Quinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapine: activation pathway to amino acid adducts

摘要: Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission virus; however, severe hepatotoxicity serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable undergoing further metabolic oxidation electrophilic quinoid prone react with bionucleophiles initiate toxic responses. We investigated ability two metabolites, 2-hydroxy-NVP 3-hydroxy-NVP, undergo subsequent reaction bionucleophiles. Both metabolites yielded same ring-contraction product upon Fremy's salt aqueous medium. This consistent formation 2,3-NVP-quinone intermediate, which stabilization by reduction was fully characterized mass spectrometry nuclear magnetic resonance spectroscopy. Additionally, we established that oxidative activation involved transient quinone quinone-imine, whereas 3-hydroxy-NVP selectively converted into 2,3-NVP-quinone. The oxidations presence model amino acids ethyl valinate (to mimic highly reactive N-terminal valine hemoglobin) N-acetylcysteine were also investigated. Ethyl reacted NVP-quinone-imine, yielding covalent adducts. By contrast, neither nor NVP-derived quinone-imine N-acetylcysteine. profile observed replicated myeloperoxidase-mediated oxidation. tyrosinase-mediated 2,3-NVP-quinone-derived products, while quinone-imine-derived products obtained lactoperoxidase catalysis. These observations suggest conversion electrophiles biologically plausible. Moreover, lack sulfhydryl groups might hamper vivo detoxification via glutathione conjugation. As result, these could be available for nitrogen-based (e.g., lysine residues proteins) ultimately eliciting events.