Metabolism of natural antioxidants: evaluation of the pathways involved in the in vivo biotransformation of tyrosol into hydroxytyrosol

Abstract

Hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol], a potent bioactive molecule mainly present in virgin olive oil and to a lower extent in wine, is also a by-product of dopamine metabolism. In a previous clinical trial designed to assess the effects of moderate wine intake it was found that hydroxytyrosol urinary recoveries were higher than the corresponding to the dose administered, suggesting an endogenous formation. The aim of the present work was to assess new mechanisms responsible for hydroxytyrosol generation by using an array of methodologies and studies ranging from in vitro assays to in vivo experiments in animal models and humans. The mechanisms identified as being involved in the generation of hydroxytyrosol were (1) CYP2A6/CYP2D6-catalyzed tyrosol-to-hydroxytyrosol biotransformation, (2) ethanol-induced increase in tyrosol bioavailability, and (3) alteration of dopamine oxidative metabolism due to ethanol. Considering these observations, it is postulated that hydroxytyrosol may contribute significantly to the health effects derived from moderate wine intake.L’hidroxitirosol [2-(3,4-dihidroxiphenil)etanol], una potent molècula bioactiva present de forma rellevant a l’oli d’oliva verge i minoritàriament al vi, és també un producte del metabolisme de la dopamina. En un assaig clínic previ dissenyat per avaluar els efectes del consum moderat de vi es trobà que les recuperacions urinàries d’hidroxitirosol eren superiors a la dosi administrada, suggerint-ne una gènesi endògena. L’objectiu del present treball fou estudiar nous mecanismes responsables de la generació d’hidroxitirosol mitjançant diverses tècniques i estudis, des d’assajos in vitro a experiments in vivo en animals i humans. Els mecanismes involucrats a la generació d’hidroxitirosol són (1) la biotransformació de tirosol a hidroxitirosol catalitzada per CYP2A6/CYP2D6, (2) l’augment a la biodisponibilitat del tirosol induïda per l’etanol, i (3) l’alteració del metabolisme oxidatiu de la dopamina per l’etanol. Globalment, aquestes observacions donen a l’hidroxitirosol un paper clau en la comprensió dels efectes beneficiosos associats al consum moderat de vi.Programa de doctorat en Biomedicina