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).

Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions

“…Several in vitro studies using humans cells and animal in vivo studies investigating olive polyphenols have supported Nrf2 activation and its consequential expression of protective genes [72,94]. Conversely, a recent human intervention study has shown no evidence of altered phase II enzyme expression (the downstream product of Nrf2 activation) in peripheral blood mononuclear cells following consumption of HT (5 mg and 25 mg per day in olive mill waste water) [95]. The olive mill waste water was tested to confirm oleuropein was not present.…”

“…Oleuropein in a human in vitro model has also been shown to activate Nrf2 and HO-1 expression [99]. However, in vivo human trials with HT have failed to find an up-regulation of phase 2 enzymes which are the by-product of EpRE and Nrf2 stimulation [95]. …”

Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans

“…Samples analyzed were obtained from a previous intervention study [9]. This work is registered at ClinicalTrials.gov (identifier: NCT02273622).…”

“…To evaluate whether the selected HT-modulated miRNAs observed in the animal supplementation studies were also modulated in humans, we investigated the effects of HT supplementation (25 mg/ day) in a double-blind, randomized, placebo-controlled trial (NCT02273622) [9]. One-week supplementation with HT resulted in a within-group increase in the expression of miR-193a-5p in PBMCs (Fig.…”

“…In particular, hydroxytyrosol (HT), the foremost phenolic component of extra virgin olive oil, has been hypothesized to possess antiinflammatory, antiaggregant and anticancer properties, among others [8]. Nevertheless, the exact molecular mechanisms underlying many of these actions are yet to be fully clarified [9]. Regarding miRNAs, previous in vitro studies suggest that Olea europaea leaf extracts alter some cancer-related miRNAs in glioblastoma cells [10].…”