title: One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes.
abstract: The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622).
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Crespo
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Joao
authors.initials: J
authors.lastname: Tomé-Carneiro
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Burgos-Ramos
authors.affiliation: Unidad de Nutrición y Ensayos Clínicos, Plataforma Genyal, IMDEA-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Viviana
authors.initials: V
authors.lastname: Loria Kohen
authors.affiliation: Unidad de Nutrición y Ensayos Clínicos, Plataforma Genyal, IMDEA-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Espinosa
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Herranz
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain; Department of Molecular Medicine, University of Padova, Italy. Electronic address: francesco.visioli@imdea.org.
authors.forename: Francesco
authors.initials: F
authors.lastname: Visioli
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004789:Enzyme Activation / Q000187:drug effects* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D050217:Metabolic Detoxication, Phase II; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000975:Antioxidants; C005975:3,4-dihydroxyphenylethanol; D010626:Phenylethyl Alcohol
keywords: Cardiovascular disease; Hydroxytyrosol; Inflammation; Mediterranean diet; Nrf2; Phase II enzymes