Metabolism of Paracetamol/Acetaminophen in Mammals
In most mammals, Paracetamol is primarily biotransformed to nontoxic products
in the liver via conjugation with glucuronic acid and, to a lesser degree, sulfate,
and eliminated by the kidneys . Concurrently, a small proportion of Paracetamol
is metabolized through the cytochrome P-450 enzyme pathway producing a highly
reactive and toxic metabolite, N-acetyl-para-benzoquinoneimine (NAPQI) . The
toxic effects of NAPQI are normally limited by its conjugation with glutathione.
Glutathione, which is widely distributed in mammalian tissues, is essential for
cellular protection against oxidative injury by electrophilic radicals. In most
mammals, Paracetamol exposure becomes toxic when glucuronidation and
sulfation pathways become saturated and cellular glutathione stores are depleted to
less than 70% of normal values. In such cases, NAPQI binds to cellular proteins
and membranes, causes disruption of protein function and damage to cell
membranes, and leads to cell injury and death, typically of hepatocytes.
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Paracetamol is primarily metabolized in the liver through Phase I (oxidation) and
Phase II (conjugation) pathways. The balance between these pathways determines
its safety (therapeutic use) and toxicity (overdose risks).
1. Phase II Metabolism (Major Pathway – Safe Elimination)
Glucuronidation (60-70%)
Enzyme: UDP-glucuronosyltransferase (UGT1A1, UGT1A6, UGT1A9)
Product: Paracetamol glucuronide** (water-soluble, excreted in urine).
Sulfation (20-30%)
Enzyme: Sulfotransferase (SULT1A1, SULT1A3)
Product: Paracetamol sulfate (water-soluble, excreted in urine).
Note: These pathways dominate at therapeutic doses, ensuring safe elimination.
2. Phase I Metabolism (Minor Pathway – Toxicity Risk)
Oxidation (5-10%) via CYP2E1 (and minor contributions from CYP3A4,
CYP1A2):
Product: N-acetyl-para-benzoquinone imine (NAPQI) – a highly reactive, toxic
metabolite.
Detoxification: NAPQI is neutralized by glutathione (GSH) → Forms non-toxic
mercapturate conjugate (excreted in urine).
Acetaminophen/Paracetamol Toxicity in Cat:
For several reasons, cats are extremely sensitive to the toxic effects of
acetaminophen. Cats form glucoronides with many compounds slowly, or not at
all, because they possess fewer isoforms of the enzymes that mediate the
conjugation, that is, glucuronyl transferases. More specifically, cats have a relative
absence of a specific high-affinity acetaminophen glucuronoyl transferase that
conjugates acetaminophen with glucuronic acid . This relative deficiency of the
glucuronide conjugation pathway results in more drug being conjugated to sulfates;
however, the sulfation pathway has a finite capacity, which is also lower in cats
than other species . Once the sulfation pathway reaches its capacity,
acetaminophen is allowed to persist in the blood and more is metabolized by
cytochrome P-450 enzymes to NAPQI. Glutathione synthesis is suppressed by high
levels of acetaminophen and the presence of NAPQI rapidly depletes glutathione
stores.
Erythrocytes are the cells most susceptible to the effects of NAPQI in cats, and
there are 2 sites in erythrocytes that are most susceptible to oxidative injury: the
iron in heme and the sulfhydryl groups of the globulin chains. Being electrophilic,
NAPQI causes the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+), which
converts hemoglobin to methemoglobin . Since cats also have a relative lack of
methemoglobin reductase in erythrocytes, methemoglobinemia is a much earlier
and more prominent feature of acetaminophen toxicity in this species, relative to
most others.
The Antidote Mechanism of paracetamol poisoning
N-Acetylcysteine (NAC) works through the 3 key mechanisms to treat paracetamol
overdose:
1. GSH Precursor
NAC provides cysteine → Boosts glutathione (GSH) synthesis → Binds and
detoxifies NAPQI.
2. Direct Scavenging
NAC itself can react with NAPQI, acting as an alternative thiol donor.
3. Anti-inflammatory & Antioxidant Effects
Reduces oxidative stress and mitochondrial damage in hepatocytes.
Problem in Overdosing in Mammals
In overdose, GSH is depleted → NAPQI accumulates → Liver necrosis.
Key Clinical Implications metabolism of Paracetamol
Therapeutic Dose:
- Mostly metabolized via glucuronidation/sulfation → Safe excretion.
Overdose (Toxic Dose):
- CYP2E1 generates excess NAPQI → GSH depletion → Oxidative stress → Liver
damage.
Treatment: N-acetylcysteine (NAC) (replenishes GSH, detoxifies NAPQI).
Why Does Paracetamol Cause Liver Damage?
Overdose saturates Phase II pathways → More NAPQI forms → Liver’s GSH is
overwhelmed → Oxidative injury to hepatocytes.
