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 thatis 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 25 mg/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).