THE TOXICITY OF ACETAMINOPHEN(PARACETAMOL

Most drugs, as well as toxins, toxoids and other
xenobiotic compounds, enter the body through
membranes of the gastrointestinal tract, lungs,
or skin. Drugs are frequently toxic if they
accumulate in the body. They are often rather
hydrophobic and are normally converted to more
polar, water-soluble substances before
elimination from the body. Two major types of
reaction take place (often termed phases 1 and
2) usually in the liver. Acetaminophen (N-acetyl-
p-aminophenol) is a widely used analgesic and
antipyretic (fever relieving) non-prescription drug
sold under a variety of trade names such as
paracetamol, panadol, among other names.
The drug is quite safe when taken in therapeutic
doses (1.2 g/day for an adult) but in large doses
(above 10 g) is highly toxic. 

This is because, in therapeutic amounts, 95% of the acetaminophen
present is enzymatically glucuronidated or
sulfated to the corresponding conjugates, which
are readily excreted. The remaining 5% is

converted, through the action of a cytochrome
P450 (CYP2E1), to acetimidoquinone(a highly
reactive quinone imine which reacts with cell
proteins),which is then conjugated with
glutathione, and subsequently excreted, thus
protecting the body from this reactive
intermediate(See figure below).
However, when acetaminophen is taken in large
amounts, the glucuronidation and sulfation
pathways become saturated and hence the
cytochrome P450-mediated pathway becomes
increasingly important. If hepatic (liver)
glutathione is depleted faster than it can be
replaced, acetimidoquinone, a reactive
compound, instead conjugates with the sulfhydryl
groups of cellular proteins, resulting in often fatal
hepatotoxicity, which is one classic hallmark of
paracetamol overdose.
As biochemists and students of biochemistry, we
can in turn, educate our people in our environs
(in simple terms) about the dangers inherent in
the abuse of this commonly used analgesic.