Acetaminophen (APAP), a widely used analgesic and antipyretic agent, is bioactivated

by cytochromes P450 to cause severe hepatotoxicity. APAP is oxidized by two

pathways to form a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), and a
nontoxic catechol metabolite, 3-hydroxy-APAP (3-OH-APAP).

Acetaminophen + P450 2E1 = NAPQI, also known as NAPBQI or

N-acetyl-p-benzoquinone imine, is a toxic byproduct produced during the xenobiotic
metabolism of the analgesic paracetamol. It is normally produced only in small amounts,
and then almost immediately detoxified in the liver.

APAP is bioactivated to the reactive intermediate (NAPQI)276 by three CYP-450

isoforms: CYP3A4, CYP2E1, and CYP1A2 of which CYP2E1 is the most important. The

contribution of CYP3A4 to the production of NAPQI is controversial.277,278 NAPQI is

then conjugated with the sulfhydryl group of glutathione to form a nontoxic conjugate.

APAP overdoses initially saturate sulfation, followed by glucuronidation; increased

NAPQI production depletes glutathione stores, leading the NAPQI to bind to intracellular

hepatic macromolecules to produce cell necrosis and damage.

At nontoxic doses, the metabolite was efficiently detoxified by glutathione forming an

acetaminophen-glutathione conjugate (Jollow et al. 1974). However, at toxic doses, the

metabolite depleted hepatic glutathione by as much as 80–90% (Jollow et al. 1974;

Mitchell et al. 1973a, b) and subsequently covalently bound to protein. The amount of

covalent binding correlated with the relative hepatotoxicity

Subsequently, the reactive metabolite of acetaminophen was identified to be

N-acetyl-p-benzoquinone imine (NAPQI). It was found to be formed by cytochrome

P-450 (CYP) by direct two-electron oxidation of acetaminophen

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