Olives and Olive Oil in Health and Disease Prevention || Olive Oil Components on Oxidative Stress and Arachidonic Acid Metabolism

Olive Oil Components on Oxidative Stress and Arachidonic Acid Metabolism

Maria Teresa Mitjavila1,3,4 and Juan José Moreno2,3,4

1Department of Physiology, Faculty of Biology, University of Barcelona, Spain2Department Physiology, Faculty of Pharmacy, University of Barcelona, Spain3RTIC, Predimed, Instituto de salud Carlos III, Spain4Instituto de Investigación en Nutricion y segundad Alimentaria

Chapter 100

3
9Olives and Olive Oil in Health and Disease Prevention.ISBN: 978-0-12-374420-3
100.1 IntroductIon

Oxidative stress is caused by an imbalance between the oxidant and antioxidant systems of the body, in favor of the oxidants (Sies, 1997). Reactive oxygen species (ROS) are produced during normal aerobic metabolism, although sev-eral conditions such as infection, inflammation, ultravio-let radiation, and tobacco smoke can increase free radical production.

Oxidative stress can modify the activity of cellular pro-teins through changes in intracellular calcium concentra-tions and phosphorylation status as well as the activation of transcription factors. Thus, we have shown that ROS enhance arachidonic acid (AA) release and AA metabo-lism in phagocytic (Martínez and Moreno, 2001) and non-phagocytic cells (Moreno, 2000).

The biological oxidative effects of free radicals on lip-ids, DNA, and proteins are controlled by a wide spectrum of enzymatic antioxidants, such as the scavenger enzymes superoxide dismutase and glutathione peroxidase, and non-enzymatic antioxidants, such as vitamin E and glutathione. Several non-enzymatic antioxidants, such as vitamins C and E, carotenoids, and phenolic compounds, may be key factors in the development of disorders related to oxidative stress (Valko et al., 2007). These antioxidants are essential compo-nents for the body and should be present in a healthy diet.

The uncontrolled production of ROS and the subsequent activation of the AA cascade contribute to the pathogenesis of cardiovascular disease (Moreno and Mitjavila, 2003) and cancer (Moreno, 2005), disorders that register the greatest morbidity and mortality in developed countries. In spite of being an alimentary model with a high content of fat and in contrast to the diets recommended for many decades by nutritionists, the Mediterranean diet is a healthy nutritional model and is related to longevity and a low frequency of chronic diseases, especially coronary heart disease, cancer

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and cognitive deterioration. However, little is known about the molecular basis for the health benefits of this diet.

Olive oil is the primary source of fat in the Mediterranean diet. The healthful properties of this oil have often been attrib-uted, at least in part, to a high content of monounsaturated fatty acids (MUFA), mainly oleic acid (18:1 n-9) (Sirtori et al., 1992), and a low content of saturated fatty acids and cholesterol, and absence of trans fatty acids (Mitjavila and Moreno, 2003). Olive oil is also characterized by low levels of linoleic acid (18:2 n-6), the precursor of AA (20:4 n-6) (Table 100.1). Moreover, it should be emphasized that virgin olive oil, unlike other vegetable oils, contains hundreds of non-fatty micronutrient constituents, including polyphenolic com-pounds (up to 1000 mg kg1), such as hydroxytyrosol, tyrosol and oleuropein (Visioli and Galli, 2000). Phytosterols, the plant counterparts of cholesterol in animals, are also present in extra virgin olive oil at an estimated concentration of 1800–2500 mg kg1 olive oil (Parcerisa et al., 2000). Finally, hydrocarbons can also be found in the unsaponifiable frac-tion of this kind of oil. The main hydrocarbon of olive oil is squalene (1200–7500 mg kg1) (Bondioli et al., 1993). Thus, if we assume a daily consumption of 50 g of olive oil, the polyphenol, phytosterol and hydrocarbon intake through olive oil would be 50 mg day1, 100–150 mg day1 and 50–300 mg day1, respectively (Table 100.2). These compounds contrib-ute to the characteristic flavor and taste of virgin olive oil, and may also be partly responsible for its beneficial effects.

In this review, we summarize the body of knowledge con-cerning the protective effects of both major and minor com-ponents of olive oil on oxidative stress and the AA cascade.

100.2 olIve oIl and cellular oxIdatIve stress

It is well established that neutrophils/mononuclear cells gen-erate a large amount of superoxide anion (O2

) by activation

sectIon | II Oxidative Stress936

Table 100.1 Key terminology in arachidonic acid cascade.

arachidonic acid (AA) is a carboxylic acid with a 20-carbon chain and four double bonds. This essential polyunsaturated fatty acid is present in the phospholipids of membranes of mammalian cells. It is a structural element and also involved in cellular signaling as a second messenger.

Phospholipase a2 (PLA2) recognizes the sn-2 bond of phospholipids and hydrolyzes fatty acids present in this position, usually, AA. PLA2 includes several unrelated protein families with different specificity by the substrate.

cyclooxygenase (COX) is an enzyme that is responsible for formation of prostanoids such as prostaglandins (PGs), prostacylins and thromboxanes (Txs). Currently, three COX isoenzymes are known, COX-1, COX-2 and COX-3. COX-1 is considered a constitutive enzyme whereas COX-2 is an inducible enzyme. COX-3 is a splice variant of COX-1.

lipoxygenase (LOX), enzymes that transform essential fatty acids such as AA into leukotrienes and hydroxyeicosatrienoic acids (HETEs). Mammalian cells express 5-LOX that produces leukotrienes (LTs) and 5-HETE, 12-LOXs that produce 12-HETE and several 15-LOXs that are involved in 15-HETE synthesis.

eicosanoids: signaling molecules made by oxygenation of twenty-carbon essential fatty acids such as AA. They exert complex control over many physiological systems and they are involved in pathophysiology, mainly in inflammation and immunity. There are several families of eicosanoids: prostanoids, leukotrienes, HETEs, epoxyeicosatrienoic acids (EETs).

of NADPH oxidase in response to a wide range of stimuli. Stimulated macrophages isolated from animals fed diets enriched with fish oil show a significant increase in ROS production, while an olive oil diet reduces ROS release (Moreno et al., 2001; De la Puerta et al., 2004). Robinson et al. (1998) reported that polyunsaturated fatty acids (PUFA) such as AA, eicosapentaenoic (EPA) (20:5 n-3) acid and docosahexaenoic acid (22:6 n-3) induce ROS production through phospholipase A2 (PLA2) activation in human neutrophils. These data contribute to explain, at least in part, the lower ROS production by macrophages in rats fed an olive-oil-rich diet with respect to cells from rats fed a fish-oil-rich diet or corn-oil-rich diet (Moreno et al., 2001).

No studies have been carried out on the direct effect of MUFA on nitric oxide (NO) generation. However, it has been shown that an olive-oil-rich diet significantly low-ers the daily antihypertension dosage required, possibly through enhanced NO levels (Ferrara et al., 2000). In this regard, an olive-oil-supplemented diet has been observed to have an additional beneficial effect by increasing the NO/ROS ratio (Moreno et al., 2001). The O2

reacts with NO to generate peroxynitrite, a potent oxidant, and lipid-derived products (Shimokawa et al., 1988). In this condition, the NO excess could have antioxidant activity and reduce lipid peroxidation (Rubbo et al., 2000) whereas peroxynitrite production is reduced. According to these authors, olive oil is more efficient in reducing oxidative stress and the subse-quent lipid peroxidation than corn oil or fish oil. Moreover, olive oil provides MUFA, which are not as readily oxidiza-ble in vitro as the PUFA provided by corn oil, sunflower oil or fish oil. Thus, an olive-oil-rich diet might reduce mem-brane susceptibility to lipid peroxidation. This hypothesis is supported by studies that have demonstrated that the inges-tion of olive oil increases resistance to lipid peroxidation (Baroni et al., 1999). The measurement of isoprostanes,

which are produced in vivo by a non-cyclooxygenase- mediated pathway involving free radical-catalyzed peroxi-dation of AA, is a considerable advancement in assessing in vivo lipid peroxidation. Evidence from animal and human studies show that isoprostane production increases markedly in conditions associated with oxidative stress. Turpeinen et al. (1998) reported that a linoleic-acid-rich diet significantly increased the excretion of urinary 8-iso-prostane whereas low isoprostane concentrations were found after the olive oil diet intervention. These observa-tions could be attributed to the minor oxidative stress, the low levels of linoleic acid substrate to isoprostane synthe-sis, or both.

Many reports describe that there is an inverse relationship between the dietary intake of antioxidant-rich foods such as olive oil and the incidence of human diseases (Halliwell, 1997). As we mentioned in the previous section, virgin olive oil contains numerous minor components with antioxidant activity. Polyphenols are known to possess antioxidant and antiradical actions as scavengers of O2

, singlet oxygen, hydroxyl radicals or lipid peroxy radicals (Hanasaki et al., 1994). Leger et al. (2000) observed that polyphenol-rich olive oil wastewater fractions decreased ROS production in cultured human promonocyte cells and scavenged O2

. Pretreatment of human hepatoma HepG2 cells with hydrox-ytyrosol prevented cell damage in addition to decreasing glutathione and increasing lipid peroxidation induced by tert-butylhydroperoxide (Goya et al., 2007). These results are consistent with the observation that minor components of olive oil protect organs against lipid peroxidation induced in vivo by ferric-nitrilotriacetate administration (Deiana et al., 2007), or induced experimentally by hypoxia-reoxygenation (González-Correa et al., 2007). Unfortunately, these effects have been reproduced in limited intervention studies. Thus, Salvini et al. (2006) showed a reduction in DNA damage in

chaPter | 100 Olive Oil Components on Oxidative Stress and Arachidonic Acid Metabolism 937

postmenopausal women ingesting extra virgin olive oil rich in phenols, particularly hydroxytyrosol. Similarly, Covas et al. (2006) reported that phenolic content of the olive oil can modulate postprandial oxidative stress and Machowetz et al. (2007) observed differences in DNA/RNA oxidation between Northern European populations that do not con-sume olive oil and Southern European populations that do. A complete review of the clinical knowledge concerning the protective role of polyphenols of olive oil on oxidative stress has been published recently by Fitó et al. (2007).

Among the minor components of olive oil, phenolic compounds are those most extensively studied experimen-tal and clinically. However, it should not be overlooked that olive oil contains other compounds that are quantitatively more significant, such as phytosterols. In this regard, Chan et al. (2007) recently observed that phytosterols of olive oil decrease susceptibility to lipid peroxidation in hypercho-lesterolemic subjects.

These antioxidant effects of olive oil recently observed in animal models and in clinical studies could be explained by the fact that polyphenols such as tyrosol, and phyto-sterols such as -sitosterol inhibit O2

and H2O2 produc-tion by stimulated macrophages (Moreno, 2003). A more detailed analysis of the -sitosterol effects revealed that this phytosterol reduces ROS release only when it is preincu-bated, suggesting that this effect may be due to its action on endogenous antioxidant systems. In this way, Vivancos and Moreno (2005) demonstrated that -sitosterol increases Mn superoxide dismutase and glutathione peroxidase activities and these effects can be correlated with the effects of the phytosterol on the redox state. Recently, Arbones-Mainar et al. (2007) reported that olive oil administration to female apoE/ mice increases the levels of antioxidant enzymes, enzymes involved in carbohydrate metabolism, and enzymes involved in the methionine cycle and glutathione synthesis. Thus, polyphenols and phytosterols modulate oxidative stress through distinct and complementary mech-anisms that enhance the biological effects of these com-pounds (Vivancos and Moreno, 2008). It is therefore likely that these compounds in their natural formulation, in this case as virgin olive oil, are more active than their isolated forms. Moreover, we must consider that olive oil is ingested together with other foods rich in antioxidant compounds in the Mediterranean diet, which might raise their effects.

100.3 effects of olIve oIl comPonents on aa amount In membranes and aa release

The fatty acid composition of cell membranes is deter-mined by the fatty acid content of the diet (Fisher, 1989; Mitjavila et al., 1996). Although dietary AA content is low, AA is abundant in membranes because mammalian cells can synthesize it from linoleic acid by elongases and

desaturases. Thus, diets with low linoleic acid content, such as those enriched in fish oil or tripalmitin, impair AA con-tent in membranes and consequently AA suitable to pro-duce eicosanoids (Mitjavila et al., 1996). In this regard, it must be noted that olive oil contains a high amount of oleic acid and only a small amount of linoleic acid, the precur-sor of AA. Moreover, olive oil can reduce the conversion of linoleic acid to AA by inhibiting the 6-desaturase (Navarro et al., 1994). Consequently, an olive-oil-rich diet markedly decreases tissue AA content and the subsequent eicosanoid production (Bartoli et al., 2000; De la Puerta et al., 2004).

Considerable amounts of AA are found esterified at the sn-2 position of the phospholipid membranes of all types of mammalian cells (Table 100.1). Under normal physi-ological conditions, the amount of free intracellular AA available is quite small, but numerous chemical (hormones, neurotransmitters, cytokines and growth factors) and physi-cal stimuli can induce AA release through the activation of phospholipase A2s (PLA2s). PLA2 comprises a large superfamily of distinct enzymes that differ in substrate specificity, cofactor requirement, and subcellular locali-zation. In almost all mammalian cells, there are multiple PLA2s. Secretory PLA2s do not distinguish between fatty acids such as oleic acid or AA at the sn-2 position whereas cytosolic PLA2s exclusively hydrolyze AA and EPA and some calcium-independent PLA2s only release AA. Thus, PLA2 activation induces MUFA and PUFA release.

The redox state of the cell may act as a molecular switch that regulates the activity of many enzymes and genes in concert. In this way, previous results have sug-gested that ROS are involved in the pathways that lead to calcium-independent PLA2 activation and consequently to AA release (Martínez and Moreno, 2001). Moreover, the phosphorylation and dephosphorylation stimulated by ROS may also enhance AA mobilization via a protein kinase C-independent pathway (Martínez and Moreno, 1996). These effects may be modulated by tyrosol and -sitosterol through ROS scavenging or the modulation of ROS pro-duction, respectively, as was reported in ROS-stimulated

Table 100.2 Components of virgin olive oil and their daily consumption by humans.

Compound Content Daily consumption

Oleic acid 550–830 g kg1 25–45 g

Linoleic acid 30–220 g kg1 1.5–10 g

Polyphenols up to 1000 mg kg1 50 mg

Phytosterols 1800–2500 mg kg1 100–200 mg

Hydrocarbons 1200–7500 mg kg1 60–300 mg


RAW 264.7 macrophages (Moreno, 2003). In this way, both minor components of olive oil modulated AA release induced by oxidized low-density lipoproteins in RAW 264.7 macrophages (Vivancos and Moreno, 2008).

100.4 effects of olIve oIl comPonents on aa metabolIsm

Free AA can be oxidized via three major metabolic routes: the cyclooxygenase (COX), the lipoxygenase (LOX) and the cytochrome P-450 monooxygenase pathways. COX catalyzes the conversion of AA to prostaglandin H2, the immediate precursor of 2-series prostaglandins (PGs) and thromboxanes (Txs). Furthermore, AA is also metabolized by LOX to produce hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs) and lipoxins, whereas cytochrome P-450 metabolizes AA to produce HETEs and epoxyeicosatrienoic acids (Figure 100.1). Consequently, AA is the precursor of a large number of biological active products, collectively termed eicosanoids; 2-series PGs such as PGE2 and 4-series LTs such as LTB4, the main AA-derived eicosanoids, have specific receptors, mainly G-protein-coupled receptors, to elicit their biological responses. Thus, the availability of free AA and its subsequent metabolism are rate-limit-ing steps in the synthesis of eicosanoids. EPA and linoleic acid are also substrates for the COX, LOX and cytochrome P-450 pathways that induce the synthesis of 3-series PGs, 5-series LTs, hydroxyeicosapentaenoic acids and hydroxy-octadecadienoic acids, respectively. These metabolites are considered less active than AA metabolites. Interestingly, cells do not produce biologically active molecules from free oleic acid by these metabolic pathways (Figure 100.2).

An elegant experimental model to study the relation-ship between the beneficial effects of olive oil consump-tion and the AA cascade in pathophysiological conditions is the lipopolysaccharide-induced endotoxic shock model. Using this model, Leite et al. (2005) observed that animals fed olive oil exhibited reduced neutrophil accumulation and low levels of PGE2, LTB4 and tumor necrosis factor-. Moreover, animals fed an olive-oil-rich diet were resistant to endotoxic shock and showed a higher survival rate than those given corn oil or soybean oil.

Taken together these data suggest that the impairment of PGE2 or LTB4 levels induced by tyrosol or -sitosterol are the result of a decrease in AA mobilization and/or the effect of these compounds on the enzymes of the COX and LOX pathways. Olive oil phenols interfere with LT genera-tion by inhibiting 5-LOX (De la Puerta et al., 1999) and 12-LOX (Kohiyama et al., 1997) activities, but not COX-2 (Moreno, 2003). However, these polyphenolic components of olive oil inhibited Tx production and platelet aggrega-tion (Petroni et al., 1995), events in which COX-1 plays a predominant role. Given that resveratrol, a polyphenol of white wine, inhibits this enzyme (Szewczuk and Penning, 2004), we cannot exclude the possibility that olive oil polyphenols affect COX-1 activity and consequently pros-tanoid production by platelets, platelet aggregation and thrombogenesis.

AA catalysis by COXs requires the activation of these enzymes by an alkyl hydroperoxide. This activation involves an initial oxidation of the heme group of the COXs and cul-minates in the generation of a tyrosyl radical in the COX active site. This tyrosyl radical abstracts hydrogen from the fatty acid in the first step of the COX reaction (Rouzer and Marnett, 2003). Thus, we must consider that these events

Prostaglandins (PGE2, PGD2, PGF2α)

Prostacyclins (PGl2)

Thromboxanes (TxA2, TxB2)

5-HETE

12-HETE

15-HETE

Leukotrienes

(LTB4, LTC4, LTD4)

Arachidonic acid

Membrane phospholipids

COX-1

COX-2CYP-450s

PLA2

5-LOX

12-LOX

15-LOX 5-HETE

12-HETE

15-HETE

20-HETE

5,6-EET

8,9-EET

11,12-EET

14,15-EET

fIgure 100.1 The arachidonic acid cascade. Main enzymes involved in the synthesis of eicosanoids from arachidonic acid. Cycooxygenases (COXs) produce prostaglandins (PGs), prostacyclins and thromboxanes (Txs); lipoxygenases (LOXs) produce hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs) and finally, cytochromes P-450 produce HETEs and epoxyeicosatrienoic acids (EETs).


may also be modified by olive oil components. Therefore, the effect of these components on prostaglandin biosynthesis may be due not only to their action on COX activity but also to their effects on COX levels. Thus, Martínez et al. (2000) reported that ROS are involved in the enhancement of COX-2 expression by macrophages. Tyrosol and -sitosterol, but not squalene, inhibit the enhancement of COX-2 expression and the subsequent PGE2 synthesis induced by phorbol esters or a ROS-generating system in RAW 264.7 macrophages (Moreno, 2003). It must be considered that the promoter region of the COX-2 gene contains several binding sites for transcriptional factors that may be modulated by the cellu-lar redox state, like NF-B (Zwacka et al., 1998). Thus, the modulation of intracellular ROS levels by tyrosol/-sitosterol could regulate COX-2 induction through the NF-B path-way (Moreno, 2003). On the other hand, we must consider that AA and EPA release can induce COX-2 over-expression whereas oleic acid release did not have an appreciable effect (Sanchez and Moreno, 1999). Therefore, an olive-oil-rich diet could control eicosanoid production through the modula-tion of AA content of membranes as well as the capacity to release and/or metabolize AA. This hypothesis, if confirmed, could explain the impairment of PGE2 synthesis by peritoneal macrophages (Moreno et al., 2001) or peritoneal leukocytes (De la Puerta et al., 2004) from rats fed a virgin olive oil diet.

The above experimental events can be associated with the clinical observations of Peck et al. (1996) who reported that olive oil intervention decreases plasma PGE2 concentra-tions. Recently, Visioli et al. (2005) examined the effect of olive oil on oxidative stress as well as thromboxane B2 (TxB2) synthesis as markers of processes considered relevant for coronary heart disease in mildly dyslipidemic patients. They reported a potential antithrombotic action of olive oil through the reduction of TxB2 production. More recently, the same

authors reported that olive oil consumption increases serum antioxidant capacity and produces a concomitant decrease in inflammatory markers from AA cascade, such as TxB2 and LTB4 (Bogani et al., 2007). Thus, it seems that the simultane-ous action of olive oil components on AA amount in mem-branes, the cellular redox state, PLA2s activation, AA release from membranes and on COX-2 over-expression can explain the effects of olive oil on eicosanoid production. These data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease, at least partially, through the protective role of the components of olive oil on the AA cascade and consequently on the thrombotic environment and endothelium state. Moreover, we must consider that the inflammatory mediators derived from AA exert profound bio-logical effects on cell proliferation, apoptosis and angiogen-esis, events that enhance the development and progression of cancers in humans (Moreno, 2005). Thus, the modulation of the AA cascade by olive oil consumption could partly explain the remarkable preventive effect on cancer development attrib-uted to olive oil in experimental models (Bartoli et al., 2000) and epidemiological studies (Martín-Moreno et al., 1994).

100.5 conclusIons

On the basis of the data discussed above, we conclude that olive oil consumption is beneficial when pathophysiological and pathological processes involve a disregulation of the AA cascade. Experimental and clinical studies indicate that the modulation of AA levels in membrane phospholipids as well as the activity of the main elements involved in AA release and the subsequent AA metabolism explain, at least in part, these effects (Figure 100.3). Thus, olive oil consumption should be considered a valuable strategy to modulate the

PG2s

COX

LOX

COX

AA EPA Linoleicacid

Oleicacid

LOX

COX

LOX

P450 P450 P450

COX

LOX

P450

HETEs

EETs

HEPEs HODEs

HODEs

TX2s

PG3s

TX3s

LT4s

HETEs

LT5s

HEPEs

fIgure 100.2 Eicosanoid production from arachidonic acid (AA), eicosapentaenoic acid (EPA), linoleic acid or oleic acid. COX pathway produces 2-series PGs and 2-series Txs from AA and 4-series LTs by LOX pathway and hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acid (EETs) by CYP-P-450 pathway. EPA was metabolized to produce 3-series PGs, 3-series Txs, 5-series LTs and hydroxyeicosapentaenoic acids (HEPEs). Linoleic acid can be metabolized by LOX and CYP P-450 to produce hydroxyoctadecadienoic acids (HODEs). Oleic acid cannot be metabolized by COX, LOX or CYP P-450 pathways.


generation of inflammatory mediators from the AA cascade and consequently the development of serious diseases with an important inflammatory component such as atheroscle-rosis/coronary heart diseases and cancer. However, further studies are required in large sample size intervention studies to confirm these promising effects of olive oil.

summary PoInts

l Oxidative stress is caused by an imbalance between the oxidant and antioxidant systems of the body, in favor of the oxidants.

l The uncontrolled production of reactive oxygen species and the subsequent activation of the arachidonic acid cascade contribute to the pathogenesis of cardiovascu-lar disease and cancer, disorders that register the great-est morbidity and mortality in developed countries.

l The Mediterranean diet is a healthy nutritional model and is related to longevity and a low frequency of chronic diseases, especially coronary heart disease, cancer and cognitive deterioration.

l Olive oil is the primary source of fat in the Mediterranean diet. The healthful properties of this oil have often been attributed to a high content of monounsaturated fatty acids and hundreds of non-fatty micronutrients such as polyphenolic compounds and phytosterols.

l Olive oil provides monounsaturated fatty acids, which are not as readily oxidizable in vitro as the poly-unsaturated fatty acids provided by corn oil, sunflower oil or fish oil. Thus, an olive-oil-rich diet might reduce membrane susceptibility to lipid peroxidation, and con-sequently phospholipase A2 activation.

l An olive-oil-rich diet markedly decreases tissue ara-chidonic acid content and the subsequent eicosanoid production.

PolyphenolsPhytosterols

Hydrocarbons

Oleic acid

Decreasessusceptibility to lipid

peroxidation

Modulates AA amountsin biomembranes

Unsaponifiablefraction

Oliv

e o

il

Mo

du

late

s ei

cosa

no

id p

rod

uct

ion

in p

ath

olo

gic

al c

on

dit

ion

s

Saponifiablefraction

Regulates AA releaseinduced by ROS

Regulates AA cascadeenzymes activation

induced by ROS

fIgure 100.3 The main effects of olive oil components on oxidative stress and the AA cascade. Saponifiable factors modulate AA levels in mammalian membranes whereas the elements of the unsaponifiable frac-tion modulate oxidative stress and enzymes/genes involved in AA cascade.

l Polyphenols and phytosterols modulate oxidative stress through distinct and complementary mechanisms that enhance the biological effects of these compounds.

l Minor components of olive oil modulated arachidonic acid release.

l The modulation of intracellular reactive oxygen species levels by tyrosol/-sitosterol could regulate cyclooxy-genase-2 induction through the transcription nuclear factor-B pathway.

l In conclusion, an olive-oil-rich diet could control eicosanoid production through the modulation of ara-chidonic acid content of membranes as well as the capacity to release and/or metabolize this fatty acid.

acknowledgments

Original works described in this review were supported by the Spanish Ministry of Science and Technology (PB91-0432, PB94-0942, PM98-0182, PM98-0191, BFI2001-3397, BFU2004-04960, BFU2007-61727), the Spanish Ministry of Health (RD06/0045/0012) and the Autonomous Government of Catalonia (1999SGR00266, 2001SGR00266, 2005SGR0269).

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Olives and Olive Oil in Health and Disease Prevention || Olive Oil Components on Oxidative Stress and Arachidonic Acid Metabolism