol
Can progress to fibrosis (cirrhosis)
Alcohol can also inhibit PPAR-a signalling, further suppressing beta-oxidation.
Durian can also worsen alcohol toxicity by inhibiting ALDH.
Cholestasis mechanism and toxicity
impair bile flow
Biomarkers are raised bilirubin, bile salts, ALT, ALP, and GGT.
Can cause hepatocyte injury as the bile salts are retained in the liver.
Antibiotics, anabolic steroids, and oral contraceptives can cause
Other hepatotoxic compounds
nitrofurantoin can cause hepatic and pulmonary toxicity.
Allyl alcohol metabolised into acrolein
