Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. Nassini R1, Materazzi S, Andrè E, Sartiani L, Aldini G, Trevisani M, Carnini C, Massi D, Pedretti P, Carini M, Cerbai E, Preti D, Villetti G, Civelli M, Trevisan G, Azzari C, Stokesberry S, Sadofsky L, McGarvey L, Patacchini R, Geppetti P.
Acetylcysteine is considered to reduce the hepatic toxicity of NAPQI (n-acetyl-p-benzo-quinoneimine), the highly reactive intermediate metabolite following ingestion of a high dose of paracetamol, by at least two mechanisms. First, acetylcysteine acts as a precursor for the synthesis of glutathione and, therefore, maintains cellular glutathione at a level sufficient to inactivate NAPQI. This is thought to be the main mechanism by which acetylcysteine acts in the early stages of paracetamol toxicity.
The hepatic cytochrome P450 enzyme system (specifically CYPA2 and CYP2E1, and to a lesser extent CYP2D6) metabolizes paracetamol. A minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinoneimine) is formed. NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione to form mercapturic acid conjugates and cysteine.
APAP, acetaminophen; ConA, Concanavalin-A; NAPQI, N-acetyl-p-benzo-quinoneimine.