Drug metabolizing enzymes are are located in lipophilic membranes of endoplasmic reticulum (Cytochrome P450 (2E1, 1A2 and 3A4))
95% of paracetamol is conjugated with glucaronic acid or sulphate and excreted in urine. This is non-toxic.
5% is oxidized by the CYPs to form N-acetyl-P-benzoquinone imine (NAPQI), which is toxic.
NAPQI is conjugated with glutathione and mercapturic acid and cysteine conjugates and excreted in bile in normal metabolism.
In overdose
the glucaronic acid and sulphate pathways become saturated, so more goes via the NAPQI pathway.
Glutathione stores become depleted as it is consumed by the NAPQI.
NAPQI accumulates and begins conjugating hepatic proteins and nucleic acids, including those of the mitochondria.
Enzymes such as glutathione peroxidase, HMG-CoA, become inhibitedandradicals begin forming as the mitochondria are damaged.
In the cytosol, MAP kinase JNK is activated, which binds to Sab proteins on the outer mitochondrial membrane, which in turn deactivates p-Src on the inner mitochondrial membrane.
This inhibits electron transport.
Moreradicalsare released and there is more oxidative stress.
There is mitochondrial and cell death leading to necrosis if not treated early enough.
Liver function tests:
GGT elevated
Bilirubin elevated
ALP elevated
AST and ALT extremely high
Becoming higher than 100 times the upper reference limit in toxic ingestion. No other hepatic conditions increase AST/ALT to these levels.
Decreased albumin once necrosis forms – many other conditions of the liver don’t reach this stage
