title: Bioactivation to an aldehyde metabolite--possible role in the onset of toxicity induced by the anti-HIV drug abacavir.
abstract: Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes.
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Universidade NOVA, 1169-056 Lisboa, Portugal.
authors.forename: Nádia M
authors.initials: NM
authors.lastname: Grilo
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Charneira
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Universidade NOVA, 1169-056 Lisboa, Portugal. Electronic address: sofia.pereira@fcm.unl.pt.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Pereira
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Universidade NOVA, 1169-056 Lisboa, Portugal.
authors.forename: Emília C
authors.initials: EC
authors.lastname: Monteiro
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal. Electronic address: alexandra.antunes@tecnico.ulisboa.pt.
authors.forename: Alexandra M M
authors.initials: AM
authors.lastname: Antunes
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity*; D001711:Biotransformation; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000378:metabolism* / Q000633:toxicity*; D004342:Drug Hypersensitivity / Q000503:physiopathology; D064420:Drug-Related Side Effects and Adverse Reactions; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D000099227:Abacavir
chemical_list: D000447:Aldehydes; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D000099227:Abacavir
keywords: Abacavir; Aldehyde metabolite; Cardiotoxicity; Drug bioactivation; Hypersensitivity reactions; Protein adducts