title: A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione.
abstract: Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies (ΔG(ǂ)) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G (d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting (ΔG(ǂ) = 26.7 kcal/mol) and consists of formation of a C-N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with ΔG(ǂ) of 13.8 kcal/mol. The depurination reaction that follows has a ΔG(ǂ) of 25.7 kcal/mol. The calculated ΔG(ǂ) for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with a QI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administered with caution.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia; Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Klopčič
authors.affiliation: Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; Department of Physical and Organic Chemistry, Institute "Jožef Stefan", Jamova Cesta 39, 1000 Ljubljana, Slovenia.
authors.forename: Matic
authors.initials: M
authors.lastname: Poberžnik
authors.affiliation: Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia. Electronic address: janez.mavri@ki.si.
authors.forename: Janez
authors.initials: J
authors.lastname: Mavri
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Marija Sollner
authors.initials: MS
authors.lastname: Dolenc
mesh_terms: D000082:Acetaminophen / Q000378:metabolism*; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D003849:Deoxyguanosine / Q000737:chemistry* / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism*; D007097:Imines / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D008958:Models, Molecular; D008968:Molecular Conformation; D011789:Quantum Theory
chemical_list: D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine; D003849:Deoxyguanosine; D005978:Glutathione
keywords: Acetaminophen; Chemical reactivity; Genotoxicity; Glutathione; Quantum chemistry; Quinone imine metabolite