Hepatotoxicity Flashcards
paracetamol (acetaminophen)
After low level doses (< 4 g/day), paracetamol is converted to glucuronide and sulphate conjugates (95%), with minor levels of NAPQI produced, or excreted unchanged.
At supra-therapeutic doses (> 4 g/day), the sulfation pathway is saturated, glucuronidation and oxidation increase, and a smaller amount is excreted unchanged.
After toxic doses (> 7-10 g), glucuronidation saturates as well and higher proportions oxidise to NAPQI via CYP450 metabolism.
Excess NAPQI eventually depletes GSH stores and starts to form protein adducts by binding cysteine groups on cellular proteins → hepatic toxicity.
The patient is decontaminated with active charcoal. If required, there is further treatment with N-acetylcysteine, which primarily works by replenishing hepatic glutathione
Metacetamol, a meta-substituted version of paracetamol, is non-toxic
Methapyrilene
Antihistaminergic with some anticholinergic properties, with strong sedative properties, originally used to treat insomnia.
Carcinogenicity in mice via activation of rat CYP2C11, possibly via a thiophene-s-oxide reactive metabolite
This reaction depletes hepatocyte Glutathione, with evidence of mitochondrial toxicity including reduced fatty acid oxidation (steatosis) and elevated ammonia.
Non-genotoxic carcinogen via modified histone methylation and DNA interactions
Thioacetamide
Oxidised to Thioacetamide-s-oxide and a very reactive thioacetamide s,s-dioxide.
It preferentially reacts with amino groups, especially lysine residues associated with histone proteins, so it affects DNA coiling and therefore replication, having non-genotoxic carcinogenic effects.
This leads to centrilobular necrosis, hyper-bilirubinaemia and cholestasis.
N-Nitrosodimethylamine
N-Nitrosodimethylamine is generated in food treated with nitrite, such as cured meat products including bacon, and found in cigarettes.
Following P450-mediated activation to a reactive ethanolamine, particularly through ethanol-induced CYP2E1, DNA adducts are formed.
Ranitidine was rapidly withdrawn when it was discovered that it decomposes to N-Nitrosodimethylamine.
Microcystin
Microcystin, toxins from blooms of blue-green algae, comprise a cyclic penta-peptide, of which microcystin-leucine arginine (MC-LR) is the most studied.
These accumulate in the liver via the OATP-1 uptake transporter
Potent inhibitors of protein phosphatases PP1 and PP2A, leading to cytoskeletal effects, apoptosis, liver failure and sometimes hepato-carcinoma.
Rifampicin blocks OATP-1 so this is useful in the treatment of Microcystin poisoning. This may cause cholestasis, another form of toxicity, but this is better tolerated
Death Cap (Amanita Phalloides)
Amanitin and Phalloidin are both found in death cap mushrooms.
Phalloidin enters hepatocytes via the OATP transporter and causes cholestasis and haemorrhagic necrosis by binding strongly to actin filaments.
Amanitin is water soluble and rapidly absorbed from the GI tract, stable to heat/cooking and not extensively metabolised.
It enters hepatocytes via the OATP1B3 transporter, causing centri-lobular hepatocellular necrosis and intra-hepatic haemorrhage. Renal toxicity is also reported.
Amanitin inhibits RNA polymerase II, blocking protein synthesis and leading to cell death –> potential use as cancer treatment.
Other features are apoptosis following loss of mitochondrial membrane potential, oxidative stress and lipid peroxidation.
Treatment: diuresis and dyalisis to flush out, antioxidants, Rifampicin to block OATP1, silibinin to block OATP1B3 specifically.
Ragwort - monocrotaline (pyrrolizidine alkaloid)
Pyrrolizidine alkaloids are widespread in plants. Monocrotaline is an example found in Ragwort.
Enters hepatocytes through OATP1 and is activated to monocrotaline pyrrole by CYP3A4.
Alkylating agent.
Prime target is sinusoidal endothelial cells, causing intrahepatic haemorrhage, but it also produces a centrilobular tissue necrosis, cirrhosis and liver failure.
The lung is a secondary target for monocrotaline toxicity. The reactive metabolite may be transported from the liver or metabolic activation may also occur in the lung.
Monocrotaline pyrrole binds to glutathione, lysine residues, and DNA –> liver cancer
Aflatoxins (Mycotoxins)
Produced by Aspergillus Flavus moulds that grow on nuts, corn wheat, peanuts and rice.
Potent hepatic carcinogens.
Aflatoxins include aflatoxin B1 (AFB1).
Metabolised by CYPs to aflatoxin epoxide, which binds to guanine residues on DNA, causing changes in structure and function and so mutations and genomic instability –> cancer.
FB1 exposure can induce oxidative stress by generating reactive oxygen species (ROS), further contributing to DNA damage and cellular dysfunction.
Glutathione can offer some protection.
Other Aflatoxin metabolites, including Aflatoxin di-hydrodiol and Aflatoxin dialdehyde, may form lysine adducts.
Toxicity causes abdominal pain, emesis, steatosis, necrosis and carcinoma, convulsions, teratogenicity.
Ethanol - Steatosis
Ethanol is converted to acetaldehyde by ADH, then acetate by ALDH.
Acetaldehyde is the main toxic agent.
Acute alcohol toxicity involves respiratory depression, potentially via GABA activation.
Chronic toxicity involves early steatosis through steatohepatitis (lipid accumulation and inflammation), eventually causing cirrhosis.
Steatosis occurs when mitochondrial beta-oxidation of fatty acids is inhibited. This is also caused by tamoxifen and tetracycline.
Cirrhosis occurs when steatohepatitis and inflammation cause fibrosis through collagen I and III deposition, at expense of collagen IV loss. Stellate cell activation is critical to this process.
Toxicity markers include raised plasma ammonia and bilirubin, and later on suppressed albumin and reduced clotting factors.
Ethanol intoxication leads to an increase in gut-derived LPS in the hepatic portal vein being presented to the liver due to a leaky gut. This leads to Kupffer cell activation, induction of iNOS and increased levels of peroxynitrite.
Ethanol inhibits PPAR-alpha signalling, further suppressing beta oxidation.
Iron overload is considered a factor in liver pathology → Ferroptosis may occur
Polymorphisms in aldehyde dehydrogenase in far eastern populations mean that individuals are very sensitive to ethanol.
Cholestasis
Cholestasis may arise through inhibition of bile secretion or blockade of the bile duct.
It may present as fatigue, pruritus (itching) and jaundice.
It causes elevated serum concentrations of substances normally found in bile, inc. bilirubin (jaundice) and bile salts like colic acid.
There are also elevated liver marker enzymes, such as ALT, ALP and GGT.
Hepatocyte injury caused by bile salts occurs as bile is not secreted, but retained within the hepatocytes.
Can be caused by: Antibiotics, Chlorpromazine, Anabolic steroids, oral contraceptives and Carbamazepine. Flucloxacillin is an antibiotic that causes rare but serious cholestasis.
Cholestasis may occur due to disruption of bile acid homeostasis or polymorphisms and modifications of transporters involved in the export of bile.
Halothane
Causes acute liver failure via an immunologic mechanism.
Halothane is converted to a trifluoroacetylated adduct which binds to liver proteins to form a CF3CO- modified hepatic microsomal protein.
Altered liver microsomal proteins are recognised as a foreign antigen and cause antibody/immune response.
Subsequent exposure causes cellular sensitisation, so there is antibody attack of hepatocytes.
This leads to immune-mediated hepatic injury (halothane hepatitis).
