Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity

Detalhes bibliográficos
Autor(a) principal: Grilo, Nádia Filipa Marques
Data de Publicação: 2012
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/8203
Resumo: Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
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spelling Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicityAbacavirAldehyde metaboliteBiomarkerCardiotoxicityDrug bioactivationHypersensitivityDissertação para obtenção do Grau de Mestre em Genética Molecular e BiomedicinaWhile the benefits of combined antiretroviral therapy have revolutionized the life expectancy of patients infected with the human immunodeficiency virus, treatment-associated toxicity is frequently observed. Abacavir is a nucleoside reverse transcriptase inhibitor associated with acute toxic events,such as hypersensitivity reactions. In addition, its long-term use has increasingly been recognized as associated with an increased risk of myocardial infarction. While the mechanisms underlying abacavirinduced hypersensitivity and cardiotoxicity are not fully understood, abacavir bioactivation to a reactive aldehyde metabolite is thought to play a crucial role in this context. However, as a short lived specie,in vivo, its formation has so far eluded detection. Our initial hypothesis was that it could be efficiently trapped by N-terminal valine of hemoglobin, forming N-terminal-valine-abacavir adducts. With the ultimate goal of gain insight into the role of abacavir metabolism in abacavir-induced toxicity, the present work was focused on obtaining evidence for the abacavir bioactivation to a reactive aldehyde metabolite, in human immunodeficiency virus - infected patients, and on the evaluation of this reactive metabolite ability to undergo protein modification. To address these issues: 1) abacavir-Edman standards were prepared to monitor the presence of these adducts in vivo; 2) the presence of abacavir-Edman adduct was screened in Wistar rats, for optimization of analytical method; and 3) in patients infected with the human immunodeficiency virus. The experimental approach used, involving N-Alkyl Edman degradation, for specific detachment of N-terminal-valineabacavir adducts from protein, followed by liquid chromatography-electrospray ionization tandem mass spectrometry analysis of detached abacavir-Edman adducts, upon comparison with standards prepared in vitro, allowed the unequivocal identification of these adducts in animal and human samples. These results represent the first report on the involvement of a conjugated aldehyde intermediate in the metabolic activation of abacavir in man. Whereas this evidence does not imply an exclusive relation between abacavir-Edman adducts and abacavir toxicity, the search for causal relationships between the formation of abacabir-derived protein adducts and the occurrence of abacavir-induced toxic events in patients is worth pursuing, and is currently underway, towards the clarification of mechanism(s) of abacavir-induced toxicity.Faculdade de Ciências e TecnologiaPereira, SofiaAntunes, AlexandraRUNGrilo, Nádia Filipa Marques2012-11-27T13:49:44Z20122012-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/8203enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T03:40:42Zoai:run.unl.pt:10362/8203Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:18:00.895196Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
title Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
spellingShingle Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
Grilo, Nádia Filipa Marques
Abacavir
Aldehyde metabolite
Biomarker
Cardiotoxicity
Drug bioactivation
Hypersensitivity
title_short Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
title_full Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
title_fullStr Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
title_full_unstemmed Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
title_sort Protein adducts from the anti-HIV drug abacavir – possible biomarkers of drug toxicity
author Grilo, Nádia Filipa Marques
author_facet Grilo, Nádia Filipa Marques
author_role author
dc.contributor.none.fl_str_mv Pereira, Sofia
Antunes, Alexandra
RUN
dc.contributor.author.fl_str_mv Grilo, Nádia Filipa Marques
dc.subject.por.fl_str_mv Abacavir
Aldehyde metabolite
Biomarker
Cardiotoxicity
Drug bioactivation
Hypersensitivity
topic Abacavir
Aldehyde metabolite
Biomarker
Cardiotoxicity
Drug bioactivation
Hypersensitivity
description Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
publishDate 2012
dc.date.none.fl_str_mv 2012-11-27T13:49:44Z
2012
2012-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/8203
url http://hdl.handle.net/10362/8203
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Faculdade de Ciências e Tecnologia
publisher.none.fl_str_mv Faculdade de Ciências e Tecnologia
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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