Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/11552
Título: Conjugation of fatty acids with coenzyme A, carnitine or glycine : role in mitochondrial energy metabolism and detoxification
Autor: Silva, Liliana Adelina Gonçalves da
Orientador: Silva, Margarida Maria Fernandes Baptista e
Palavras-chave: Valproic acid
Fatty acid oxidation
Coenzyme A
Teses de mestrado - 2013
Data de Defesa: 2013
Resumo: Carnitine and glycine conjugation are two distinct phase II reactions with relevance for detoxification, and share common substrates, the acyl-Coenzyme A (CoA) esters. The metabolism of valproic acid (VPA), an “epigenetic” drug in clinical practice for decades, has been used within our group as a model system to elucidate drug-induced mitochondrial dysfunction and liver disease, probably common to other carboxylic acid xenobiotics which may be activated to CoA esters. The pharmacotoxicological properties of VPA and their unequivocal interaction with mitochondrial energy metabolism are at the basis of the current project, whose prime objectives were: 1.) the characterization in biological samples of metabolites biomarkers of mitochondrial energy metabolism dysfunction; 2.) application of high resolution chromatographic methods coupled to mass spectrometry to the study of metabolites conjugates, namely the glycine and carnitine esters (acylglycines and acylcarnitines, respectively). Both studies may provide information on the homeostasis of the precursors, acyl-CoAs, and ultimately, the fatty acids and organic acids. A thorough approach on the metabolic significance of acylglycines in biological fluids was undertaken, using stable isotope dilution gas chromatography coupled to mass spectrometry to measure propionyl-, butyryl-, isobutyryl-, 2-methylbutyryl-, isovaleryl-, 3-methylcrotonyl-, hexanoyl- and suberylglicine. The in vivo profiles of these intermediary metabolites were evaluated in biological samples from Wistar rats subjected to a VPA regimen; pediatric patients undergoing chronic treatment with VPA and patients identified with inborn errors of metabolism. The accumulation of acyl-CoA esters intermediates gave rise to a VPA-associated increase on the corresponding products, acylglycines. In addition, novel insights on VPA biotransformation were achieved. As predicted, propionyl-CoA, the end product of VPA thiolytic cleavage was converted to propionylglycine adding a novel phase II reaction to VPA metabolism. Moreover, we initiated the set-up of a new method in our laboratory for the qualitative characterization of carnitine and acylcarnitines using positive electrospray tandem mass spectrometry in plasma and urine. The characterization of short- to long-chain acylcarnitines profiles was performed and additional studies are in course to validate the procedure and quantify the compounds. The differential determination of free carnitine and acylcarnitines levels including acetylcarnitine or palmitoylcarnitine, will support the study of fatty acid oxidation flux, the functional analysis of carnitine acyltransferases activity or the biomonitoring of carnitine or acetylcarnitine as potential therapeutic agents. The overall obtained results allowed to study not only the intermediary metabolism in vivo, which reflects the function and/or dysfunction in cell, but also the biochemical pathways of VPA detoxification, potentially common to other acidic drugs, their metabolites or endogenous molecules.
Descrição: Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2013
Peer review: yes
URI: http://hdl.handle.net/10451/11552
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