Monitoring abacavir bioactivation in humans: Screening for an aldehyde metabolite

Grilo, Nádia M.; Antunes, Alexandra M. M.; Caixas, Umbelina; Marinho, Aline T.; Charneira, Catarina; Oliveira, M. Conceição; Monteiro, Emília C.; Marques, M. Matilde; Pereira, Sofia A.

doi:10.1016/j.toxlet.2013.02.021

Cited by 21 publications

(16 citation statements)

References 33 publications

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“…11A) (Walsh et al, 2002). This can react with proteins and other macromolecules in a Michael-type mechanism to form adducts that are possibly immunogenic (Grilo et al, 2013(Grilo et al, , 2014.…”

Section: Alcohol and Aldehyde Dehydrogenasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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Section: Alcohol and Aldehyde Dehydrogenasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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“…The identification and quantification of adducts formed with N -terminal Val of Hb for biomonitoring proposes are based on a modified Edman procedure in which adducted N -terminal Val are specifically detached as hydantoins, upon reaction with an isothiocyanate. The demonstration of the in vivo bioactivation of the anti-HIV drugs nevirapine and abacavir to reactive metabolites [36,37,38] and the studies on the occupational and environmental exposures to ethylene oxide, acrylamide and acrylonitrile [39,40,41,42], are among the most significative applications of the targeted version of this methodology. Törnqvist’s group led the development of this approach and the shift to untargeted adductomics was possible with the use of fluorescein isothiocyanate (FITC), as the derivatizing agent [43].…”

Section: Sample Pre-treatment and Adducts Enrichmentmentioning

confidence: 99%

“…The MRM analysis of adducts obtained upon HSA pronase E digestion to aminoacids was used by Sabbioni et al [55] for the identification of Lys adducts of 4,4′-methylenediphenyl diisocyanate (MDI) in workers with and without diisocyanate occupational asthma, which enabled the identification of substantially higher levels of adducts in asthma case suggesting that HSA MDI-Lys adducts are suitable for industrial biomonitoring. Selected reaction monitoring (SRM), in which a specific parent ion is selected for subsequent targeted fragmentation reaction, was also used for the targeted identification of specific protein covalent modifications formed upon bioactivation of anti-HIV drugs [36,38].…”

Section: Ms Data Acquisitionmentioning

confidence: 99%

Mass Spectrometry-Based Methodologies for Targeted and Untargeted Identification of Protein Covalent Adducts (Adductomics): Current Status and Challenges

et al. 2019

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Protein covalent adducts formed upon exposure to reactive (mainly electrophilic) chemicals may lead to the development of a wide range of deleterious health outcomes. Therefore, the identification of protein covalent adducts constitutes a huge opportunity for a better understanding of events underlying diseases and for the development of biomarkers which may constitute effective tools for disease diagnosis/prognosis, for the application of personalized medicine approaches and for accurately assessing human exposure to chemical toxicants. The currently available mass spectrometry (MS)-based methodologies, are clearly the most suitable for the analysis of protein covalent modifications, providing accuracy, sensitivity, unbiased identification of the modified residue and conjugates along with quantitative information. However, despite the huge technological advances in MS instrumentation and bioinformatics tools, the identification of low abundant protein covalent adducts is still challenging. This review is aimed at summarizing the MS-based methodologies currently used for the identification of protein covalent adducts and the strategies developed to overcome the analytical challenges, involving not only sample pre-treatment procedures but also distinct MS and data analysis approaches.

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“…In particular, an adduct of abacavir aldehyde with hemoglobin was observed in HIV patients receiving this drug [60]. This prompted studies on the formation of adducts between this compound and other proteins.…”

Section: Drug-protein Adduct Formationmentioning

confidence: 99%

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

González-Morena¹,

Montanez²,

Aldini³

et al. 2017

CPD

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Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be life-threatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, non-covalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.

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Monitoring abacavir bioactivation in humans: Screening for an aldehyde metabolite

Cited by 21 publications

References 33 publications

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Mass Spectrometry-Based Methodologies for Targeted and Untargeted Identification of Protein Covalent Adducts (Adductomics): Current Status and Challenges

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

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