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Hydroxytyrosol And Potential Uses In Cardiovascular Diseases, Cancer, And AIDS

Jun 28, 2017

Abstract

Hydroxytyrosol is one of the main phenolic components of olive oil. It is present in the fruit and leaf of the olive (Olea europaea L.). During the past decades, it has been well documented that this phenolic compound has health benefits and a protective action has been found in preclinical studies against several diseases. Here, we review its bioavailability in human beings and several assays showing significant results related with cardiovascular diseases, cancer, and acquired immunodeficiency syndrome (AIDS). Mechanisms of action include potent anti-oxidant and anti-inflammatory effects, among others. The importance of hydroxytyrosol in protection of low-density lipoproteins and consequently its implication in the reduction of cardiovascular disease risk has been highlighted by the European Food Safety Authority, concluding that 5 mg of hydroxytyrosol and its derivatives should be consumed daily to reach this effect at physiological level. We discuss the potential uses of this compound in supplements, nutraceutic foods, or topical formulations in the disease risk reduction. Finally, we conclude that more studies are needed to sustain or reject many other health claims not yet fully documented and to validate these newly available hydroxytyrosol-based products, because it seems to be a good candidate to reduce the risk of diseases mentioned.

Introduction

Hydroxytyrosol and Mediterranean diet

Hydroxytyrosol (HOTYR) is a simple phenolic compound naturally occurring in olive and olive oil, the main source of fat in Mediterranean diet. Nowadays, it is very popular the benefits of this diet for the maintenance of human health and wellbeing. Anyway, the concept of Mediterranean diet may be misunderstanding, being necessary its clarification. It was originally defined as the dietary pattern found in some of the olive-growing regions in the Mediterranean Basin of the 1960s. Thus, a current simple accepted definition is closely related to the diet characteristics as source of separate types of fats. In this way, Mediterranean diet highlights by its high proportion in plant foods where the main source of fat is olive oil, resulting in a higher proportion of mono unsaturated/polyunsaturated fats relative to saturated ones .

The healthy benefits of the Mediterranean diet are popularly known and are supported by numerous studies, as the well-known “The Seven Countries Study,” which highlighted the cardiovascular disease related mortality in Mediterranean region compared with other countries with distinct dietary habits in the 1960s . This study can be considered as pioneer and opened a high number of researches on those foods with critical influence in the benefits of the Mediterranean diet. Among them, the PREDIMED trial (“Prevención con dieta Mediterránea”) is a large (7447 subjects), parallel-group, multicenter, randomized trial for a follow-up period of 4.8 years, whose participants were assigned to three dietary intervention: Med-diet supplemented with virgin olive oil, Med-diet supplemented with nuts, and low-fat diet. The results showed an important reduction of three of every thousand persons per year in the risk of major cardiovascular events among high-risk persons.

Among the separate foods taking part of the Mediterranean diet, olive oil is considered a crucial element, being one of the most traded and consumed product in the world directly related to the healthy attribution of this popular diet . In November 2004, the Food and Drug Administration (FDA) allowed the health benefits of olive oil due to monounsaturated fat in reducing the risk of coronary heart disease and recommended a daily intake of two tablespoon (23 g) .

The responsible parameters of the healthy attributions of olive oil and table olives remain poorly understood. Olive oil is mainly composed of two groups of compounds: saponifiable lipids (98.5–99% of the total composition) and an unsaponifiable fraction. The main triglyceride fatty acid is the oleic acid with 55–83% of the total fatty acid content. It also includes moderate amounts of palmitic and linoleic acids and a low percentage of stearic and linolenic acids. On the other hand, the unsaponifiable fraction contains a large variety of compounds responsible for stability and organoleptic characteristics of olive oil. This fraction consists of primarily of hydrocarbons (squalene, carotene, lutein), terpene compounds, sterols, phenolic compounds, and aliphatic alcohols among others. Phenolic compounds from olive oil include four different groups: simple phenols, i.e., tyrosol (TYR), hydroxytyrosol, polyphenols (flavonoids), secoiridoids (oleuropein), and lignans .

Although the major components of olive oil are its monounsaturated fatty acids, mainly oleic acid, we cannot attribute the beneficial effects of the Mediterranean diet only to these substances because other oils, such as rape-seed or canola oil are also rich in monounsaturated fatty acids and may produce the same benefit. For this reason, attention has focused on the phenolic compounds, which have showed a strong anti-oxidant capacity, of virgin olive oil that distinguish themselves from other types of fat. The amount of phenolic compounds present in olive oil greatly varies depending on cultivar, degree of maturation, climate, and manufacturing process . Thus, extra virgin olive oil, obtained from the cold pressing or centrifugation of the olives, is the one with higher content of total phenolic compounds. An early study showed a total phenolic content of 232 mg/kg in virgin olive oil versus 62 mg/kg values of refined olive oil (up to 80% less usually lost during the refining process).

In this sense, olives, olive oil source, have higher amounts of phenolic compounds that extra virgin olive oil (oil with higher anti-oxidant capacity). Depending on the variety of olive and the type of processing, the phenolic content varies significantly. As an example, total phenolic content estimated in black olives was 16.40 g/kg dry weight, representing hydroxytyrosol 5.78 g/kg. Tyrosol, phloretic acid, dihydrocaffeic acid, acteoside, luteolin, and apigenin were also found. The green olives content was much lower with 4.48 g/kg of hydroxytyrosol and only traces of other phenolics.

Hydroxytyrosol, 2-(3,4-dihydroxyphenyl)-ethanol (HOTYR), is a phenolic compound present in the fruit and leaf of the olive (Olea europaea L.), which belongs to the family Oleaceae, comprising species distributed throughout the temperate regions of the world, and essentially localized in the Mediterranean basin. Hydroxytyrosol is one of the main components of virgin olive oil, olive mill waste water (OMWW), and olive leaf extract (OLE), which was early identified as the strongest in vitro anti-oxidant potential among all the olive oil polyphenols . As mentioned above, the content of this compound is largely dependent on the oil quality. Amounts range from 14 mg/kg in extra virgin olive oil, up to <2 mg/kg . Other estimations increased the estimation to total phenolic content of olive oil in ranges from 487.5 to 1950 mg/l, and HOTYR specifically from 20 to 84 mg/l . Hydroxytyrosol in oil is found free, in acetate form or as a part of more complex compounds like oleacein, oleuropein, and verbascoside ( (Figure (Figure1).1). Oleuropein is responsible for the bitter taste of olives and decreases as the fruit ripens turning into unglycosylated form, oleuropein aglycone by enzymatic hydrolysis, and finally converted into hydroxytyrosol, being this one an indicator of maturation of the olives(Figure (Figure22).


Absorption and Bioavailability

The term bioavailability is commonly used to indicate the proportion of a substance that reaches the systemic circulation after oral administration considering both its absorption and its local metabolic transformation.

There are several assays dealing with the absorption of olive oil phenolic compounds both in animals and human beings. Visioli et al. found a high correlation for TYR and HOTYR in human urine respect the ingested of different phenolic amounts in olive oil. The urine hydrolyzed using glucuronidase enzyme revealed the high grade of conjugation of HOTYR and an increasing conjugation degree in higher phenolic content oils was found. Miró-Casas also demonstrated the absorption of hydroxytyrosol in a study with human beings after ingestion of olive oil. The recovery reached for hydroxytyrosol was 121.1% when was administered as a maintenance dose of 25 ml/day for 1 week. These data have been also found in other studies and different explanations have been offered, like the hydrolysis of precursors also present in olive oil, long-term accumulation and dopamine metabolism. Studies using different techniques to determine the amount of absorbed hydroxytyrosol as isotopic labeled estimated absorption around 99% of totally intake in oil and 75% in aqueous solution, being <3% in fecal content. Around 55–66% of absorption was found too with aqueous supplements in ileostomy patients.

Related to phenolic compounds absorption, the influence of the delivery vehicle seems to be crucial. In human beings, HOTYR absorption was higher when subjects ingested virgin olive oil than in refined oil (phenol-free) enriched with phenolic compounds, or when HOTYR was incorporated into a yogurt as functional food, with urinary recoveries of 44, 23, and 5.8%, respectively. In this direction, clinical trials have demonstrated that the amount of hydroxytyrosol in free form was undetectable being 98% in conjugated form, mainly glucuronides, in plasma, and urine . These data provided an idea of the bioavailability of hydroxytyrosol, to highlight that olive oil phenolics are well absorbed at the intestinal level, suggesting that the intestinal/hepatic metabolism of the ingested phenolics is extensive. Almost all phenolic content are present in plasma and urine in conjugated forms mainly glucurono-conjugates. Taking into account that the amount of free HOTYR in plasma and urine is almost undetectable, some authors suggest to attribute the biological activity to metabolites of HOTYR. In this direction, there are controversial studies about the biological activities of HOTYR and its conjugated forms. In a study in rats, 3-O-glucuronide conjugated HOTYR showed higher activity as a radical scavenger than its corresponding free form . More recently, Khymenets et al.  showed that two glucuronides, 3-O-Gluc-HOTYR and 4-O-Gluc-HOTYR, did not show radical scavenging activity and capacity to protect low-density lipoproteins (LDL) against oxidation compare to HOTYR. In both articles, DPPH assay is used but under different concentrations and solvent. Thus, there is a need for standardization for free-radical assays in order to provide reliable data .


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