Formation of Sulfur Adducts of N‑Acetyl‑p‑benzoquinoneimine, an Electrophilic Metabolite of Acetaminophen in Vivo: Participation of Reactive Persulfides

While N-acetyl-p-benzoquinoneimine (NAPQI), an electrophilic metabolite of acetaminophen (APAP), has been found to undergo GSH conjugation associated with its detoxification, interaction of NAPQI with nucleophilic per- and polysulfides produced by cystathionine γ-lyase (CSE), cystathionine β-synthase, and/or other enzymes is not known. In the present study, we found that sulfur adducts such as the NAPQIH₂–SSSCys adduct and the NAPQIH₂–SSG adduct are produced in biological samples of mice upon APAP exposure. Our in vitro experiments indicated that the formation of these novel APAP metabolites is, at least in part, attributable to the interaction of CysSS_nSH produced by CSE and GSH persulfide with APAP-derived NAPQI.