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Lamprecht M, editor. Antioxidants in Sport Nutrition. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Antioxidants in Sport Nutrition.

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Chapter 4Antioxidants in Sport Nutrition

All the Same Effectiveness?

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4.1. BASIC MECHANISMS OF OXIDATIVE DAMAGE

While oxygen is vital for life of an aerobic organism, the by-products of its metabolism can be harmful to cells. The very small not-to-water-reduced part of oxygen leads to the production of reactive oxygen intermediates, also known as ROS. This is happening ubiquitary but in particular in the working muscle during or after exercise (Alessio et al. 2000; Caillaud et al. 1999; Clarkson and Thompson 2000). ROS includes superoxide (Image o2dot.jpg), nitric oxide (NO) and hydroxyl radicals (HO) and also non-radicals such as singlet oxygen (1O2) or hydrogen peroxide (H2O2). Depending on the type of exercise, a number of potential mechanisms for the generation of ROS within the muscle have been proposed, such as (a) increased formation of Image o2dot.jpg in the mitochondrial respiratory chain, (b) xanthine oxidase (XO) catalysed degradation of AMP (adenosine monophosphate) during ischaemic muscular work leading to increased production of Image o2dot.jpg, (c) increased ROS formation in the oxidative-burst reaction due to activation of polymorphoneutrophils (PMNs) after exercise-induced muscle damage, (d) loss of calcium homeostasis in stressed muscles, (e) enhanced cytokine production and activation of nuclear factor kappa B (NF-κB), catecholamine autooxidation and many more (König et al. 2007; Niess et al. 1999; Vina et al. 2000). Owing to the unpaired electron in its outer orbit, ROS tend to extract electrons from other molecules to reach a chemically more stable state. However, the generation of ROS is per se not harmful and necessary for the proper functioning of metabolic processes, muscular contraction and immune defence. Muscle antioxidant defence systems are upregulated in response to exercise. NF-κB and mitogen-activated protein kinase are the two major oxidative-stress-sensitive signal transduction pathways that have been shown to activate the gene expression of a number of enzymes and proteins that play important roles in maintenance of intracellular oxidant–antioxidant homeostasis (Ji 2008).

It is only when the body’s natural antioxidant defence system is insufficient to detoxify formed ROS that oxidative stress with damage or destruction of cellular macromolecules such as lipids, proteins, nucleic acids and components of the extracellular matrix may occur. Oxidative stress has been associated with decreased physical performance, muscular fatigue, muscle damage and overtraining (König et al. 2001; Margonis et al. 2007; Tiidus 1998). Therefore, it is sometimes suggested that reducing oxidative stress (e.g. by antioxidant supplementation) would improve exercise tolerance and performance. However, to minimise oxidative stress, the organism contains a powerful antioxidant defence system that depends on nutritionally derived antioxidant vitamins such as vitamin E and C, β-carotene, flavonoids, polyphenols as well as endogenous antioxidant (enzyme) compounds, such as glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD), as already described in Chapters 2 and 3 (Clarkson and Thompson 2000; Dekkers et al. 1996). Therefore, oxidative stress during or following exercise can occur only if the exercise-induced generation of ROS is higher than the detoxifying potential of the antioxidant defence systems. Many studies have investigated the effect of physical exercise with respect to the onset and magnitude of oxidative stress and the protective role of antioxidants, however, with various outcomes (König et al. 2001; Peternelj and Coombes 2011; Powers et al. 2004). There is strong support for the assumption that the manifold designs and methods employed to induce and measure oxidative stress are a major cause for conflicting results: Factors such as gender, age, type of exercise (concentric vs. eccentric, maximal vs. submaximal etc.), level and years of training and particularly the exercise-induced local and systemic stress response could account for both differences in ROS generation and the development of antioxidant defence mechanisms. Nevertheless, antioxidants, either endogenously produced or dietary substances that can act as antioxidants, play a major role in the whole network. In the following section antioxidants which are related to physical activity will be described regarding their mode of action and it will be distinguished between various homologues/chemical forms and their antioxidative effectiveness.

4.2. SHORT LOOK ON THE ANTIOXIDANT DEFENCE MECHANISMS

The protective mechanisms against oxidative stress can be divided into two major categories: endogenously produced enzymatic antioxidants that include SOD, glutathione peroxidase (GPX), CAT, glutaredoxin (GRX) and thioredoxin (TRX). Non-enzymatic antioxidants include nutritionally derived vitamins and provitamins (vitamin E, vitamin C and β-carotene), flavonoids and polyphenols, proteins such as thiols (mainly GSH) and various other low-molecular-weight compounds as ubiquinone, uric acid (UA) and many more (Dekkers et al. 1996; König et al. 2001; Peternelj and Coombes 2011). These substances can either prevent ROS formation or scavenge radical species and convert them into a less active molecule. Furthermore, they avoid the transformation of less active ROS (e.g. Image o2dot.jpg) into more potent forms (e.g. HO), enhance the resistance of sensitive biological targets to ROS attack and assist in the repair of radical-induced damage. The main radical-scavenging functions of the various antioxidants are outlined in Table 4.1. Although most antioxidants are located in specific cellular sites or compartments, they act synergistically and some of them cooperate in the so-called antioxidant chain reaction. This means that, for example, the –SH pool from reduced GSH regenerates vitamins C and E and vitamin C recycles vitamin E. In contrast to other vertebrates, the human organism is not able to synthesise antioxidant vitamins; therefore, non-enzymatic antioxidants such as vitamin E, vitamin C, β-carotene, polyphenols and flavonoids have to be provided by the diet. This implies that the plasma and tissue levels of these non-enzymatic antioxidants are dependent on the quality of foods. In contrast, the enzymatic antioxidants are synthesised within the human organism and several lines of evidence suggest that their production can be upregulated in response to chronic exposure to oxidants (Ji 2008). Although the response may depend on exercise intensity or training duration (Neubauer et al. 2010; Tiidus et al. 1996), most studies have reported an increase in antioxidant enzyme activity following chronic physical exercise (Elosua et al. 2003; Hellsten et al. 1996; Rowiński et al. 2013). This may represent an important mechanism to explain findings from some investigations showing less oxidative stress in trained individuals.

TABLE 4.1

TABLE 4.1

Enzymatic and Non-enzymatic Antioxidants, Location and Main Function

4.3. ANTIOXIDANT SUPPLEMENTATION AND EXERCISE-INDUCED OXIDATIVE STRESS: A CONTROVERSY

Over the past few decades, there have been plenty of exercise studies with measures of oxidative stress as the main outcome when using antioxidant supplementations (see Chapters 7 through 12).

The most common antioxidants used were vitamin E and vitamin C and various antioxidant combinations, also including the latter vitamins. More recently, polyphenols or supplements containing them have been investigated. Not very often, carotenoids, selenium α-lipoic acid or N-acetylcysteine have been used. To draw a general conclusion, it can be said that the outcome was inconsistent, from lowering a oxidative stress biomarker to also increasing then (see reviews König et al. 2001; Peternelj and Coombes 2011).

Furthermore, on the population level, many studies have revealed that the ‘classical’ antioxidants C and E are not only effective in reducing the risk of chronic diseases, but also increasing them slightly (e.g. Abner et al. 2011; Bjelakovic et al. 2007; Gerss and Köpcke 2009). A deeper insight into the network of vitamins C and E can be found particularly in Chapter 3.

4.4. SPECIFIC LOOK ON THE MAIN ANTIOXIDANTS AND THEIR ACTION

Since it is a common practice for athletes to use antioxidants, there is a wide range of vitamins, minerals and different extracts marketed as supplements. However, very often, not in the most active form, overdosed when compared to recommended daily allowances (RDIs), not highly bioavailable and especially as an extract, not even well characterised. Many of the orally taken supplements also have an impact on the antioxidative enzymes or GSH.

4.4.1. Glutathione

GSH is the most abundant non-protein thiol source in the muscle. Its concentration in the cells is usually in a millimolar range but is having a wide range across organs depending on their radical production. It serves various roles in the cellular defence system by directly scavenging radicals, removing hydrogen and organic peroxides, recycling a variety of other antioxidants such as vitamin E and reducing semi-dehydroascorbate radicals. The various ways of acting and the interaction with exogenic substances show the dependency of the GSH activity on the consumption of substances acting as antioxidants (see review from Powers et al. 2004).

The same is true for SOD, CAT or glutathionperoxidase, which belongs to the consumption of their active micronutrients such as iron, manganese, zinc or selenium.

4.4.2. Bilirubin and UA

Bilirubin and UA represent important endogenous antioxidants mainly found in the plasma. UA serves as a free radical scavenger, can trap peroxyl radicals in aqueous phases and therefore contribute to the plasma antioxidant defence (Wayner et al. 1987). During exercise, energy-rich purine phosphates are used and catabolised, resulting in accumulation of hypoxanthine, xanthine and UA in tissues. The conversion of hypoxanthine into xanthine and UA is associated with the formation of toxic oxygen-free radicals (Sjödin et al. 1990).

Plasma concentrations of the potent hydrophilic antioxidant UA are known to increase during intense exercise (e.g. Neubauer et al. 2008), produced from increased purine metabolism (Liu et al. 1999) and probably also because of impaired renal clearance (Mastaloudis et al. 2004).

Bilirubin has been shown to efficiently scavenge peroxyl radicals and act as a metal-binding species, thus functioning as a selective antioxidant. Similar to UA, bilirubin has also been shown to increase after exercise (Neubauer et al. 2010). Since bilirubin is released into the plasma fluid by destruction of red blood cells, haemolysis which arises during physical activity (e.g. during marathon distance running) can be one explanation.

However, there is now novel information published on hyperbilirubinaemia, showing significant antioxidative effects, protection from non-communicable diseases (NCDs) such as cardiovascular disease (CVD) (Novotny and Vitek 2003) and cancer (Temme et al. 2001; Zucker et al. 2004) as well as a severe impact on lipid metabolism (Bulmer et al. 2013; Wallner et al. 2013). Released bilirubin in the plasma is immediately bound to albumin in blood and transported to the liver. In the liver, unconjugated bilirubin is conjugated to glucuronic acid, consequently gets water soluble and is finally called conjugated bilirubin. A mutation in the gene promoter region of bilirubinuridine–diphosphate–glucuronyl transferase (40–60% impaired glucuronidation) can cause hyperbilirubinaemia, arising in approximately 5–10% of the general population. So far, no link has been drawn to physical activity and adaptation processes in hyperbilirubinaemic subjects, but it is highly expected that a high bilirubin plasma concentration has significant effects on metabolism during physical activity.

4.4.3. Vitamin E: A Group of Tocopherols

Very often, it is ignored that the term vitamin E represents a family of eight natural, structurally related compounds. These compounds contain a chromanol ring with a phytyl side chain, which is saturated for tocopherols and unsaturated for tocotrienols. The α-, β-, γ- and δ-tocopherols and the α-, β-, γ- and δ-tocotrienols differ in the number and the position of methyl groups substituted on the ring.

The forms of vitamin E in most supplements are the synthetic all-rac-α-tocopheryl acetate or all-rac-α-tocopheryl succinate; however, both show not the highest vitamin E activity.

Of all compounds with vitamin E activity, α- and γ-tocopherols are the principal vitamins found in human and animal diets and comprise most of the vitamin E content of tissues.

Interestingly, the intake of γ-tocopherol has been estimated to exceed that of α-tocopherol by a factor of 2–4 in North America (see review Wagner et al. 2004). This is due to the fact that soya bean oil is the predominant vegetable oil in the American diet (76.4%) followed by corn oil and canola oil (both 7%). In Europe, the consumption of the α-form exceeds γ-tocopherol with a ratio of approximately 2:1. However, most of the supplementation studies in exercise science and also on the population level to prevent chronic diseases have been performed with α-tocopherol (Wagner et al. 2004).

The ability to donate the phenolic hydrogen is thus very important for the antioxidant activity of the tocopherols as they scavenge the peroxyl radicals. The lack of the C-5 methyl group decreases the electron density in the phenolic ring, making γ-tocopherol a less potent hydrogen donor than α-tocopherol (Kamal-Eldin and Appelqvist 1996). The bond dissociation energies for the phenolic hydrogens are 75.8 and 79.6 Kcal/mole in the case of α- and γ-tocopherols, respectively (Wright et al. 1997). This makes α-tocopherol a more efficient hydrogen donor and radical scavenger than γ-tocopherol. However, the higher hydrogen-donation ability is a double-edged sword as it makes α-tocopherol participate more readily in side reactions, leading to partial loss of its antioxidant activity. This also contributes to the negative findings of high dose supplementation with various α-tocopherol forms.

4.4.4. Vitamin C

In contrast to tocopherols is vitamin C (ascorbic acid) hydrophilic which acts better in the aqueous environment. It is widely distributed but found in high amounts in leukocytes, adrenal and pituitary glands. Besides its scavenging activity, it is well known to recycle the tocopherol radical, thereby being reduced to the dehydroascorbic acid which can then be regenerated, for example, by GSH.

Some decades ago, the intake of vitamin C was too low; however, nowadays, owing to the availability of fruits and vegetables, the intake has increased and vitamin C is enriched in almost every food, particularly meat and sausages, as antioxidant. Therefore, the vitamin C intake via dietary sources exceeds the recommendations nowadays.

Further, pharmacokinetic data indicate a plasma steady state after a vitamin C intake of 200 mg, whereas the ascorbic acid contents of neutrophils, monocytes and lymphocytes are saturated at a daily intake of 100 mg (Levine et al. 1996). Similar to α-tocopherol, it is also well known that vitamin C turns its antioxidative activity towards pro-oxidative activity after high dose supplementation, particularly in the presence of transition metals such as Fe3+.

Taking the latter into consideration, the total intake of vitamin C should not exceed the recommendations manifold; more details and recommendations are given in this book (Neubauer and Yfanti). Furthermore, recent studies have shown that antioxidative supplements (mainly vitamins C and E) hinder the beneficial cell adaptation to exercise (Gomez-Cabrera et al. 2008, 2012; Ristow et al. 2009).

4.4.5. β-Carotene

Supplementation with carotenoids, particularly β-carotene, should be done with care and with hands on the dose. Particularly for β-carotene, no acceptable daily intake (ADI) is set, since it contributes to an increased risk of cancer (particularly lung cancer) in heavy smokers at an intake of 20 mg/day or higher (Albanes et al. 1996; Omenn et al. 1996; The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group 1994). Carotenoids act along two different main pathways—physical and chemical radical quenching. Physical quenching implies the deactivation of singlet oxygen by energy transfer to the excited oxygen species leading to the carotenoid, yielding a triplet-exciting carotenoid. The energy of this carotenoid is dissipated to recover the ground state; the carotenoid itself remains interactive in the process and is able to undergo more cycles of deactivation. Chemical quenching contributes <0.05% to the total 1O2-quenching by carotenoids, but is responsible for the eventual destruction of the molecule. Besides this quenching ability, carotenoids are able to scavenge peroxyl radicals by chemical interactions. However, mainly, β-carotene acts only at low oxygen partial pressure as antioxidant; hyperoxide conditions, often present during and after physical activity, results in a shift to a pro-oxidant (Wagner and Elmadfa 2003).

4.4.6. Further Antioxidants in Use

From the other antioxidants used, much less data are available, particularly with regard to physical activity.

Flavonoids are a family of secondary active plant constituents which have been associated with antioxidative potential, although very often only in in vitro studies. The most prominent ones are flavonones, isoflavonones, flavanones, anthocyanins and catechins. Their biological activities are very broad such as anti-inflammatory, anti-mutagen, anti-tumoral or anti-ischaemic. Most of the observed activities are based on their anti-oxidative potential as a radical scavenger. As polyphenols, they also act as a regenerator of vitamin E radicals or β-carotene. Since they are broadly found in plant products such as black or green tea, grapes and red wine, supplementation must be considered with care. Many of the supplements carrying ‘plant extracts’ are not well defined and concentrations should be carefully evaluated, if given at all. Furthermore, they could contain contaminants, which are doing more harm than good and were also responsible for ending the careers of athletes. One other crucial point is their bioavailability which is regularly very low (see reviews Powers et al. 2004; Peternelj and Coombes 2011).

However, recent studies could show the beneficial effects of polyphenols or extracts (grape, beetroot, Rhodiola rosa or Eckonia cava algae) with regard to oxidative stress in physically active persons, but no effects such as ergogenic acids (e.g. Lafay et al. 2009; Breese et al. 2013; Wylie et al. 2013; Oh et al. 2010). Further, they did not improve muscle force output.

Solely, the antioxidant mechanisms cannot be responsible for the observed effects of polyphenols; therefore, other links are proposed such as the influence on cell-signalling cascades and the interaction with key proteins in these cascades.

Ubiquinones are lipid-soluble quinone derivatives containing an isoprene or farnesyl tail. In humans, predominantly, ubiquinone-10, also called coenzyme-Q, is bioactive. It is found in the diet (soy bean oil, nuts, fish and meat) but also, very often, supplementation is taking place. The antioxidant effects are attributed to their phenolic ring structure, which acts as a radical scavenger, but it is also used to regenerate other primary antioxidants such as tocopherols.

Coenzyme-Q is very popular among athletes, but shows no significant benefit on exercise performance, regardless of age or training status. However, positive effects by Q10 were also shown, such as improved VO2max, faster recovery rate and fatigue recovery (see review from Peternelj and Coombes 2011).

4.5. SUMMARY

The heterogenic role of ROS in living organisms and the beneficial but also deleterious effects of antioxidant supplementation show the complexity of the network and the dependency of various conditions. Since nutritional status, in general, has been improved in the last few decades in many countries worldwide and, at the same time, negative effects of long-term supplementation studies published, the need for high dose supplementation is questionable, particularly for hobby athletes who just fulfil the recommendations for an active person. However, if taking supplements, the chemical form and the concentration must be carefully observed, since the mode of action of many substances can change depending on their concentration, their microenvironment and the network they are acting in. On the basis of the data published, a balanced diet including a large variety of fruits, vegetables, nuts and grain remains the best nutritional approach to maintain optimal antioxidant status.

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