Electron attachment to antipyretics: possible implications of their metabolic pathways.
The empty-level structures and formation of negative ion states via resonance attachment of low-energy (0-15 eV) electrons into vacant molecular orbitals in a series of non-steroidal anti-inflammatory drugs (NSAIDs), namely aspirin, paracetamol, phenacetin, and ibuprofen, were investigated in vacuo by electron transmission and dissociative electron attachment (DEA) spectroscopies, with the aim to model the behavior of these antipyretic agents under reductive conditions in vivo. The experimental findings are interpreted with the support of density functional theory calculations. The negative and neutral fragments formed by DEA in the gas phase display similarities with the main metabolites of these commonly used NSAIDs generated in vivo by the action of cytochrome P450 enzymes, as well as with several known active agents. It is concluded that xenobiotic molecules which possess pronounced electron-accepting properties could in principle follow metabolic pathways which parallel the gas-phase dissociative decay channels observed in the DEA spectra at incident electron energies below 1 eV. Unwanted side effects as, e.g., hepatoxicity or carcinogenicity produced by the NSAIDs under study in human organism are discussed within the "free radical model" framework, reported earlier to describe the toxic action of the well-known model toxicant carbon tetrachloride.
Institute of Molecule and Crystal Physics, Ufa Research Centre, Russian Academy of Sciences, Prospekt Oktyabrya 151, 450075 Ufa, Russia. sapsh@anrb.ru
Stanislav A
SA
Pshenichnyuk
Alberto
A
Modelli
D000082:Acetaminophen / Q000737:chemistry* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism; D058633:Antipyretics / Q000737:chemistry* / Q000378:metabolism; D001241:Aspirin / Q000737:chemistry* / Q000378:metabolism; D004583:Electrons; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry* / Q000378:metabolism; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D010615:Phenacetin / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory
D000894:Anti-Inflammatory Agents, Non-Steroidal; D058633:Antipyretics; D007477:Ions; D000082:Acetaminophen; D010615:Phenacetin; D001241:Aspirin; D007052:Ibuprofen