Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.17/1773
Título: Evidence for Nevirapine Bioactivation in Man: Searching for the First Step in the Mechanism of Nevirapine Toxicity
Autor: Caixas, U
Antunes, A
Marinho, A
Godinho, A
Grilo, N
Marques, M
Oliveira, MC
Branco, T
Monteiro, E
Pereira, S
Palavras-chave: HSJ MED
Anti-Retrovirais
Marcadores Biológicos
Estudos de Caso e Controlos
Cromatografia Líquida
Infecção por HIV
Hapteno
Hemoglobinas
Nevirapina
Proteínas
Efeitos Adversos
Espectrometria de Massas em Tandem
Espectrometria de Massas por Ionização por Electrospray
Data: 2012
Editora: Elsevier
Citação: Toxicology. 2012 Nov 15;301(1-3):33-9
Resumo: Despite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions. All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58±0.8 fmol/g of hemoglobin). This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.
Peer review: yes
URI: http://hdl.handle.net/10400.17/1773
Aparece nas colecções:MED - Artigos

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