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Development and Validation of an Analytical Method for Quantification of Dopamine Metabolism in Plasma Samples by LC-MS/MS

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Development and Validation of an Analytical Method for Quantification of Dopamine Metabolism in Plasma Samples by LC-MS/MS Ana Sofia Abrantes Dias Development and validation of an analytical method for quantification of dopamine metabolism in plasma samples by LC-MS/MS Dissertação apresentada para provas de Mestrado em Química Forense Doutor Bruno José Fernandes Oliveira Manadas Professora Doutora Maria João Moreno junho 2017 Universidade de Coimbra Este projeto foi realizado no grupo Life Sciences Mass Spectrometry do Centro de Neurociências e Biologia Celular (Universidade de Coimbra, Portugal), orientado pelo Doutor Bruno Manadas. O trabalho foi financiado pela Fundação para a Ciência e Tecnologia (FCT), Portugal, com os projetos PTDC/SAU-NEU/103728/2008, PTDC/NEU-NMC/0205/2012, PTDC/NEU-SCC/7051/2014 e UID/NEU/04539/2013, e co-financiado pelo Programa COMPETE 2020 (Programa Operacional Fatores de Competitividade), pelo QREN, a União Europeia (FEDER – Fundo Europeu de Desenvolvimento Regional), e pela Rede Nacional de Espectrometria de Massa (RNEM), sob o contracto REDE/1506/REM/2005. The present work was performed in the Life Sciences Mass Spectrometry group of Center for Neuroscience and Cell Biology (University of Coimbra, Portugal), and under scientific guidance of Doctor Bruno Manadas. The work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, projects references PTDC/SAU-NEU/103728/2008, PTDC/NEU-NMC/0205/2012, PTDC/NEU- SCC/7051/2014 and UID/NEU/04539/2013, and cofinanced by "COMPETE 2020 Programa Operacional Fatores de Competitividade, QREN, the European Union (FEDER – Fundo Europeu de Desenvolvimento Regional) and by The National Mass Spectrometry Network (RNEM) under contract REDE/1506/REM/2005. Agradecimentos A realização desta tese não teria sido possível sem o contributo, estímulo e empenho de várias pessoas e, como tal, gostaria de expressar toda a minha gratidão a todos os que, direta ou indiretamente contribuíram para que esta tarefa fosse possível. A todos deixo aqui os meus sinceros agradecimentos. Desta forma, quero começar por agradecer ao Dr. Bruno Manadas pela possibilidade de desenvolver este projeto no seu laboratório, no Centro de Neurociências e Biologia Celular. Pela competência e orientação científica, pelos conhecimentos transmitidos e pela disponibilidade revelada ao longo do trabalho, assim como pelas críticas, correções e sugestões relevantes feitas durante a orientação. Agradeço ainda à Prof.ª Maria João pela orientação e ajuda prestadas ao longo do trabalho, assim como pelo interesse e acompanhamento no seu desenvolvimento. Quero também agradecer à Vera e à Joana pela orientação e transmissão de conhecimentos prestada ao longo do desenvolvimento deste trabalho. Agradeço a disponibilidade e a paciência, assim como toda a partilha de saber que foi um valioso contributo para a elaboração desta tese. Quero agradecer igualmente às restantes colegas de laboratório, Cátia, Margarida e Sandra, pelos momentos de boa disposição, uma vez que foram uma forma de motivação para encarar todos os desafios com mais ânimo. Aos meus amigos, obrigada pela amizade e cumplicidade, pelos momentos de convívio e descontração que me permitiram relaxar e esquecer todo este stress, mesmo que por breves momentos. Acima de tudo, deixo um enorme obrigada ao Luís. A tua importância na minha vida tornou-se ainda maior. Todo o teu apoio, compreensão e afeição foram fundamentais, peço desculpa por todos os momentos de stress, mas no final sempre me soubeste acalmar e ver as coisas de uma forma positiva. Tenho sorte em ter-te ao meu lado! Aos meus pais, um obrigada muito especial, por tudo o que fizeram por mim, pelo amor incondicional e pela forma como, ao longo de todos estes anos, me souberam ajudar. Obrigada pela confiança em mim depositada, pelo apoio em todos os momentos bons e menos bons que a vida académica me proporcionou e por toda a compreensão. Por me terem ajudado a crescer, por terem aceite e apoiado todas as minhas escolhas e por me terem tornado na pessoa que sou hoje. Sem vocês eu não teria esta oportunidade de lutar pelos meus sonhos e objetivos e, como tal, quero partilhar convosco a alegria de os conseguir vencer. Sem dúvida são as pessoas mais importantes da minha vida. A vocês devo tudo o que sou! Agradeço ainda aos restantes familiares, por todo o apoio e palavras de incentivo, assim como todos aqueles que, mesmo não estando aqui diretamente mencionados, tiveram um papel relevante para mim durante este ano. Table of contents| i Table of contents TABLE OF CONTENTS ............................................................................................................... i ABBREVIATIONS ..................................................................................................................... v RESUMO ............................................................................................................................... xi ABSTRACT ............................................................................................................................ xv 1. INTRODUCTION .................................................................................................................. 1 1.1. Parkinson’s disease .............................................................................................................. 1 1.2. Genesis of Parkinson’s disease ............................................................................................. 5 1.2.1. Histopathology of Parkinson’s disease ......................................................................... 5 1.2.2. Etiology and pathogenesis of Parkinson’s disease ....................................................... 7 1.2.2.1. Oxidative stress .................................................................................................... 8 1.2.2.2. Mitochondrial dysfunction ................................................................................... 9 1.2.2.3. Ubiquitin-proteasome system impairment ....................................................... 10 1.2.2.4. Neuroinflammation ............................................................................................ 11 1.2.2.5. Neuromelanin .................................................................................................... 12 1.2.2.6. Genetic changes ................................................................................................. 13 1.3. Dopamine role in Parkinson’s disease ................................................................................ 16 1.3.1. Dopamine biosynthesis .............................................................................................. 16 1.3.1.1. L-tyrosine ........................................................................................................... 17 1.3.1.2. Levodopa ............................................................................................................ 18 1.3.2. Dopamine metabolism ............................................................................................... 18 1.3.2.1. 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid ... 21 1.3.3. Peripheral synthesis of dopamine .............................................................................. 21 2. ANALYTICAL METHODOLOGIES ......................................................................................... 25 2.1. Analytical methodologies for sample preparation ............................................................. 25 2.1.1. Sample preparation of plasma ................................................................................... 26 2.1.1.1. Protein precipitation .......................................................................................... 26 2.2. Techniques ......................................................................................................................... 27 2.2.1. Chromatography ........................................................................................................ 31 2.2.1.1. High-performance liquid chromatography ........................................................ 31 2.2.2. Mass spectrometry..................................................................................................... 34 2.2.2.1. Isotopic abundances .......................................................................................... 39 |Table of contents ii 2.3. Analytical method validation ............................................................................................. 39 2.3.1. Selectivity ................................................................................................................... 41 2.3.2. Linearity ..................................................................................................................... 41 2.3.3. Working range ........................................................................................................... 41 2.3.4. Limit of detection and limit of quantification ............................................................ 42 2.3.5. Precision .................................................................................................................... 42 2.3.6. Accuracy ..................................................................................................................... 43 2.3.7. Carry-over .................................................................................................................. 43 2.3.8. Recovery .................................................................................................................... 43 2.3.9. Matrix effects ............................................................................................................
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