A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione

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 (Delta G double dagger) 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 (Delta G double dagger 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 Delta G double dagger of 13.8 kcal/mol. The depurination reaction that follows has a Delta G double dagger of 25.7 kcal/mol. The calculated Delta G double dagger 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.