Author: Enrico Varriale
Date: 31/03/2012



Hydroxytyrosol (3,4-dihydroxyphenylethanol; DPE) is a phytochemical found in olive leaf and has been reported to exert several biological and pharmacological activities. It also exists in olive oil, in the form of its elenolic acid ester oleuropein and, especially after degradation, in its plain form. The major phenolic compounds in olive oil are oleuropein, hydroxytyrosol, tyrosol and oleocanthal. Oleuropein, along with oleocanthal, are responsible for the bitter taste of extra virgin olive oil. Hydroxytyrosol itself in pure form is a colorless, odourless liquid. The olives, leaves and olive pulp contain large amounts of hydroxytyrosol (compared to olive oil), most of which can be recovered to produce hydroxytyrosol extracts.

How does it work?

  • has anti-inflammatory activity;
  • has strong antioxidant activity;
  • stimulates mitochondrial function and biogenesis.

Anti-inflammatory activity

Hydroxytyrosol induces apoptosis of immune cells:

Studying the effect of this compound on the proliferation and survival of HL60 cell line (Human promyelocytic leukemia cells) there was evidence that concentrations from 50 to 100 microM DPE, comparable to its olive oil content, caused a complete arrest of HL60 cell proliferation and the induction of apoptosis. This was demonstrated by flow cytometric analyses, poly(ADP-ribose) polymerase cleavage, and caspase 3 activation. The apoptotic effect requires the presence of two ortho-hydroxyl groups on the phenyl ring, since tyrosol, 2-4-hydroxyphenylethanol, did not induce either cell growth arrest or apoptosis. DPE-dependent apoptosis is associated with an early release of cytochrome c from mitochondria which precedes caspase 8 activation, thus ruling out the engagement of cell death receptors in the apoptotic process. 3,4-Dihydroxyphenylethanol induced cell death in quiescent and differentiated HL60 cells, as well as in resting and activated peripheral blood lymphocytes, while did not cause cell death in two colorectal cell lines. These results suggest that DPE down-regulates the immunological response, thus explaining the well-known antinflammatory and chemopreventive effects of olive oil at the intestinal level.
Hydroxytyrosol, a natural molecule occurring in olive oil, induces cytochrome c-dependent apoptosis. November 2000

Hydroxytyrosol inhibits iNOS, cytokines, prostaglandins and COX-2 expression:

The effects of hydroxytyrosol (HT) and acqueous olive extracts (OVW) were studied in murine macrophages stimulated with lipopolysaccharide (LPS). HT inhibited production of NO and PGE₂ with an IC₅₀ of 11.4 and 19.5 µM, respectively, reflecting strong anti-inflammatory activity. HT and OVW diminished secretion of cytokines (IL-1 α, IL-1 β, IL-6, IL-12, TNF- α), and chemokines (CXCL10/IP-10, CCL2/MCP-1). HT and OVW concentration-dependently reduced the expression of genes of inducible nitric oxide synthase (iNOS), IL-1 α, CXCL10/IP-10, MIP-1 β, matrix metalloproteinase-9, and prostaglandinìè E₂ synthase (PGES). The effects of HT were partly mediated VIA the NF- κB pathway, as shown by RT-PCR analysis. HT was identified as the main bioactive compound of OVW. The effects of HT on NO and chemokine production point to their impact on chronic inflammatory processes in endothelium or arthritis.
Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages. November 2011

Hydroxytyrosol stimulates the promoter transcriptional activation and protein expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PPARGC1α).
This protein up-regulates gene expression of PPARα and PPARγ, thus inhibits NF-kB pathway.

Antioxidant activity

Hydroxytyrosol is the main antioxidant found in olive oil and a very efficient scavenger of free radicals. Typically, hydroxytyrosol is a superior antioxidant and radical scavenger to oleuropein and tyrosol. Hydroxytyrosol is believed to be one of the most powerful antioxidants. Its oxygen radical absorbance capacity is 40,000 umolTE/g, which is ten times higher than that of green tea, and two times higher than that of CoQ10.
Major phenolic compounds in olive oil: metabolism and health effects. Nov 2002

Hydroxytyrosol is thought to be protective because it has the ability to increase PGC-1α and improve mitochondrial and cellular ROS-related functions.
Is well known that the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells. PPARγ coactivator 1α (PGC-1α) is a potent stimulator of mitochondrial biogenesis and respiration. PGC-1α is coinduced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1α is required for the induction of many ROS-detoxifying enzymes, including glutathione peroxidase 1 and superoxide dismutase 2. PGC-1α null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively. Increasing PGC-1α levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1α is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.
Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators October 2006

Furthermore, hydroxytyrosol has the same beneficial effects on the mitochondria of retinal pigment epithelial cells (derived from the retina) treated with the toxic chemical acrolein, a model for the slowly accumulating damage to the eyes that results in age-related macular degeneration (vision loss). This suggests that hydroxytyrosol may also be useful in treating or delaying age-related macular degeneration.
Hydroxytyrosol protects against oxidative damage on retinal pigment epithelial cells(09)00206-X/abstract November 2010

Mitochondrial effects:

In cultured adipocytes (fat cells), hydroxytyrosol increases PGC-1α expression (as we have seen before) and operates a stimulation of mitochondrial biogenesis that leads to enhancement of mitochondrial function and cellular defense systems. HT over the concentration range of 0.1–10 μmol/L stimulated the promoter transcriptional activation and protein expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PPARGC1α, the central factor for mitochondrial biogenesis) and its downstream targets; these included nuclear respiration factors 1 and 2 and mitochondrial transcription factor A, which leads to an increase in mitochondrial DNA (mtDNA) and in the number of mitochondria. The HT treatment resulted in an enhancement of mitochondrial function, including an increase in activity and protein expression of Mitochondrial Complexes I, II, III and V; increased oxygen consumption; and a decrease in free fatty acid contents in the adipocytes. The mechanistic study of the PGC1α activation signaling pathway demonstrated that HT is an activator of 5′AMP-activated protein kinase and also up-regulates gene expression of PPARα, CPT-1 and PPARγ.
Inappropriate increases in PGC-1a activity have been linked to a number of pathological conditions including heart failure and diabetes. PGC-1a is highly expressed in metabolically active tissues including brown fat, skeletal muscle and heart.
Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes July 2010

Sources of hydroxytyrosol (the Mediterranean diet)

Olive oil

The Mediterranean diet has been associated with a lower incidence of cardiovascular disease and certain cancers. Extra-virgin olive oil (produced by only physical and no chemical processing) is the principal source of fat in the Mediterranean diet and has been identified as an important contributor to the reduced mortality associated with this diet. Hydroxytyrosol is considered one of the biofactors associated with the healthful effects of olive oil.
Indeed, recent research indicates that hydroxytyrosol stimulates mitochondrial function — perhaps constituting a new mechanism by which olive oil lowers the risk of various disease. Diabetes and obesity, for which cardiovascular disease is the most common and serious complication, both involve dysfunctional glucose metabolism. Because mitochondrial respiration plays a critical role in glucose metabolism, mitochondrial dysfunction likewise has been shown to be associated with these conditions.


Although extra-virgin olive oil is the principal source of hydroxytyrosol, this biofactor also occurs in wine — a second hallmark of the Mediterranean diet. Remarkably, it appears that alcohol in wine further boosts hydroxytyrosol levels in the body. A study comparing the effects of wine and olive oil consumption showed that even though the amount of hydroxytyrosol per serving of wine was less than in olive oil (about 0.3 to 0.4 milligrams per 200 to 300 milliliters wine, versus 1.7 milligrams in 50 milliliters oil), bodily amounts as assessed from urinary excretion measurements were 40% higher than could be attributed independently to either wine or olive oil intake.
This hydroxytyrosol increase, however, could be attributed to an additional effect of the wine. The alcohol in wine or distilled spirits may suppress the conversion of endogenous dopamine to dopac (3,4-dihydroxyphenylacetic acid) and redirect it, via a reductive pathway, to dopal (3,4-dihydroxyphenylacetaldehyde) and then to hydroxytyrosol. In a recent dietary study of 506 males who consumed a diet containing both olive oil and red wine, after adjusting for the contributions of olive oil and wine to hydroxytyrosol, urinary hydroxytyrosol levels increased linearly with alcohol intake. In addition to the direct consumption of hydroxytyrosol in wine and olive oil, dietary alcohol can play an indirect role in raising levels of this beneficial biofactor.

In Mediterranean countries such as Italy and Greece, dietary intakes of olive oil polyphenols are estimated at around 10 to 20 milligrams per day with a daily intake of 25 to 50 milliliters of olive oil. If the olive oil is not chemically treated, about 0.5 to 1 milligram of the polyphenolic fraction is hydroxytyrosol or hydroxytyrosol derivative. A daily serving of one to two glasses of wine could add another 0.3 to 0.4 milligram of hydroxytyrosol.

Biofactors in food promote health by enhancing mitochondrial function September 2011

Drink olive oil for a better life

Mediterranean countries have lower rates of mortality from cardiovascular disease and cancer than Northern European or other Western countries. This has been attributed, at least in part, to the so-called Mediterranean diet, which is composed of specific local foods, including olive oil. Traditionally, many beneficial properties associated with this oil have been ascribed to its high oleic acid content. Today, it is clear that many of the beneficial effects of ingesting virgin olive oil are due to its minor compounds, like hydroxytyrosol. The main findings in terms of its beneficial effects in cardiovascular disease and cancer, including its properties against inflammation, are very important for the prevention and treatment of diseases with high incidences in Western countries.

Hydroxytyrosol: from laboratory investigations to future clinical trials. April 2010

Olives and olive oil in cancer prevention

Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells

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