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Quinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapine

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dc.contributor.authorHarjivan, Shrika G.
dc.contributor.authorPinheiro, Pedro F.
dc.contributor.authorMartins, Inês L.
dc.contributor.authorGodinho, Ana L.
dc.contributor.authorWanke, Riccardo
dc.contributor.authorSantos, Pedro P.
dc.contributor.authorPereira, Sofia A.
dc.contributor.authorSA, Pereira
dc.contributor.authorBeland, Frederick A.
dc.contributor.authorMarques, M. Matilde
dc.contributor.authorAntunes, Alexandra M M
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblOxford University Press
dc.date.accessioned2023-05-11T22:07:53Z
dc.date.available2023-05-11T22:07:53Z
dc.date.issued2015
dc.descriptionFunding: This work was supported in part by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013 and IF/ 01091/2013/CP1163/CT0001), and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. RW, ALG, ILM and SGH thank FCT for postdoctoral and doctoral fellowships (SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010 and SFRH/BD/ 80690/2011, respectively). AMM also acknowledges Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013), and the LRI Innovative Science Award. We thank the Portuguese NMR and MS networks (IST nodes) for providing access to the facilities.
dc.description.abstractNevirapine (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 of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Frémy's salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Frémy's salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent13
dc.format.extent1945388
dc.identifier.doi10.1039/c5tx00176e
dc.identifier.issn2045-452X
dc.identifier.otherPURE: 3955463
dc.identifier.otherPURE UUID: 92310fe2-cd16-43d0-a824-32bbeafdc72e
dc.identifier.otherScopus: 84945273743
dc.identifier.otherPubMed: 20392079
dc.identifier.otherWOS: 000363260200013
dc.identifier.otherORCID: /0000-0002-8456-9995/work/59470823
dc.identifier.urihttp://hdl.handle.net/10362/152628
dc.identifier.urlhttps://www.scopus.com/pages/publications/84945273743
dc.language.isoeng
dc.peerreviewedyes
dc.subjectHealth, Toxicology and Mutagenesis
dc.subjectToxicology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleQuinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapineen
dc.title.subtitleActivation pathway to amino acid adductsen
dc.typejournal article
degois.publication.firstPage1565
degois.publication.issue6
degois.publication.lastPage1577
degois.publication.titleToxicology Research
degois.publication.volume4
dspace.entity.typePublication
person.familyNamede Azeredo Pereira
person.givenNameSofia
person.identifier562223
person.identifier.ciencia-id6B13-7601-73A2
person.identifier.orcid0000-0002-8456-9995
person.identifier.ridM-2976-2019
person.identifier.scopus-author-id35190948700
rcaap.rightsopenAccess
relation.isAuthorOfPublicationf4809377-832b-40b5-92ca-0bb1c6fe14f3
relation.isAuthorOfPublication.latestForDiscoveryf4809377-832b-40b5-92ca-0bb1c6fe14f3

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