Selenium in food and the human body: A review

S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / s c i t o t e n v

Review

Selenium in food and the human body: A review Miguel Navarro-Alarcon ⁎, Carmen Cabrera-Vique Department of Nutrition and Food Science, University of Granada, 18071-Granada, Spain

AR TIC LE I N FO

ABS TR ACT

Article history:

Selenium levels in soil generally reflect its presence in food and the Se levels in human

Received 27 March 2008

populations. Se food content is influenced by geographical location, seasonal changes,

Received in revised form 16 June 2008

protein content and food processing. Periodic monitoring of Se levels in soil and food is

Accepted 16 June 2008

necessary. Diet is the major Se source and approximately 80% of dietary Se is absorbed

Available online 26 July 2008

depending on the type of food consumed. Se bioavailability varies according to the Se source and nutritional status of the subject, being significantly higher for organic forms of Se. Se

Keywords:

supplements can be beneficial for subjects living in regions with very low environmental

Selenium

levels of Se. Several strategies have been followed: (1) employment of Se-enriched fertilizers;

Dietary intake

(2) supplementation of farm animals with Se; (3) consumption of multimicronutrient

Bioavailability

supplements with Se. Nevertheless, detailed investigations of possible interactions between

Supplementation

Se supplements and other food components and their influence on Se bioavailability are

Biomarkers

needed. Suppliers also need to provide more information on the specific type of Se used in

Disease prevention

supplements. In addition, research is lacking on the mechanisms through which Se is involved in hepatocyte damage during hepatopathies. Although Se potential as an antioxidant for the prevention of cardiovascular diseases (CVD) is promising, additional long-term intervention trials are necessary. As a result, indiscriminate Se supplements cannot be reliably recommended for the prevention of CVD in human beings. Some interesting findings reported an association of Se intake with a reduced prevalence and risk for prostate and colon cancer. However, random trials for other cancer types are inconclusive. As a final conclusion, the general population should be warned against the employment of Se supplements for prevention of hepatopathies, cardiovascular or cancer diseases, because benefits of Se supplementation are still uncertain, and their indiscriminate use could generate an increased risk of Se toxicity. © 2008 Elsevier B.V. All rights reserved.

Contents 1.

Selenium content in foods and beverages . . . 1.1. Meat, chicken, fish and eggs . . . . . . 1.2. Milk and dairy products . . . . . . . . . 1.3. Fruits and vegetables . . . . . . . . . . 1.4. Legumes, nuts, cereals and by-products 1.5. Miscellaneous . . . . . . . . . . . . . .

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⁎ Corresponding author. Tel.: +34 958 243865; fax: +34 958 249577. E-mail address: [email protected] (M. Navarro-Alarcon). 0048-9697/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.scitotenv.2008.06.024

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2. 3. 4. 5. 6. 7. 8. 9. 10.

Selenium bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . Selenium total dietary intake. . . . . . . . . . . . . . . . . . . . . . . . . Selenium supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . Physiological role of selenium . . . . . . . . . . . . . . . . . . . . . . . . Assessment of body nutritional status on selenium . . . . . . . . . . . . Selenium metabolism and pharmacokinetics . . . . . . . . . . . . . . . . Selenium deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicity of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Body selenium metabolism in several diseases . . . . . . . . . . . . . . . . 10.1. Selenium metabolism in hepatopathies . . . . . . . . . . . . . . 10.2. Selenium metabolism in cardiovascular diseases . . . . . . . . 10.3. Selenium metabolism in cancers . . . . . . . . . . . . . . . . . 10.4. Influence of selenium supplementation trials on the prevention and body limitations associated with ageing . . . . . . . . . . . 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Selenium content in foods and beverages

Se content in food and beverages varies geographically both within and between countries. The Se content of animal products reflects the Se levels in their consumed diet (Barclay et al., 1995), whereas the Se content of plants is directly affected by Se levels in the soil in which are grown. Se in the form of selenate or selenite is taken up by plants and mainly transformed into Se-Met in cereal grains (Sathe et al., 1992). Plant absorption of Se principally depends on the concentration and physicochemical forms existing in the soil. Factors such as the type of rocks, pH and redox potential in the soil, the existence of some organic and inorganic compounds, soil moisture and salinity, soil sulphate concentration, plant species, soil-management practices, oxidation state of the element (the absorption of Se6+ is higher than that of Se4+), nature of draining waters, and climatic conditions all influence the distribution, status and availability of this element (Aro et al., 1995; Barclay et al., 1995; Combs, 2001). In acid soils Se is mainly present as selenite which has very low solubility and plant availability. In alkaline soils, Se is oxidized to selenate, which is more soluble and more available for uptake in the crops. In many regions of the world Se soil levels generally reflect the Se status in human populations (Goyer and Clarkson, 2001; Burk and Levander, 2002). There are some zones where Se levels in soil are very low (b0.05 ppm), such as parts of China, Finland and New Zealand. In these regions, diseases caused by Se deficiency in livestock and the effect on human health are well known. Nevertheless, in regions of high Se soil concentrations (N5 ppm), there is a net excess of this element as observed in Canada, Ireland, some regions of the western USA, and some zones of China, France, Germany, etc. (Simonoff and Simonoff, 1991; Aro et al., 1995). McNaughton and Marks (2002) reported that foods from the USA generally have higher Se levels than Australian foods, and that foods from United Kingdom and New Zealand have lower levels. Efforts have been made to increase the Se content in plants by adding Se to the soil. Food protein content is another important factor influencing Se presence in food since Se can replace sulphur in the

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amino acids as selenomethionine (Se-Met), selenocysteine (Se-Cys) and selenocystathionine due to their physicochemical similarity (Simonoff and Simonoff, 1991; Navarro-Alarcon and López-Martínez, 2000). Further, selenocompounds would be used in the synthesis of Se-amino acids (mainly, SeMet and Se-Cys), and finally incorporated in vegetable proteins. Thus, the Se forms included in the vegetable proteins of animal feed would ultimately be employed in the synthesis of the animal's own proteins, facilitating their accumulation in livestock. Most plants do not have the ability to accumulate large amounts of Se (concentrations rarely exceed 100 μg/g, dry weight). However, various plant species such as garlic (Allium sativum), Indian mustard (Brassica juncea), canola (Brassica napus), and some mushrooms have been recognized as Se accumulators. They have the ability to take up large amounts of Se (N1000 mg Se/kg) without exhibiting any negative effects (Dumont et al., 2006). This is mainly due to the reduction of the intracellular Se concentration of Se-Cys and Se-Met which are normally incorporated into proteins. When consumed in appropriate amounts, these foods can be a significant food source of Se (Dumont et al., 2006). Industrial and agricultural activity has hastened the release of Se compounds from geologic sources, making them available to fish and wildlife in aquatic and terrestrial ecosystems around the globe. In recent years, the results of many investigations on contaminant Se conclude that Se exhibits its toxicity in animals primarily through the food chain (Lemly, 1999; DeForest et al., 1999; Hamilton, 2004). Agricultural drain water, sewage sludge, fly ash from coalfired power plants, oil refineries, and mining of phosphates and metal ores are all sources of Se contamination in the aquatic environment. Specifically, bivalves (being filter-feeders) have been identified as the most sensitive indicators of Se contamination (Hamilton, 2004). Fish can take up Se from water, plants, or by eating other marine species. Accumulation of Se in marine animals from dietary sources (phytoplankton ad zooplankton) is more important than that accumulated directly from the water. In addition, Se compounds are widely used in glass manufacture, electronic applications, photocopy

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Table 1 – Se content in foods and beverages according to several authors Type of sample

Origin

Milk and dairy products Cow's milk Greece Ireland Gouda cheese Yoghurt

Butter Condensed milk Ice-cream Fresh buffalo milk

Greece Greece Croatia Spain Greece Australia Spain Spain UK Egypt

Fruits and vegetables Apple Australia

Se content (ng/g) 13.1–21.9 14–18 85.4 ± 10.0 21.9–26.9 29.9 50.0 ± 30.0 4.4–13.8 0.7–14.2 75.0 ± 25.0 100.0 ± 40.0 15.0–17.0 53

4.5

Garlic

Australia Greece Australia Greece Greece Australia Australia Greece Slovakia

30.0–50.0 1.4 ± 0.2 40.0–76.0 3.9 ± 0.5 2.6 ± 0.6 5.00 30.0–70.0 4.6 ± 1.4 3.5

Celery Lettuce Onion

Greece Australia Australia India

13.4–13.7 9.3–14.2 3.0–22.8 127

Green peas

India

180

Pepper

India

150

Greece

4.2 ± 0.3

Kiwi Grapes Sharon fruit Mango Orange Potato

Legumes, nuts, cereals and derivatives Lentils USA 28.0 New Zealand 18.0 Bread Greece 70.0–131.8 Pasta Greece 5.8 ± 0.2 Pasta, boiled Australia 35.6–50.0 Rice Greece 19.1 ± 1.4 Italy 20.1 ± 45.3 Peanuts

USA

75.0

Meat, chicken, fish and eggs Beef, steak Australia Lamb Spain

80–200 27–30

Rabbit

Spain

74–106

Pork Pork kidney

USA Spain

144–450 849–1543

Pork liver

Spain

256–800

Ham Oyster

Australia Australia

200 770

Reference

Pappa et al. (2006) Murphy and Cashman (2001) Pappa et al. (2006) Pappa et al. (2006) Klapec et al. (2004) Cabrera et al. (1996) Pappa et al. (2006) Fardy et al. (1994) Cabrera et al. (1996) Cabrera et al. (1996) Barclay et al. (1995) Akl et al. (2006)

McNaughton and Marks (2002) Marro (1996) Pappa et al. (2006) Marro (1996) Pappa et al. (2006) Pappa et al. (2006) Marro (1996) Marro (1996) Pappa et al. (2006) Kadrabova et al. (1997) Pappa et al. (2006) Marro (1996) Marro (1996) Singh and Garg (2006) Singh and Garg (2006) Singh and Garg (2006) Pappa et al. (2006)

USDA (1999) NZ-ICFRL (2000) Pappa et al. (2006) Pappa et al. (2006) Marro (1996) Pappa et al. (2006) Panigati et al. (2007) USDA (1999)

Tinggi (1999) Díaz-Alarcon et al. (1996a) Díaz-Alarcon et al. (1996a) USDA (1999) Díaz-Alarcon et al. (1996a) Díaz-Alarcon et al. (1996a) Tinggi (1999) Marro (1996)

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Table 1 (continued) Type of sample

Origin

Meat, chicken, fish fish and eggs Salmon Australia Egypt Tuna (in oil)a Sardines Australia Eggs Greece Australia Miscellaneous Apple juice Beer Cornflakes Extra virgin olive oil Olive oil Honey Herbal tea Tea infusionb Cardamon Mustard seeds Black pepper Vinegar Tap water Sugar, raw Chocolate Margarine

Se content (ng/g)

Reference

270–368 810.0 570 172.8 0.7–14.2

Marro (1996) Akl et al. (2006) Fardy et al. (1994) Pappa et al. (2006) Marro (1996)

Australia Australia Greece Australia Greece

0.7–5.1 5.00 19.7 ± 0.6 62.9 1.1 ± 0.6

Marro (1996) Marro (1996) Pappa et al. (2006) Marro (1996) Pappa et al. (2006)

Australia Greece India

5.30 1.7 ± 0.004 190 ± 18

Marro (1996) Pappa et al. (2006) Manjusha et al. (2007) Australia 5.00 Marro (1996) India 80 ± 4 Manjusha et al. (2007) India 248 ± 15 Manjusha et al. (2007) India 116 Singh and Garg (2006) Spain 0.653–2.344 Díaz et al. (1997) Pappa et al. (2006) Greece 2.2 ± 0.7c USA 69.0 Marro (1996) UK 41.0 Barclay et al. (1995) USA 39.0 USDA (1999) Australia 0.71–18.6 Marro (1996) USDA (1999) USA Ndd-10 New Zealand 6.00–16.0 NZ-ICFRL (2000)

Data are referred to wet weight. Processed fishery food. b Tea, brewed 5 min. c Data expressed as μg/l. d nd, Not detectable. a

machines, inorganic pigments, rubbers, ceramics, plastics and lubricants (Akl et al., 2006). Food processing such as cooking (boiling, baking or grilling) could decrease Se food content by volatilization (Dumont et al., 2006; Sager, 2006). For example, Se losses of 40% in asparagus and mushrooms were observed when boiled for some minutes (Navarro-Alarcon and López-Martínez, 2000; Dumont et al., 2006). Some Se losses have also been noted when roasting chicken and fish (Thomson and Robinson, 1990). However, other researchers did not find any decrease, and even reported that processes such as cooking, aeration or lyophilization significantly increases Se content in all food (Zhang et al., 1993). Considering the disparate results found in the many studies we considered, more research in this area should be performed to clarify the specific influence that different cooking processes exert on Se content of food. Therefore, we concluded that the content of trace elements in food should not be based exclusively on food tables, but should take into account loss during food processing and preparation, variation due to seasonal changes or geographical location, as well as food habits. Consequently, thorough

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and periodic determinations of trace elements such as Se is advisable. In addition, lack of data for some foods may introduce errors into the estimate of dietary intake of essential elements such as Se.

with others such as McNaughton and Marks (2002), and Pappa et al. (2006) who all consider that milk and dairy products contribute a considerable fraction of the total dietary intake of Se, particularly for infants.

1.1.

1.3.

Meat, chicken, fish and eggs

Data on Se content in different foods are collected in Table 1. Meat, chicken, fish and eggs are protein-rich foods containing high levels of Se (Klapec et al., 2004; Sirichakwal et al., 2005). In these food groups, Ventura et al. (2007) encountered Se levels ranging from 87.6 to 737 ng/g. Fish and eggs showed the highest Se concentration (Pappa et al., 2006; Haratake et al., 2007). Meat, fish and eggs contribute the major part of dietary Se in several countries such as Greece, Portugal and Japan (Pappa et al., 2006; Haratake et al., 2007; Ventura et al., 2007). In Japan, fish was the greatest Se contributor (up to 60% of daily total intake) rather than the staple foods (rice and vegetables) (Haratake et al., 2007). Literature on Se content in fish from different locations ranged between 62.7 and 506.7 ng/g in Greece (Pappa et al., 2006), 120.0–632.0 ng/g in Australia (McNaughton and Marks, 2002), 126 to 502 ng/g in the USA (USDA, 1999), and 195 to 512 ng/g in New Zealand (NZ-ICFRL, 2000). Tinggi (1999) reported Se content in eggs from Australia to have a mean concentration of 90 ng/g in white and 260 ng/g in yolk (boiled eggs). Marzec et al. (2002) reported that Se levels in meat products ranged from 55.0 to 329 ng/g. These values were higher than those for the other food groups. Meat showed large variations in Se concentration, reflecting the differences in Se concentrations of the feed consumed by the animals (McNaughton and Marks, 2002; Pappa et al., 2006). According to Pappa et al. (2006), mean concentrations of Se in meat from Greece ranged from 48.8 to 94.1 ng/g, with pork measuring significantly higher beef. In sausages from Spain, Diaz-Alarcon et al. (1996a) encountered Se levels ranging from 89.0 to 739 ng/g. These authors concluded that meat products and cereals (mostly bread) are the main contributors to daily Se intake in healthy individuals from South-eastern Spain. A total of 55% of daily Se intake came from these two food groups due to their high Se concentrations and/or consumption. These findings are in agreement with other researchers (Srikumar et al., 1992; Donovan et al., 1992) who conclude that vegetarians and lactovegetarians suffer significantly decreased daily Se intake, which could contribute to a nutritional Se deficiency.

1.2.

Milk and dairy products

It has been found that Se concentrations in milk from different animal species decreases in the following order: human N sheep N goat N cow milk. It is known that Se concentrations in milk are negatively correlated with its fat content (Pappa et al., 2006). A similar trend was observed by Barclay et al. (1995) in cheeses. A survey of Se content of Australian cow milk showed a wide variation with higher levels in summer (23.8 ± 4.6 ng/l) than in winter milk (20.7 ± 4.2 ng/l). Cabrera et al. (1996) determined Se content in dairy products and observed a wide variability among the data due to the different concentrations of Se present in milk, eggs, cereal, fruit and other foodstuffs used in their manufacture. These authors agree

Fruits and vegetables

Fruit contains low concentrations of Se (Table 1). This fact could be explained by the low protein fraction (and therefore, the high water content) of these products. Similarly, fresh vegetables were also shown to be poor sources of Se (Sirichakwal et al., 2005). Ventura et al. (2007) reported similar Se data for fruit and vegetables from Portugal (1.7 to 24.9 ng/g). However, it is known that vegetables such as B. juncea and the better known species of the Brassica genus (broccoli, Brussel sprouts, cabbage, cauliflower, collards, kohlrabi, mustards and kale), garlic, chives and onions tend to have higher Se concentrations and the extent to which they are consumed is reflected in the Se content of human tissue and body fluids (Ip and Ganther, 1994; Dumont et al., 2006; Kapolna and Fodor, 2007). These plants have a greater fraction of sulphur containing amino acids and their derivatives, but they also contain other sulphur compounds like glycosinolates or sulfoxides. Adequate analogues of these can be formed by substitution of sulphur with Se, resulting in higher Se levels (Ip and Ganther, 1994). Garlic and onions seem to be a good dietary source of Se, and both have valuable anti-carcinogenic activities. Furthermore, their intake does not result in excess accumulation of Se in tissues; nor could any perturbation in the action of Se enzymes be observed, even at high Se intakes (Dumont et al., 2006). Similarly, Manjusha et al. (2007) found high Se content in mushrooms (1340 ng/g). Some, but not all mushrooms tend to accumulate Se because they are another vegetable species with a high content of sulphur containing compounds. Agaricus bisporus is one of the most commonly studied mushrooms for Se speciation purposes and is also the most commonly consumed mushroom in Europe and the USA. Other mushrooms that accumulate Se are Boletus edulis and B. macrolepiota (Dumont et al., 2006). Plants that accumulate Se may be used as a natural source of mineral supplements for both animals and human beings, especially in areas that are Se deficient.

1.4.

Legumes, nuts, cereals and by-products

Pappa et al. (2006) reported that the Se content in legumes from Greece ranged from 24.4 to 443.9 ng/g, with a mean value of 165.2 ng/g, lentils presenting the highest concentration (Table 1). They encountered Se concentrations between 7.0 and 32.27 ng/g in nuts. Pistachios proved to be the richest, whereas almonds were the poorest Se source. Protein-rich nuts (pistachios, walnuts) present higher Se concentration than other products (Ip and Ganther, 1994; Dumont et al., 2006). Manjusha et al. (2007) encountered a mean content of Se in Brazil nuts of 3800 ng/g. Brazil nuts (Bertholletia excelsa) are known for their high Se concentration and one single Brazil nut could exceed the RDA for Se (Dumont et al., 2006). The proteins found in Brazil nuts are very high in Se-containing amino acids, mainly Se-Met. Dumont et al. (2006), in a wide review of the literature, reported levels of Se in cereals of 10.0–550.0 ng/g (referred to fresh weight). Marro (1996) encountered Se levels in white bread of

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80.0–109.0 ng/g (mean of 92.6 ng/g) and in whole meal bread of 100.0–152.0 ng/g (mean of 125.0 ng/g). Tinggi et al. (1992) reported that the major source of Se in Australia comes from wheat products such as bread (60.0–150 ng/g) and pasta (10.0–100 ng/g) as was also reported by Diaz-Alarcon et al. (1996b). Pappa et al. (2006) reported mean Se concentrations of bread ranging from 70.0 to 131.8 ng/g. The differences of Se content between brown, whole-wheat and white bread were not statistically significant (p N 0.01), although brown bread seemed to be much richer in Se than the others.

1.5.

Miscellaneous

Water Se content is usually trivial compared to the content of this element in food (Food and Nutrition Board—Institute of Medicine, 2000). Diaz et al. (1997) indicated that drinks and potable water are generally poor sources of Se (Table 1). Molnar et al. (1995) analyzed Se content in fast food from the UK and encountered the highest levels in products based on certain mushrooms, spinach and fish. Generally, foods produced from Se-rich raw ingredients were themselves high in Se. They remarked that the Se content of food varies from sample to sample, even in cases of the same product. In baby foods from Spain such as sole with vegetables or with potatoes, angler fish with vegetables and hake with rice, Viñas et al. (2000) detected Se levels that ranged from 21.5 ± 1.3 to 72.8 ± 5.3 ng/g. Roca et al. (2000) determined Se levels in virgin olive oil, olive oil and marc oil produced in Southern Spain ranging from undetectable to 178.51 ng/g. No statistically significant differences were found between the three types of oil. Singh and Garg (2006) determined Se content in Indian spices and condiments ranging from 12 to 670 ng/g. The highest levels were detected in turmeric (500 ng/g) and sweet neem (670 ng/g). Additional Se food content data from other studies and locations are summarized in Table 1.

2.

Selenium bioavailability

Selenium is one micronutrient whose deficiency and toxic concentrations are very close each other. Therefore, it is important to know its abundance or deficiency in food and diet and to determine the correct balance of Se in human beings and animals. In general, estimates of the total element content of a given food are unreliable and the bioavailability of the nutrient must be considered. It is a priority to know the element bioavailability or amount absorbed and used by the organism, because usually only a fraction is absorbed and transformed into a biologically available form (Cabrera et al., 1996; Cabañero et al., 2007). Ideally, a complete evaluation of bioavailability should involve measurements of total nutrient content, absorbable fraction, amount actually absorbed, and percent utilized by the organism. In vivo bioaccessibility studies are both expensive and laborious, and the possibility of measuring certain parameters during the experiments is often limited (Cabañero et al., 2007). In vitro bioaccessibility methods of simulated digestion are an alternative to in vivo bioavailability procedures for calculating the percentage of an element that is transformed into absorbable forms in the

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digestive tract. The results of such bioaccessibility studies are usually expressed as the soluble fraction of the element under given experimental conditions of pH, enzyme addition, temperature, and duration of contact (Cabañero et al., 2007). These bioaccessibility methods comprise a two-phase simulation of gastrointestinal physiology: the stomach and intestinal phases. In vitro bioaccessibility analytical procedures are often useful because they are simple, rapid, inexpensive, and allow individual experimental variables to be easily controlled (Cabrera et al., 1996). Consequently, bioaccessibility experiments offer an appealing alternative to human and animal studies (Cabañero et al., 2007; Velasco-Reynold et al., 2008). Se bioavailability strongly depends on the chemical form of Se found in the food. Specifically, selenocompounds identified in plants include selenate, selenite, selenocystine, Se-Met, selenohomocysteine, Se-methylselenocysteine, γglutamil-selenocystathionine, Se-Met selenoxide, γ-glutamylSe-methylselenocysteine, selenocysteineselenic acid, Seproponylselenocysteine selenoxide, Se-methylselenomethionine, selenocystathionine, dimethyl diselenide, selenosinigrin, selenopeptide and selenowax. However, the presence of Se-Cys in plants is still controversial (Whanger, 2002). On the other hand, selenocompounds in animal tissues are Se-Cys, selenotrisulfides of cystine, selenate and selenite. Se bioavailability is affected by its chemical form (generally, organic compounds of Se are more bioavailable than the inorganic forms) (Thomson, 2004). The influence of other dietary factors such as total protein, fat, and the presence of heavy metals has been also described. Se interacts with several trace elements, and these interactions can be additive, antagonistic, or synergistic, and in some cases they reverse the interaction, i.e. antagonism changed to synergism (Hamilton, 2004; Akl et al., 2006). Perhaps one of the most reported interactions between inorganic elements is the antagonistic interaction between Hg and Se. Se is recognized to decrease Hg toxicity when both elements are simultaneously administrated (Caurant et al., 1996; Cabañero et al., 2007). Approximately 80% of dietary Se is absorbed, although this figure depends on the types of food consumed. Overall absorption of all forms of Se is relatively high (70–95%), but varies according to the source and the Se status of the subject. Wheat and meats are the most important Se dietary sources. Se tends to be present in relatively high concentrations and, compared with Se salts, Se in these foods is highly bioavailable (Finley, 2006). Several studies have shown that Se bioavailability in meat is high because Se forms in foods of animal origin are mostly Se-Cys and Se-Met (Van der Torre et al., 1991; Dumont et al., 2006). Se-Met is an essential selenoaminoacid, which is the major nutritional source of Se for animals, and it is known to be highly bioavailable. It is absorbed in the small intestine, being incorporated into the long-term body reserves (Hinojosa et al., 2006). Although Se content in fish is high, in some cases fish is a poor source of available Se, due in part to its high Hg content and other heavy metals, which bind to Se forming insoluble inorganic complexes (Van der Torre et al., 1991; Pappa et al., 2006). However, when looking at the bioavailability of Se in fish, source and species are important. For example, existing data shows high Se availability from salmon (Ornsrud and Lorentzen, 2002). Dumont et al. (2006) reported that the order of bioavailability for Se species of

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Atlantic salmon is: Se-Met N selenite N Se-Cys N fish meal. Absorption of Se from fish by humans is comparable to that from plants. Fox et al. (2004) indicated that Se in fish is a highly bioavailable source of dietary Se, and that cooking the fish did not affect Se absorption or retention. These authors also observed that Se from yeast is less bioavailable. Finley (2006) observed that reports on Se bioavailability from yeast are mixed; one group reported that Se from yeast was effective for increasing the concentration of Se in red blood cells, but compared with selenite and selenate, was ineffective for increasing GPx activity. Contrarily, another group reported that Se from yeast was almost twice as bioavailable as Se from selenite and selenate for restoration of depleted GPx activity. These discrepancies may reflect differences in the study populations as well as a difference in the chemical speciation of Se in yeast. Cabrera et al. (1996) reported a mean absorbable fraction of Se of 80.0 ± 10.0% in dairy products such as yogurt, custard, cream cheese, curd, crème caramel, ice-cream, and condensed milk. Barrionuevo et al. (2003) indicated that the goat-milk has an important and beneficial effect on the Se bioavailability. Finley et al. (2004) concluded that the chemical forms of Se species also differ among foods. For example, in broccoli, which is a Se-accumulating plant that contains many methylated forms of Se, its bioavailability has been reported to be low. However, red meats such as pork or beef could accumulate Se when the animal is fed high Se diets, and Se from such meats has been reported to be highly bioavailable for selenoprotein synthesis. Lacour et al. (2004) reviewed 1290 valid studies providing reliable evidence of the therapeutic benefits of Se supplements in environmentally associated health disorders. They concluded that none of the studies showed evidence of therapeutic benefits from Se supplementation in environmentally associated health disorders. Several pharmacological factors of human Se supplements influence Se bioavailability such as the physicochemical form, interactions with other micronutrients in the supplement, interaction with other medications being taken, taking the supplements in fasting or meal conditions, and finally timing, dose and scheduling of supplementation. These factors are very interesting because most studies focus on the influence of dietary factors on Se bioavailability from supplements such as fibre content, presence of oxalate, phytate, protein, polysaccharides, and amino acids, etc (Lacour et al., 2004). Several studies have been conducted on the bioavailability of various Se forms (Lacour et al., 2004; Stibilj et al., 2005). In general, animal trials demonstrated that bioavailability of organic Se (Se-Met and Se-yeast) was higher than inorganic forms (selenite and selenate). The same trend was observed in human studies (Lacour et al., 2004; Dumont et al., 2006).

3.

Selenium total dietary intake

Diet is the major source of Se and intake of this essential element depends on its concentration in food and amount of food consumed (Navarro-Alarcon et al., 2005). Combs (2001) indicated that an adequate adult diet should have at least 40 μg/day of Se to support the maximum expression of Se enzymes and perhaps as much as 300 μg/day to reduce cancer

risk. Deprivation of Se is associated with reduced antioxidant protection, redox regulation and energy production as a consequence of suboptimal expression of one or more of the Se-containing enzymes (Thomson, 2004). At the same time, supranutritional intakes of Se (more than required for Se-Cys enzyme expression) appear to reduce cancer risk (Combs et al., 2001). Hamilton (2004) reported the existence of three Se levels of biological activity: (1) trace concentrations are required for normal growth and development; (2) moderate concentrations can be stored and homeostatic functions maintained; and (3) elevated concentrations can result in toxic effects. Accordingly, low Se status is likely to contribute to morbidity and mortality due to infectious as well as chronic diseases, and increasing Se intakes in all parts of the world can be expected to reduce cancer rates (Tinggi, 2003). The Recommended Dietary Allowance (RDA) for Se for both men and woman is 55 μg/day (0.7 μmol/day) (Food and Nutrition Board—USA Institute of Medicine, 2000). This recommendation is based on the amount needed to maximize synthesis of the selenoprotein glutathione peroxidase (GPx), as assessed by the plateau in the activity of the plasma isoform of this enzyme. The Tolerable Upper Intake Level (UL) for adult is set at 400 μg/day (5.1 μmol/day) based on selenosis being the adverse effect (Food and Nutrition Board—USA Institute of Medicine, 2000). In Finland the effect of fertilizing of soil with sodium selenate significantly increased the daily dietary intake of Se from 39 to 92 μg per person per day (Varo et al., 1988). In Denmark the Se dietary intake has been estimated to 343 μg/week, and meat, fish, egg, milk, cheese and cereals have been identified as the most important sources (Johansen et al., 2000). Marzec et al. (2002) evaluated the average daily intake of Se in Poland to be less than or near recommended levels, but concluded that Se food supplements are unnecessary. Several researchers (Srikumar et al., 1992; Donovan et al., 1992) revealed that vegetarians and lactovegetarians significantly decrease daily Se intake, and consequently could induce a deficient Se nutritional status. Benemariya et al. (1993) determined the daily dietary intake of Se in Burundi, Africa as 17 μg, and concluded that rural populations risk Se deficiency. However, data for most parts of Africa, Southern Asia, and South America are scarce or absent. Table 2 shows the daily intake of Se from selected countries. These data demonstrate the wide variability between countries. But we consider that healthy individuals with a balanced and varied diet should have an appropriate Se nutritional level and do not need a supranutritional intake of this element.

4.

Selenium supplementation

Several authors considered that Se supplementation can be beneficial for individuals in regions with very low environmental Se levels (Simonoff and Simonoff, 1991; Chan et al., 1998; Grashorn, 2006). In some areas where soil Se is low, different strategies have been followed to supply the population with sufficient Se: (1) Use of Se-enriched fertilizers: In order to reach Se RDAs, some countries like Finland, for example, decided in 1984 to add sodium selenate to farmlands (Varo et al., 1988).

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Table 2 – Estimated Se intakes (μg/day) from selected countries Country

Se (μg/day)

Belgium Canada China (Keshan area) Finland Before using Se fertilizer After using Se fertilizer Greece Libya Lithuania México Netherlands New Guinea Norway Scotland, United Kingdom Sweden Switzerland Spain (South-eastern)

28–61 98–224 3–11

Robberecht et al. (1994) Gissel-Nielsen (1998) Dumont et al. (2006)

25

Aro et al. (1995)

67–110 39.3 13–44 100 61–73 67 20 80 30–60 38 70 72.6

Anttolainen et al. (1996) Pappa et al. (2006) El-Ghawi et al. (2005) Golubkina et al. (1992) Valentine et al. (1994) Foster and Sumar (1997) Donovan et al. (1992) Meltzer et al. (1992) MacPherson et al. (1997) Dumont et al. (2006) Dumont et al. (2006) Díaz-Alarcon et al. (1996a) Dumont et al. (2006) Barclay et al. (1995) Longnecker et al. (1991)

Turkey United Kingdom USA

30 34 60–160

Reference

Hartikainen (2005) indicated that this supplement positively affects not only the nutritive value of the entire food chain (soil to plants to animals to humans) but also improves plant yields. The level of Se addition proved optimal and no abnormally high concentrations in the food chain were observed. In fact, plants act as effective buffers, because their growth is reduced at high Se levels. They also tend to synthesize volatile compounds in order to reduce excess Se. Thus, supplementing fertilizers with Se can be considered a very effective and readily controlled way to increase the average daily Se intake nationwide. In 1985, the first results were observed, showing increased Se levels in milk, meat, and eggs from 7 to 8, 4 to 5, and 2 to 3 times, respectively (Varo et al., 1988). According to Hartikainen (2005), in meat and meat products from Finland, Se increased 13-fold from 1985 to1991, and fertilization induced drastic changes in Se concentrations of agricultural products. For instance, in spring cereals the increase was generally 20–30 fold during the first years of supplementation. Milk has been the most sensitive indicator, and was the first to reveal changes in food quality induced by Se fertilization. Se supplementation of fertilizers has substantially affected average Se intake. Higher values of total Se intake in Japan, Australia, Finland, and the USA are partly due to Se-enriched fertilizers (Aro et al., 1995; Anttolainen et al., 1996; Dumont et al., 2006). In China, Se supplementation has been widely used to control Keshan and Kashin–Beck diseases (Tan et al., 1987), even though the latter disease probably is a combined result of deficiencies of two trace elements, Se and iodine. Hartikainen (2005) reported that the impact of Se fertilization on the occurrence of human diseases is difficult to judge. Furthermore, areas with seleniferious soil (concentrations N 1 mg/kg) become

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exploited for the production of Se-rich plants meant for export to other countries. Agricultural products are a rather sensitive indicator of available Se in soil (Hartikainen, 2005). Experiments with tomatoes have shown that Se levels can be increased by a factor of 100 by using Seenriched fertilizer (Aro et al., 1995). Certain fertilizers, however, (sulphate, phosphorus and nitrogen) can lower Se uptake and modify the synthesis of Se-containing amino acids (Aro et al., 1995). This technology needs further investigation since there are no data available on the effect of Se-fertilizers on microbial population of the soil (Surai, 2006). (2) Supplementation of farm animals with Se. The need for Se has resulted in the rise of direct Se enrichment of certain foods, such as using Se-enriched fertilizer. However, part of the Se in these food products is lost (volatilization, degradation) during harvesting and manipulation prior to consumption (Dumont et al., 2006). In Australia, subclinical Se deficiency has largely been eliminated as a result of intervention programs which give Se supplements to animals. Tinggi (2003) reported a number of Australian Se supplement strategies to increase Se in farm animals. These strategies include: a) direct application of Se to pastures to increase Se uptake by plants for animal feed; b) supply of sodium selenite or selenate incorporated into salt blocks or licks; c) direct administration of Se to animals by drenching with Se salt solutions such as sodium selenite; and d) the use of Se pellets that slowly release Se in the animal's gut. Recently, a technological process to produce Seenriched eggs, meat and milk has been developed and successfully introduced in various countries worldwide (Surai, 2006). Indeed, Se-enriched eggs are produced in more than 25 countries worldwide. Se-pork and Se-milk are on the market shelves in Korea. Such products can deliver 50% RDA of Se with a single egg or portion (80– 100 g) of Se-pork or Se-chicken. Recently, a new brand of Se-enriched eggs called Vi-Omega-3 was developed in Greece delivering 22 μg Se with a single egg (Pappa et al., 2006). Bourre and Galea (2006) described a new natural multi-enriched egg as an important source of omega-3 fatty acids, vitamins D and E, carotenoids, iodine, and selenium (45% RDA). These authors remarked that these eggs are beneficial for everyone and particularly appropriate for older people. Muñiz-Naveiro et al. (2006) indicated that it is possible to obtain Se-enriched cow milk at different concentrations without altering the original composition of the milk. Lyons et al. (2007) remarked that optimizing Se nutrition for poultry and farm animals increased efficiency of egg, meat and milk production and, more importantly, improved quality. Recent advances in genomics and proteomics, along with newly described selenoproteins, will be a driving force in reconsidering old approaches to Se nutrition (Kellof et al., 2000). Grashorn (2006) described the production of poultry enriched with conjugated linoleic acid, omega-3 fatty acids and selenium in such a way that 100 g of enriched tissue provides 3 to 11%, 60 to 70% and/or 200% and 60% of the RDA for humans, respectively. However, these authors indicated that some

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observed aberrations in meat quality make more research necessary. Detailed investigations on possible interactions between other nutrients in Se-enriched food are still missing. Several investigations are in progress by various research groups to measure Se bioavailability and organoleptical properties of food enhanced by this element (Finley, 2006). (3) Human intake of multimicronutrient supplements containing Se. During the last decade, the pharmaceutical market became overwhelmed with nutritional supplements or ‘nutraceuticals’ based on Se. Two different types can be distinguished: a) multi-vitamin and multi-mineral preparations containing inorganic Se, other trace elements and vitamins, and b) supplements based on Saccharomyces cerevisiae yeast. Se-enriched yeast supplements have been widely studied (Dumont et al., 2006). Selenized yeast has been the primary Se dietary supplement and is the most attractive source of Se-Met due to its low cost and ability to act as a precursor for Se-containing protein synthesis (Hinojosa et al., 2006). Se-yeast can be consumed in food or as a nutritional supplement. Another possibility is to use selenized yeast instead of conventional yeast for baking bread. The use of Se-yeast for this purpose could result in higher population Se intake since bread is such a commonly consumed product. Moreover, Se in Se-yeast is stable even at higher temperatures (Dumont et al., 2006). S. cerevisiae has a high protein content which improves Se absorption. Mostly, Se is added to the growth medium as Na2SeO3, and Se is mainly incorporated as Se-Met in proteins. S. cerevisiae may assimilate up to 3000 μg Se/g. Moreover, the production of Se-enriched yeast is more manageable than the production of Se-enriched plants (Dumont et al., 2006). Data on toxicity of Se from Seyeast are rather scarce (Dumont et al., 2006). These authors remarked that the overall production of Se supplements urgently needs control because suppliers provide information on total Se concentration, but little or no information on the Se species present. Stibilj et al. (2005) investigated the advertised values of Se in food supplements, and discovered that the difference between the advertised and measured Se values varied by 10% in 9 out of 13 supplements. Furthermore, 2 of the 14 supplements did not comply with the recommendations stated in the 27th edition of the USA Pharmacopoeia, which states that minerals and vitamins in food supplements should be within the range 90 to 200% of the declared value. B'Hymer and Caruso (2000) evaluated six different brands of yeastbased Se food supplements obtained from local stores in the USA. All Se supplements were found to have near label values based on total Se, and had reasonable uniformity in tablet to tablet content. Nevertheless, each brand had dramatically different profiles for the chemical form of Se present within the supplement. In recent years, our habits have been strongly influenced by publicity about the necessity of multimicronutrient supplements in the normal diet as a method of fortifying inadequate diets with micronutrients such as Se. Different population groups are considered a higher risk of deficiency, such as

infants, the elderly, athletes, and healthy people with a high concern for diet and fitness. There is a belief that physical activity increased vitamin and mineral requirements, mainly those related with the oxidative stress such as Se. This could be an important reason why a majority of athletes ingest large doses of micronutrient supplements (Navarro-Alarcon and López-Martínez, 2000). Additionally, the relationship between Se, disease and degenerative pathologies related to aging has also contributed to an increase in consumption of supplements.

5.

Physiological role of selenium

Selenium is a component of several selenoproteins with essential biological functions (Van Cauwenbergh et al., 2004) (Table 3). This element acts as a cofactor of the GPx family of enzymes which protect against oxidative stress. Specifically, Se-dependent GPx enzyme recycles glutathione, reducing lipid peroxidation by catalyzing the reduction of peroxides, including hydrogen peroxide (Fig. 1). In general all these enzymes at their reduced state catalyse the breakdown of lipid hydroperoxides and hydrogen peroxides in human cells (NavarroAlarcon and López-Martínez, 2000; Van Cauwenbergh et al., 2004; Hartikainen, 2005; Navarro-Alarcon et al., 2005). From all these associated enzymes, GPx and selenoprotein P are also involved in the regulation of the inflammatory response (Van Cauwenbergh et al., 2004). Moreover, the antioxidative function of Se can help to ameliorate the damage induced by the ultraviolet-β radiation in humans. In farm animals diseases associated with Se deficiency have been an important problem. White muscle disease is a nutritional muscular dystrophy that is the most common Se deficiency disease (Peter and Costa, 1992). Usually actively growing animals suffer from this disease, showing symptoms weakness, problems with feeding, and cardiac implications that very often produce death. On the other hand, subclinical deficiency levels are associated with poor growth, impairment of animal production, and decrease in immune efficiency (Peter and Costa, 1992). On the other hand, the selenoprotein P is a plasma protein whose source is the liver and kidney. This protein constitutes the main plasma Se carrier carrying more than 60% of plasma Se. Besides, it is known that the protein levels depend on the body's Se status, such that it has been used as a biomarker of body Se content. Particularly, the selenoprotein P acts as an extra cellular antioxidant associated with the vascular endothelium which diminishes the peroxinitrile (ONOO−) level that represents reactive nitrogen specie (Li et al., 2007). Iodothyronine-50-deiodinases (IDIs) are enzymes that convert the hormone tetraiodine thyroxin (T4) to triiodine thyroxin (T3) during the thyroid hormone metabolism (Table 3). Consequently, these enzymes are involved in the synthesis of thyroid sulphated hormones (Navarro-Alarcon et al., 2005). An association between Se status and low plasma T3 levels showing diminished IDI function has been reported by several researchers (Strain et al., 1997). There exist three types of IDIs called type I, II and III with different physiological activities: type I is mainly responsible for the T3 levels in the blood stream and is specifically inhibited by the propyl thiomecile. IDI type II also participates in the transformation of T4 to T3 when the

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Table 3 – More significant mammalian selenoproteins and corresponding biological function (Burk and Levander, 2002; Sunde, 2000; Whanger, 2002) Selenoproteins

Biological function

Glutathione peroxidases [GPx1 (in erythrocytes or cystolic), GPx2 Antioxidant enzymes that protect against the oxidative stress by (gastro intestinal), GPx3 (in plasma or extracellular) and GPx4 scavenging of hydrogen peroxide and lipid and phospolipidic (phospholipid hidroperoxide or intracellular)] hydroperoxides. Finally, H202 and a wide range of organic hydroperoxides are transformed to water and corresponding alcohols, respectively. Iodothyronine deidodinases (three isoforms: type I in liver, kidney and Synthesis and metabolic regulation of thyroid sulphated hormones (T3, T4 and T2). thyroid gland; type II in encephalon; and type III inactivant) Thioredoxin reductases (also three isoforms) Reduction of intracellular substrates like dehydroascorbic being related with anticancer effects. Specifically it participates in the reduction of nucleotides in the DNA synthesis as well as in the regulation of gene expression by redox control of binding of transcription factors to DNA. Selenoprotein P Extracellular antioxidant associated to the vascular endothelium that protects endothelial cells against damage from peroxynitrite. Selenoprotein W Although it is necessary for muscle function its biological function is still unknown. Selenophosphate syntetase (two isoforms) Necessary for the biosynthesis of selenophosphate and, consequently, for that of S-Cys necessary for the selenoprotein synthesis. Mitochondrial capsule selenoprotein GPx4 form that shields developing sperm cells from oxidative damage. Prostate epithelial selenoprotein It is a 15 kDa selenoprotein that seems to have redox function that resembles that of GPx4 in the epithelial cells of ventral prostate. DNA-bound spermatid selenoprotein It is a 34 kDa selenoprotein with a biological activity like the GPx. 18 kDa selenoprotein Essential selenoprotein preserved in selenium deficiency.

thyroid gland is stimulated. This enzyme is the only one composed of two Se atoms. Finally the IDI type III catalyses the change from T4 to inverse T3 and from T3 to T2 protecting the brain from possible plasma Se concentrations lower than 67 μg/l, which have been related to diminished peripheral capacity for the change of T4 to T3 (Duffield et al., 1999; Thorne, 2003). Thioredoxin reductase (TR) is also a Se-dependent enzyme (Sunde, 2002) involved in the reduction of intracellular substrates (Table 3). When rats were administered considerably higher Se amounts than the RDA, their TR activity was directly enhanced (Allan et al., 1999, Thorne, 2003). For some forms of Se at very high doses, the TR enzyme has been associated with anticancer effects (Ganther, 1999). Several studies have also found that Se protects animals against toxicity associated with high exposure and/or intake of heavy metals like mercury, lead, cadmium and silver (Levander and Burk, 1994; Caurant et al., 1996; Thorne, 2003; Navarro-Alarcon et al., 2005; Cabañero et al., 2007; Kibriya et al., 2007; Mousa et al., 2007). Experimental findings have reported that Se-deficient rodents are susceptible to the prenatal toxicity of methyl mercury. In this sense, important changes of selenoenzymes activity, namely GPx and IDIs, have been found in neonates (Watanabe, 2001). Kibriya et al. (2007) suggested that long-term Se supplements may revert some of the gene expression changes presumably induced by chronic As exposure in individuals with pre-malignant skin lesions. In recent years, genomic and proteomic concerns have been considerably raised. For example, Kibriya et al. (2007) found that in one study that many genes, after Se supplementation, were upregulated. However, previously, these authors, in subjects with As induced skin lesions, found the same genes to be down-regulated. Consequently, these findings could help to define the biological effect of Se supplementation in

humans. Similarly, Mousa et al. (2007) also discovered that the pro-angiogenesis action of sodium arsenite or stimulation of basic fibroblast growth factor (b-FGF) was originated by the activation of the extracellular signal-regulated kinases 1 and 2 (ERK-1/2) pathway. However, this pathway was significantly blocked (p b 0.01) by different Se compounds (dimethyl selenone, diphenyl selenone, sodium selenite or Se-Methyl SeCys) demonstrating that pro-angiogenesis As action was reversed by Se-derived compounds (Mousa et al., 2007). Wangher et al. (2001) also reported that Se even counteracts the neurotoxicity of Hg, Cd, Pb and V by a mechanism that causes their accumulation in the brain, presumably in a non toxic complex.

6. Assessment of body nutritional status on selenium When a Se deficiency is established, the activity of Sedependent enzymes diminishes depending on the enzyme type and body tissue. Of all the enzymes, the activities of the plasmatic and hepatic GPxs are the most dependent on the Se supply. Therefore, they are employed as evaluation indices of nutritional Se status. Specifically, GPx appears as 4 isoforms of which the presence of classic or citosolic-GPx in plasma is a good Se status indicator in humans (Persson-Moschos et al., 1995). Additionally, several human fluids and tissues (whole blood, plasma, serum, hair and toenails) can also be used to assess the nutritional Se status. In fact, in most studies the Se status has been assessed by measuring the element either in serum or plasma erythrocytes, platelets or whole blood, and by determining the GPx activity in whole blood or platelets. Recently, levels of selenoprotein P, a Se-rich protein mainly present in plasma, have also been used as good Se indicator in

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Fig. 1 – Antioxidant action of Se as cofactor of the glutathione peroxidase of the erythrocyte (taken from Navarro-Alarcon et al., 2005). GSSG: oxidized glutathione. GSH: reduced glutathion. GSSG-R: glutathion reductase. G-6-PD: glutathion 6-phosphate deshidrogenase. SOD: superoxide dismutase.

human beings (Persson-Moschos et al., 1995). Human nail clippings have also been employed in epidemiological studies as indicators of Se exposure (Slotnick and Nriagu, 2006). It is believed that nail clippings show the exposure that occurred over the past 6 to 12 months. On the contrary, blood and urine are markers of shorter exposure periods (Navarro-Alarcon and López-Martínez, 2000; Slotnick and Nriagu, 2006). In fact, urine and blood Se levels show recent intake for no longer than several days for urine or several weeks for blood-based measurements, respectively. From all biomarkers previously reported, blood, plasma and serum Se levels are usually employed to evaluate Se status and intake (Thomson, 2004; Batáriová et al., 2005). For long-term Se status, toenails and hair levels are often employed as markers (Mannisto et al., 2000; Slotnick and Nriagu, 2006). Collecting them is non-invasive and it is easy to store samples long-term (Slotnick and Nriagu, 2006). However, highly variable intra hair biology and pharmacokinetics

(Harkins and Susten, 2003) as well as contamination by Secontaining shampoos affect hair sample suitability. Nails, on the contrary, have less external contamination and growth rates are less variable (Slotnick and Nriagu, 2006). On the other hand, Se urinary excretion is closely correlated with plasma and serum and could be used to monitor recent dietary intake of Se. Thomson (1998) reported that Se urinary excretion constitutes between 50 and 60% of the total amount excreted, so dietary intake could be estimated simply by multiplying by two the daily urinary excretion of Se. Despite everything previously stated, tissue Se concentration may not accurately show functional activity, which varies depending on the Se specie ingested. Therefore, more accurate and reliable biomarkers of element status should show the Se amounts available for functional selenoproteins (Thomson, 2004). In certain circumstances, it is also necessary to concurrently measure the concentration of several selenoproteins. In

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this sense GPx activity (GPx3 and GPx1) (Table 3) is used to assess the effect of different Se species supplementation as well as monitoring element status in population groups (Zachara et al., 2006) assuming that maximum enzyme activity is not reached [approximately at 100 μg Se/l of blood (Nève, 1991; Thomson, 2004)]. Taking into account everything previously stated, platelet GPx seems to be a more sensitive indicator of increased Se intake during supplementation trials, showing enhancements in its activity after 1 to 2 weeks. Due to the fact that Se deficiency diminishes levels of selenoproteins, they are being used nowadays [namely selenoprotein P, tyroxine (T4) to tri-iodothyronine (T3) ratios, TR] to monitor body Se nutritional status (Persson-Moschos et al., 1995; Tinggi, 2003; Thomson, 2004; Xi et al., 2005; Karunasinghe et al., 2006). It has been reported that the use of GPx as an index of Se status may not be appropriate (Xi et al., 2005). They also found that the full expression of selenoprotein P requires a greater Se dietary exposure than that for plasma GPx activity. Consequently, Xi et al. (2005) concluded that selenoprotein P is a better indicator of Se nutritional status. Nevertheless, Wang (2006) stated that due to the fact that selenoprotein P does not adequately focus

on the clinical specificities of different Se-responsive diseases, the adoption of selenoprotein P as the principal standard for Se status evaluation would not be appropriate. Therefore, biomarkers should be selected to match the characteristics of different Se-responsive diseases (Wang, 2006). Table 4 summarizes mean and range of serum, plasma and whole blood Se levels measured in healthy individuals from different countries as biomarkers of Se nutritional status of defined population groups. As a general tendency, Se concentrations in serum and plasma were lower in females than in males but not at a statistically significant level (p N 0.05), as was previously reported (Navarro-Alarcon and López-Martínez, 2000; Van Cauwenbergh et al., 2004). Most of the studies collected in Table 4 (≅ 63%) reported “normal” Se concentrations: serum or plasma Se levels ranging from 61–99 μg/l (Nève, 1991). Large geographical variation in Se intake due to varying soil Se levels has been found, which correlates to the high variability in Se serum and plasma levels measured in different countries. This variability depends on geographical location, climatological characteristics like annual rain, Se species existing in soils, soil pH, type of plants cultivated, diet

Table 4 – Mean serum, plasma and whole blood Se levels measured in healthy individuals from different countries Population group (age and characteristics)

n (sex)

Mean Se (μg/l)

Se range (μg/l)

Area (country)

Health adult individuals

130 (56 M, 74 F)

74.9 ± 27.3

30.2–175.0

General population Pregnant women

158 F

126.0 76.6

46.2–106.9

Healthy individuals from 6 to 75 years old

395 (187 M, 208 F)

74.7 ± 25.2

7.9–182.3

Adult population (20–40 years old)

201 (66 M, 135 F)

100.0

35.8–185.6

Healthy volunteers aged 19–74 years old

40 (20 M, 20 F)

67.4 ± 38.6

20.0–129.8

Healthy adult subject aged 24–45 years old

50

89.5 ± 15.6

Lower Silesian region (Poland) Bydgoszc (Poland)

Healthy volunteers (mean age: 39.6 years)

30 (23 M, 7 F)

73.2 ± 9.9

56.5–94.5

Individuals of the NHANES III (1988–1994) Healthy Caucasian volunteers sampled once a month during 1 year (23–69 years) Healthy volunteers recruited from blood donor aged 43.2 ± 1.7 years old Healthy individuals aged N 16 years old

14,619 (7,102 M, 7,517 F) 26 (13 M, 13 F)

124.5 ± 0.2 (M) 122.0 ± 0.2 (F) 84.3

– – 51.4–121.7

Rio de Janeiro (Brazil) USA

31 (17 M, 14 F)

216.2 ± 7.4

160 (106 M, 24 F)

100.6 ± 13.0

75.0–134.0

Tehran (Iran)

Healthy adult blood donors aged 20–45 years old Elderly women aged 60–70 years old

2,414 (1,781 M, 633 W) 187 F

84.2 ± 20.2

b40.0–N 120.0

Czech Republic

92.4 ± 17.4

–

Healthy individuals aged 18–65 years old

153 (81 M, 78 F)

85.9 ± 24.0

41.7–183.0

Hannover (Germany) Vienna (Austria)

Institutionalized elderly people aged 60–80 years old Healthy adult individuals aged 48.5 ± 13.2 years old Subjects aged ≥ 15 year old and that have been living in their own for over 5 years Healthy adult women

205 (80 M, 125 W) 50 (25 M, 25 F)

86.2 ± 17.0

401 (128 M, 272 F) 41 F

Granada (South-eastern Spain) Singapore Valencia (Eastern Spain) Canary Islands (Spain) Mumbai (India)

Antwerp region (Belgium) Taiwan (China)

Asturias (Northern Spain) Taiwan (China)

129.0 ± 21.5 75.0 ± 28.3

35.2–160.4

105.0

66.4–137.0

Zhou Koudian (China) Helsingborgh (Southern Sweden)

Reference Navarro et al. (1995) Hughes et al. (1998) Ferrer et al. (1999) Díaz-Romero et al. (2001) Raghunath et al. (2002) Luty-Frackiewicz et al. (2002) Czuczejko et al. (2003) Da Cunha et al. (2003) Kafai and Ganjii (2003) Van Cauwenbergh et al. (2004) Ko et al. (2005) Safaralizadeh et al. (2005) Batáriová et al. (2005) Wolters et al. (2006) Gundacker et al. (2006) González et al. (2006) Lin et al. (2006) Li et al. (2007) Rossborg et al. (2007)

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composition, technological and cooking treatments, as well as additional factors influencing Se bioavailability like food composition and other nutrients present in diet.

7.

Selenium metabolism and pharmacokinetics

Although it has been reported that Se metabolism in the body is not completely understood, it is known that Se-Cys is the major selenocompound present in selenoproteins of body tissues (Sunde, 2000). The total amount of Se in the human body varies from 10 to 20 mg. Fifty percent of body Se is located in the skeletal muscles, although organs like the kidneys, testes and liver have the highest relative concentration of Se. On the other hand, cells that reveal a higher consumption of Se are those of the immune system, erythrocytes and platelets. Se is mainly eliminated from the body by urine, although significant losses via faeces also occurs (Burk and Levander, 2002). Additionally, low amounts of Se are lost through the skin and respiration. It is known that several Se species present in foods are usually well absorbed in the gut of human beings (the usual absorption rate ranges from 50 to 100%) (Sunde, 2000; Navarro-Alarcon et al., 2005). Se-Met is absorbed by the same active transport mechanism used by methionine because Se can substitute for sulphide atoms due to its similar ionic radius. The selenate is actively absorbed by a mechanism common to sulphate, depending on the Na+ gradient and maintained by the Na+/K+ ATPase. On the other hand, Se-Cys and selenite are not absorbed by active transport and their capture is not inhibited by similar sulphur compounds or by body Se status (Mataix Verdu and Llopis, 2002). Several selenocompounds exist in animal and plant tissues (Fig. 2) (Gammelgaard et al., 2008). Specifically, selenate is the major inorganic selenocompound found in both animal and plant tissues (Whanger, 2002). On the other hand, Se-Met is the predominant selenocompound in cereal grains, grassland, legumes and soybeans, and, in some cases, Se-enriched yeast. Finally, Se-methylselenocysteine is the major selenocompound in Se enriched plants such as garlic, onions, broccoli flowers and sprouts, and wild leeks (Whanger, 2002). Se-Cys, mainly from meat, is directly used in the GPx synthesis. Nevertheless, Se-Met from plants can directly replace methionine amino acid during the synthesis of Se-containing proteins (Fig. 2). On the other hand, selenate and selenite incorporate directly into the Se pool when used in synthesis of specific selenoproteins and Se-containing proteins, independent of their origin (animal or vegetable) (Brody, 1999; Mataix Verdu and Llopis, 2002; Navarro-Alarcon et al., 2005). In general, the human body metabolizes the various Se forms into selenide as HSe− (Fig. 2) which seems to be the common point for regulating Se metabolism (Brody, 1999; Burk and Levander, 2002; Mataix Verdu and Llopis, 2002; NavarroAlarcon et al., 2005). It has been found that animals synthesize many different intermediary metabolites during the conversion of inorganic Se to organic forms or vice versa (Ganther, 1999). As mentioned above, HSe− ion is a key metabolite formed from inorganic sodium selenite via selenodiglutathione through reduction by thiols and NADPH-dependent reductases and released from Se-Cys by liase action (Bjorn-

stedt et al., 1992). Although the main pathway in animals is methylation, demethylation back to inorganic Se can also occur. Hydrogen selenide (by a previous activation to selenophosphate) provides Se for synthesis of selenoproteins (Ganther, 1999). After the catabolism of Se-containing proteins and, subsequently, component amino acids, the Se of the SeMet is finally available for its specific use. In this sense, Se entered into the upregulated metabolism and could be incorporated in macromolecules to be transported to other organs or even excreted (Burk and Levander, 2002). Serum and plasma Se levels depend on the Se bioavailable fraction present in diet. In plasma, two selenoproteins have been cited as extracellular carriers of Se, namely selenoprotein P and GPx-3. However both of these selenoproteins contain Se as Se-Cys making neither of them likely carriers of Se. Nevertheless, low molecular weight forms of Se have been identified as possible Se carriers in plasma. Of all the organs, the liver and kidneys show the highest capacity to accumulate this element. High Se levels found in the liver counteract methyl mercury toxicity by facilitating its accumulation as mercuric selenide (Caurant et al., 1996). Although the mechanism that regulates production of excretory metabolites has not still been discovered, urine excretion has been reported to be the body's mechanism for maintaining Se homeostasis (Mataix Verdu and Llopis, 2002). Therefore, under physiological conditions, Se homeostasis is not regulated by absorption but rather by urinary excretion (Gammelgaard et al., 2008). Despite this, the transporters, receptors and enzymes involved in the absorption or movement of Se across membranes of intestinal cells are generally unknown (Sunde, 2002). Intestinal excretion of Se is a secondary path of elimination. It has also been observed that when the body Se status is low, urinary Se excretion is diminished to keep element homeostasis in a narrow range, as reported for patients with cardiovascular diseases (Navarro-Alarcon et al., 1999). However, when large amounts have to be excreted, respiration can also contain volatile Se compounds, usually in the form of dimethyl selenide (Fig. 2). In a study of healthy men confined to a metabolic research unit and fed diets naturally high or low in Se, Hawkes et al. (2003) reported that urinary Se measurements responded rapidly to changes in Se intake. These researchers remarked that urinary excretion rose rapidly in the high Se group, but decreased only with severe Se restriction demonstrating a low adaptation to Se excretion. Additionally, Hawkes et al. (2003) reported that fecal excretion decreased by half in the low Se group, a finding that indicates an underappreciated role in metabolic adaptation to low Se. Zachara et al. (2006) reported that losses in urine represent 50–78% of the ingested element. These researchers also confirmed that the level of Se excretion in urine was proportional to the level of Se intake. Various selenocompounds are claimed to be present as urinary Se metabolites such as selenite, selenate, methylselenol, mehylselenite, trimethylselenonium ion, Se-Met, selen o d i g l u ta t h i o n e , S e - C i s , s e l e n o e t h i o n i n e , S e - C y s , methylselenomethionine, selenocistamine, selenoadenosylMet and selenosgars 1, 2 and 3 (Francesconi and Pannier, 2004). Among all of these Se compounds, only the trimethylselenonium ion has been found in human urine (Francesconi and Pannier, 2004). Suzuki (2005) and Kuehnelt et al. (2007)

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Fig. 2 – Main Se forms in diet and human organism: Se metabolism (adapted from Navarro-Alarcon et al., 2005). 1Although in some vegetables (cereal grains, grassland legumes and soybeans) the Se-Met is the main Se form, however the identification of selenocysteine in vegetables is still inconclusive. Other Se forms present in vegetals are selenate, selenite, selenocystine, selenomethionine, selenohomocysteine, Se-methylselenocysteine, γ-glutamil-selenocystathionine, selenomethionine selenoxide, γ-glutamyl-Se-methylselenocysteine, selenocysteineselenic acid, Se-proponylselenocysteine selenoxide, Se-methylselenomethionine, selenocystathionine, dimethyl diselenide, selenosinigrin, selenopeptide and selenowax (Whanger, 2002). 2Selenocysteine is the predominant selenoamino acid in animal tissues while selenate is the major inorganic selenocompound followed by selenite. Another organic Se form found in animal tissues is selenotrisulfide of cystine. 3Se compound eliminated in the expired air in element overdosing that originates a typical garlic stink in breath. 4Selenopersulfide. 5 GS-Seleno-N-acetyl-galactosamine. 6,7,8Se-methylseleno-N-acetylgalactosamine, Se-methylseleno-N-acetylglucosamine, Se-methylseleno- galactosamine, respectively. Additional ways of excretion. 9Trimethylselenonium. 10 Se-Methylselenocystein. 11γ-glutamil-Se-methylselenocysteine11.

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reported that new Se-containing selenosugars are the major urinary metabolites in humans, the trimethylselenonium ion being less significant. Specifically, the metabolite methyl-2acetamido-2-deoxy-1-seleno-β-D-galactopyranoside (called selenosugar 2) has been identified (Francesconi and Pannier, 2004; Suzuki, 2005). Similarly to that stated above, Kuehnelt et al. (2006) found during a Se supplement trial using selenite (200 μg of Se) that selenocompounds are converted by unknown mechanisms into trymethylselenonium and selenosugars as urine metabolites in a percentage ranging from 1 to 5% and from 20 to 53% of urinary total Se, respectively. Nevertheless, Francesconi and Pannier (2004) concluded that even though available data shows that selenite, selenosugar 2 and selenosugar 3 (methyl 2-amino-2-deoxy-1-seleno-βDgalactopyranoside) constitute three of the typical urinary species, there are still species that remain unknown. Future research is required to determine how factors such as nutritional status and biological and chemical effects influence the type and concentration of Se urinary metabolites (Francesconi and Pannier, 2004).

8.

Selenium deficiency

Selenium is an essential mineral in human nutrition closely associated with the population health. The element essentiality in mammals was not discovered until 1979 due to its overlapping function with vitamin E (Strain and Cashman, 2002). Low Se intake from agricultural products has negative effects on human health. Serious health consequences have been reported in low Se areas of China and Eastern Siberia, where Se deficiency causes endemic Keshan disease in the Keshan region of China. This pathology is an endemic juvenile cardiomiopathy with myocardial insufficiency that primarily affects children aged 2 to 10 years old, and to some extent women of child-bearing age (Hartikainen, 2005). This disease is caused by low soil Se levels in Keshan (mean Se content 0.125 μg/ g). Consequently, a very low Se intake from a diet of Keshan food products was found, in some cases, lower than 10 μg Se/day. Additionally, Se deficiency in other regions of China caused a type of osteoarthritis called Kashin–Beck disease (Li et al., 2007). This endemic disease is a human rheumatoid state resulting in enlarged joints, shortened fingers and toes and dwarfism in extreme cases (Hartikainen, 2005). In this disease, oxidative damage attacks cartilage leading to deformation of the bone structure (Ge and Yang, 1993). Kashin–Beck disease affects children aged from 5 to 13 years old in certain areas of China and the former Soviet Union. This pathology is a multiple degeneration and necrosis of the hyaline cartilage, although Se's role in the formation of this connective tissue is still unknown. However, the interaction between the metabolism of thyroid hormones and Se can help treat this deficiency (Nève, 1999) in areas where the soil is Se deficient as it occurs in Zaire. Both endemic diseases are mainly confined to the Northeast part of China. The principal characteristics of the zone are dark brown and black soils very low in bioavailable Se as water-soluble element fractions (Tan et al., 1994). Low Se intake by inhabitants from these areas is caused by insufficient Se flux through the soil–plant–animal–human chain. This finding seems to be related to the capacity of organic

matter to reduce selenate (Se6+) to selenite (Se4+), element specie that seems to form strong inner sphere complexes with Fe oxides. On the contrary, selenate (Se6+) is weakly adsorbed, therefore having a higher bioavailability (Hayes et al., 1987). On the other hand, the Se6+ is easily assimilated and bioavailable for plants and its levels increase with the alkalinity of soils (Diaz-Alarcon et al., 1996c). Supplementation of farmland with Se salts such as sodium selenite in China and Finland significantly diminished the incidence of disorders reported. This Se supplementation exerted a prophylactic effect, raising from 2 to 8 times the Se levels in milk, eggs, meats, etc. (Hartikainen, 2005). Since 1970, Se in human serum has been periodically monitored in healthy adults from Finland due to the fact that they were among the lowest reported in the world (Hartikainen, 2005). Se supplemented fertilizers were used which significantly improved Se intake and serum Se levels in the Finnish population. Nowadays, Se values in Finland (94.8 to 111.6 μg/l) are usually higher than those of other European countries (Navarro-Alarcon and López-Martínez, 2000; Van Cauwenbergh et al., 2004; Hartikainen, 2005). However, there is a seasonal aspect of Keshan disease difficult to explain by considering only Se deficiency. Recent literature describes a certain non-virulent strain of the poxvirus Coxsackie (B3 strain) which, when infecting Se-deficient mice, mutates to a virulent strain causing cardiac injuries (Beck et al., 2003). This could explain the cardiomyopathy in children with Keshan disease, because they usually infect with this virus type. The genome of the virus strain codifies one GPx, which apparently serves to protect it against the hydrogen peroxide produced by the host's leucocytes. An absence of this enzyme affects the virus genome. Therefore, some of the resulting mutations increase the virus' virulence. As previously stated, this deficiency creates some cardiac pathologies like myocardial necrosis by injuring cellular membranes and proteins by oxidative stress. Hartikainen (2005) deduced from animal studies that Keshan disease produced by dietary Se deficiency has a second aetiology of infection by enterovirus. Similarly, for the Kashin–Beck disease, Se deficiency in diet is probably associated with iodine intake (Nève, 1999).

9.

Toxicity of selenium

Although RDA and upper limits for Se have been established by the Food and Nutrition Board-Institute of Medicine (2000), controversy still exists about what Se concentrations should be considered adequate but not be toxic (Sunde, 2000). This is because Se toxicity depends on the Se compound, method of administration, animal species, exposure time, idiosyncrasy, physiological status, and interaction with other metals, etc., (Burk and Levander, 2002). Chronic Se toxicity in humans results in selenosis (Goldhaber, 2003) characterized by hair loss, fingernails changes and brittleness, gastrointestinal disturbances, skin rash, garlic breath, and abnormal functioning of the nervous system. Other related toxic effects are a disruption of endocrine function, synthesis of thyroid hormones and growth hormones, and an insulin-like growth factor metabolism. Particularly high levels of dietary Se were significantly associated

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with diminished T3 levels, impairment of natural killer cells and hepatotoxicity (Goldhaber, 2003). Other researchers state that high Se levels catalyse hydrosulphide oxidation which exerts an inhibitory effect on protein synthesis or an enhanced risk of the cancer (Villa Eliaza et al., 1999). These toxic symptoms are associated with Se intakes of 3200 to 6700 μg Se/day. Milder symptoms such as fingernail changes have been reported for Se intakes of 1260 μg Se/day (Sunde, 2000). In one study of 400 Chinese with Se intakes up to 853 μg Se/day, and another study of 142 subjects living in high Se areas of South Dakota and Wyoming with Se intakes up to 724 μg Se/day, no evidence of Se poisoning was reported (Sunde, 2000). But, other researchers did report selenosis with Se intakes of ≥850 μg Se/ day. Consequently, the Environmental Protection Agency of USA set a reference dose of 5 μg Se/kg/day, taking into account an epidemiological study of 400 Chinese in which selenosis was observed in 5. This agency defined 1262 μg Se/day as the element intake at which clinical selenosis appeared, which was related to a whole blood Se level of 1350 μg Se/l. As a result, the Food and Nutrition Board—Institute of Medicine (2000) fixed the upper Se levels (the highest daily level of Se intake that is likely to pose no risk of adverse health effects in almost all individuals) at 400 μg Se/day. Although environmental toxicity of Se in humans is rare, symptoms such as hypochromic anaemia, leucopoenia, damaged nails, etc have been found in long-term workers who manufacture Se rectifiers. Additionally, high accidental ingestion of Se has been related with vomiting, diarrhoea, mottling of the teeth as well as neurological disturbances like acroparesthesias, weakness, convulsion, etc., (Sunde, 2000; Mataix Verdu and Llopis, 2002; Tinggi, 2003). In any event, the toxicity of Se depends on many factors like the Se species, amount ingested, age, physiological status, and dietary interaction with other nutrients (Mataix Verdu and Llopis, 2002). Due to the fact that the Se RDA for healthy adults (55 μg Se/ day) is not far from the established upper limits (400 μg Se/day) (Food and Nutrition Board—Institute of Medicine, 2000), high levels of Se dietary supplements should be considered with caution. This conclusion correlates with other researchers who found that Se dietary intakes of about 300 μg Se/day could have toxic effects on growth hormone and insulin-like growth factor-1 metabolism, as well as synthesis of thyroid hormones (Kaprara and Krassas, 2006).

10.

Body selenium metabolism in several diseases

10.1.

Selenium metabolism in hepatopathies

Se deficiency has been associated with hepatocyte damage and necrosis similar to that caused by excessive alcohol consumption. This effect usually occurs concurrently with low body vitamin E concentrations. Therefore, microsomal peroxidation of hepatocytes is induced by the endoplasmic reticule changes (Simonoff and Simonoff, 1991; Navarro-Alarcon et al., 2002). However, the pathologic mechanism of liver injury in chronic alcoholic liver disease has not yet been defined (Jablonska-Kaszewska et al., 2003). But, it seems that one possible mechanism involves free radical reactions which

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produce lipid, nucleic acid and protein peroxidation (Czuczejko et al., 2003; Pemberton et al., 2005; Czeczot et al., 2006). Specifically, alcohol metabolism in the hepatocytes increases the lipidic oxidation of cell membranes provoking a chronic transient state characterized by leukocyte infiltration and a rise in collagen formation. In fact, one of the most effective defence mechanisms is associated with the activity of several antioxidative enzymes among which GPx has to be recognized (Pemberton et al., 2005). This enzyme, with Se as significant cofactor, is directly involved in numerous reactions which protect the human organism, and specifically liver cells, from oxidative stress. During the progression of alcoholic hepatic disease, the liver has an initial steatosis, then it changes to hepatitis and finally, in the last step of this process cirrhosis develops. Cirrhosis damage is non-reversible due to intense hepatocyte damage creating loss of liver function, compromising metabolism and overall health (Czeczot et al., 2006). Nevertheless, the pathologic mechanisms are not well understood and medical assays have generated controversial results. However, it is known that alcohol consumption enhances free radical production and the resulting oxidative stress is directly implied in the disease (Pemberton et al., 2005; Manzanares, 2007). Specifically, ethanol causes microsomal proliferation and reactive oxygen species (ROS) like superoxide (O2">U) and hydrogen peroxide (H2O2) generated by the ethanolcytochrome P450 2E1 (CYP 2E1). Additionally, the action of aldehyde oxidase on acetaldehyde (first metabolite in ethanol metabolism in the liver) can also produce superoxides. These ROS, by means of the catalysed Fenton and Harber–Weiss reaction, lead to the formation of highly reactive hydroxyl radicals (OH">U) which have the capacity to generate 1hydroxy-ethyl radicals CH3–CH2O· directly from ethanol (Pemberton et al., 2005). Accumulation of all these alcohol-induced ROS can overwhelm antioxidant defences causing, among other oxidant actions, peroxidative damage to phospholipids of membranes. ROS are capable of attacking proteins, polysaccharides, nucleic acids and polyunsaturated fatty acids, resulting in cellular injury and death (Geoghegan et al., 2006). These oxidant species may also trigger the cytokine release from immune cells, activate inflammatory cascades and increase the expression of adhesion molecules. The accumulation of granulocytes in organs leads to enhanced generation of ROS that amplifies the inflammatory response and tissue injury (Geoghegan et al., 2006). Contrarily, Bonnefont-Rousselot et al. (2006) report that routine blood oxidative stress markers are not sensitive indices of oxidative stress in the liver and are therefore not good predictive markers of hepatic steatosis. However, Czeczot et al. (2006) remarked that the antioxidant system of cirrhosis is severely impaired. Additionally, chronic alcoholics are frequently malnourished and consequently suffer insufficient Se supply due to diminished food intake. Since diet is the primary Se source, excessive alcohol consumption which impairs food intake also limits Se supply (Navarro-Alarcon et al., 2002). A constant Se deficiency characteristic of chronic alcoholics would develop a decrease in GPx activity and, consequently, of catalytic elimination of hyroperoxides otherwise enhanced by high alcohol intake. As a result, accumulation of toxic substances in the liver occurs progressively, along

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Pathology and/or status Hepatophathies

Chronic liver diseases

Chronic hepatitis C

Alcoholic liver disease Hepatopathies

Viral hepatic diseases

Hepatopathies

Group

n (sex)

Mean Se (μg/l)

Se range (μg/l)

Age (years)

41.0 ± 12.4 52.4 ± 15.6. 74.9 ± 27.3 48.6 ± 11.8 66.4 ± 14.1 43.0 ± 13.3 58.4 ± 16.6

17.7–61.5 15.8–80.5 30.2–175.0 – – – –

– – – 54 54 52 52

(14M, 10 F) (21 M, 28 F) (15 M, 5 F)

67.4 ± 11.7 89.5 ± 15.6 159.1 ± 5.3 55.1 ± 3.8 216.7 ± 7.4 139.1 ± 5.8 46.1 100.6 114.5 ± 15.8

– – – – – – 31.9–60.6 92.3–105.4 –

42 42 49.5 ± 2.4 ‘‘ 43.2 ± 1.7 ‘‘ 46.8 ± 10.0 45.7 ± 14.8 49.5 ± 3.0

47 (36 M, 11 F) 50 (25 M, 25 F)

90.8 ± 7.1 124.3 ± 22.6

– –

40 (20 M, 20 F) 20 (10 M, 10 F) 18 (9 M, 9 F)

123.5 ± 20.4 117.5 ± 25.3 108.5 ± 21.8

50 (25 M, 25 F) 15 (8 M, 7 F) 15 (10 M, 5 F) 15 (10 M, 5 F)

Cirrhosis group Hepatitis group Control group Chronic hepatitis C or C virus infection group Alcoholic, autoimmune or cryptogenic chronic liver disease group Healthy controls

12 (8 M, 4 F) 38 (23 M, 15 F 130 (56 M, 74 F) 59

Hepatitis group ‘‘ Control group ‘‘ Cirrhosis group Control group Non-alcoholic fatty liver disease group Viral hepatitis group Hepatitis B virus carriers group Chronic hepatitis B group Hepatic cirrhosis group Hepatocellular carcinoma group Control group Cirrhosis group Hepatocellular carcinoma group Adjacent healthy liver group

33 ‘‘ 31 ‘‘ 24 49 17

64

50 (20 M, 13 F) (17 M, 14 F)

Statistical differencesa Yesb Yesb Yesb Yesb Yesb Yesb

Sample type Serum Serum Serum Plasma Whole blood Plasma Whole blood

No

Plasma Whole blood Plasma Erythrocyte Plasma Erythrocyte Serum Serum Plasma

43.5 ± 1.6 49.9 ± 12.5

No

Plasma Serum

– – –

52.1 ± 11.6 56.3 ± 9.5 58.5 ± 10.1

No No Yesc

Serum Serum Serum

129.0 ± 21.5 0.023 ± 0.008d 0.023 ± 0.008c,d

– – –

48.5 ± 13.1 39 58

No Yesb

Serum Liver tissue Livers tissue

0.031 ± 0.015d

–

58

Yesc Yesc

Yesb

Liver tissue

Area (country)

Reference

Motril (Spain)

Navarro-Alarcon et al. (2002)

Poland

Czuczejko et al. (2003)

China

Ko et al. (2005)

United Kingdom

Pemberton et al. (2005) Bonnefont-Rousselot et al. (2006)

Paris (France)

Taiwan (China)

Lin et al. (2006)

Poland

Czeczot et al. (2006)

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Table 5 – Selenium levels in serum, plasma, whole blood, tissue and erythrocytes in healthy control subjects and patients with different pathologies

Cancer

Acute myocardial infarction (AMI) AMI CVD

3 (3 M) 20 (11 M, 9 F) 15 (9 M, 6 F) 21 (9 M, 12 F) 130 (56 M, 74 F) 36 (14 M, 22 F) 498 (200 M, 298 F)

42.6 ± 2.42 51.8 ± 26.6 59.5 ± 20.9 55.3 ± 27.3 74.9 ± 27.3 88.4 ± 16.6 85.2 ± 15.0

39.8–44.2 8.85–100.0 21.3–97.9 13.2–112.5 30.2–175.0 – –

– – – – – 53 65

AMI group Control group AMI group Ischemic cardiopathy group Control group AMI group

683 M 729 M 32 (27 M, 5, F) 50 (38 M, 12 F)

86.8 ± 15.8 105.8 ± 13.4 58.7 ± 27.2 55.5 ± 16.7

– – 21.6–118.5 19.2–86.0

b 70 53 – –

130 (56 M, 74 F) 27 ‘‘ 24 (20 M, 4 F) ‘‘ 49 ‘‘ 58 (35 M, 23 F) ‘‘ 89 F 543 F 751 (296 M, 456 F) 751 (296 M, 456 F)

74.9 ± 27.3 63.7 ± 12.0 0.48 ± 0.04 82.2 ± 14.6 0.51 ± 0.03 53.8 ± 18.3 71.4 ± 18.2 52.5 ± 13.6 73.1 ± 18.1 112.9 121.6 86.9 ± 15.8 79.0 ± 14.2

30.2–175.0 – – – – – – – – 109.0–117.6 120.0–124.0 – –

– – – 51 51 – – 57 57 73.9 75 65 ± 3 74 ± 3

Control group AMI

AMI group Control group

Mortality predictione Occurrence of CV events

a

Died group Lived group Group at baseline Group at the end of the study followed for 9 years

Yesb Yesb Yesb Yesb No

Yesc Yesc Yesc

Yesc No

No No

Serum Serum Yesb

Serum Serum Serum Serum Serum Plasma Plasma

Motril (Spain)

Navarro-Alarcon et al. (1998)

France

Coudray et al. (1997)

Whole blood Whole blood Serum Serum

8 European countries and Israel Motril (Spain)

Kardinaal et al. (1997)

Plasma Erythrocytes Plasma Erythrocytes Plasma Whole blood Plasma Whole blood Serum Serum Plasma Plasma

Turkey

Bor et al. (1999)

Poland

Zachara et al. (2001)

Baltimore (USA) Baltimore (USA) Nantes (France)

Ray et al. (2006)

Navarro-Alarcon et al. (1999)

Arnaud et al. (2007)

Statistical differences were established when compared Se levels measured in patients with those found in healthy subjects that constitute the control group. p b 0.001. c p b 0.05. d Se was measured as μmol Se GPx/min per mg protein. e The main causes of death among the women who died (14.1%) during the 60 months of follow-up were: CVD (32.6%), cancer (18%), stroke (9.0%), infection (6.7%), chronic obstructive pulmonary disease (5.6%), accidents (3.4%), diabetes mellitus (2.0%), renal disease (2.0%), other (13.5%) and unknown (6.7%). b

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AMI

Respiratory cancer group Digestive cancer group Hematological cancer group Gynecological cancer group Control group AMI group Control group

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with alcohol toxicity. Czuczejko et al. (2003) found that disturbances in antioxidant parameters in the blood of patients with chronic liver disease may be the cause of the peroxidative damage of cells. Several case/control studies of serum, plasma and/or whole blood Se levels and erythrocyte and/or platelet GPx activities have been conducted in individuals with different hepatopathies. A previous review by our research group (Navarro-Alarcon and López-Martínez, 2000) discovered that in 12 of 13 studies conducted between 1985 and 1998, measured serum or plasma Se levels were significantly lower than those of the healthy control group. In this review, six additional studies have been discovered (Table 5), four of which report body Se levels significantly lower in patients with hepatopathies than for healthy subjects. The results were independent of the Se nutritional biomarker employed, namely serum Se (Navarro-Alarcon et al., 2002; Pemberton et al., 2005) plasma and erythrocytes Se (Ko et al., 2005), and plasma and whole blood Se (Czuczejko et al., 2003). It has also been reported that the reduction of body Se levels are more pronounced with the advance of the disease. Therefore, as hepatitis progresses to cirrhosis, the most pronounced Se impairment is reached in the final stages when the highest liver injury occurs (Navarro-Alarcon et al., 2002). This finding confirms that the severity of liver damage is one of factors affecting the impairment in Se body status found in patients with hepatopathies. However, low peripheral Se levels cannot automatically be considered as hepatopathy promoters. In fact, these diminished Se levels are really the consequence of an impairment of body mechanisms which control enhanced oxidative stress during the genesis and progression of hepatopathies to more severe stages like non-reversible cirrhosis (Navarro-Alarcon et al., 2002). During non-invasive monitoring of oxidative stress in 24 alcoholic cirrhosis disease patients, Pemberton et al. (2005) found that the levels of 8-isoprostane and malonaldehyde (as markers of lipid peroxidation) were significantly increased when compared with controls (p b 0.001). Concomitantly, serum Se GPx, and vitamins A, C and E (as antioxidants) were all significantly diminished (p b 0.001). Consequently these authors conclude that oxidative stress is a significant feature of alcoholic cirrhosis as reported for other hepatic diseases like chronic liver disease (Czuczejko et al., 2003) or hepatocellular carcinoma (Czeczot et al., 2006; Lin et al., 2006).

10.2.

Selenium metabolism in cardiovascular diseases

As reported in our previous study, an inverse correlation exists between the appearance of some cardiopathies and low Se levels in the environment, diet, and blood (Navarro-Alarcon and López-Martínez, 2000). Extreme dietary deficiencies lead to endemic Keshan and Kashin–Beck disease. Here we review 12 serum and plasma Se level studies in patients with cardiovascular diseases (CVDs: myocardial infarction, arteriosclerosis, congestive heart failure, diverse cardiopathies, cardiomiopathies, arterial hypertension, chronic heart disease, coronary arteriosclerosis and ischemic cardiomiopathy) versus healthy controls. In ten of the studies, Se levels were significantly lower than normal (Navarro-Alarcon and LópezMartínez, 2000). Additionally, of the five studies showed in

Table 5, only half showed Se biomarker levels were significantly lower for patients vs. healthy controls (p b 0.05). Wei et al. (2004) did a prospective study of serum Se concentrations and heart disease (HD), stroke, other diseases, and total death. These authors measured baseline serum Se concentrations in 1103 individuals from Linxian (China) randomly selected from a larger trial cohort. After examining the relation between baseline serum Se and the subsequent risk of death from HD and stroke over 15 years of follow-up (from 1986–2001). Wei et al. (2004) only found inverse correlation trends between Se level and death for HD (p = 0.07). Contrarily, Lewin et al. (2002) used the human endothelial cell line EAhy 926 to determine the importance of Se in preventing oxidation damage induced by test-butyl hydro peroxide or oxidized low density lipoprotein (LDLox). These researchers showed that cells pre-treated with 0.4 nM selenite prior to exposure to 1 μM gold tioglucose were significantly more resistant to damage from test-BuOOH than Se-deficient cells. These authors suggested that Se supplementation, acting through induction of TR and GPx has the potential to protect the human endothelium from oxidative damage (Lewin et al., 2002). In general, these findings demonstrate controversial results as it still has not been determined if differences are etiological or biological consequences of the various cardiopathies. Nevertheless, it has been reported that a serum Se level b55 μg/l is associated with an increased risk of coronary heart disease. Moreover, Helmersson et al. (2005) report that low Se levels predict mortality and CVD in some populations. These authors investigated the longitudinal association between serum Se and several standard indicators of oxidative stress like F2-isoprostane and prostaglandin F2α (indicator of cyclooxigenase-mediated inflammation) in a 27 year follow-up of Swedish men (n = 615; 50 years old). Helmersson et al. (2005) concluded that high concentrations of serum Se predict reduced levels of oxidative stress (8-isoprostaglandin F2α) and subclinical cyclooxigenase-mediated (but no cytokinemediated) inflammation. Therefore, the association between Se, oxidative stress and inflammation may be related to the cardiovascular protective properties of Se (Helmersson et al., 2005) Ray et al. (2006) performed a 60 month longitudinal study of 632 women (70–79 years old). They found that high serum Se and carotenoid levels were significantly associated with a lower risk of mortality (Table 4). Of the five major causes of death studied, almost half were related to the cardiovascular system. HD was the primary cause with 32.6%, and stroke was in third place with 9% (Ray et al., 2006). It has been reported that Se levels decrease during ageing (De Yong et al., 2001; Arnaud et al., 2007). In a 9-year study of an elderly French population, Arnaud et al. (2007) used multivariate linear regression models to find the relation between plasma Se variability and 11 risk factors (age, education, marital status, smoking, alcohol consumption, obesity, dislipidemia, diabetes, hypertension and personal history of CVD). They found that cardiovascular events (p = 0.003) and chronic obesity (p = 0.02) significantly increased with a reduction in plasma Se (Arnaud et al., 2007). By other means, Faure et al. (2004) also reported the importance of Se supplementation in the prevention of CVD in type 2 diabetic patients. It is known that the enhancement of Se GPx activity

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improves the antioxidant system and results in less peroxide formation which is indirectly implicated in the activation of nuclear factor-kappa B (NF-κB). Activated NF-κB has been identified in situ atherosclerotic plaques (Collins and Cybulsky, 2001), and has also been linked to development of late diabetic macro vascular complications in humans. Antioxidants inhibit NF-κB activation which, contrarily, is directly activated by hyperglycaemia in diabetics. Specifically, Faure et al. (2004) found that supplementing type 2 diabetic patients with Se (n = 21; Se supplementation trial: 960 μg Se/day for 3 months) significantly reduced NF-κB activity (p b 0.05), reaching the same level as the non-diabetic control group (n = 10). To the contrary, Navas-Acien et al. (2008) concluded that current evidence is insufficient to support using Se in the role of cardiovascular disease prevention. Additionally, these authors stated that subjects living in high Se intake regions should be aware that Se supplements may increase the risk of diabetes and hypercholesterolemia. Navas-Acien et al. (2008) concluded that large, high-quality, randomized controlled trials (RCTs) and observational studies are needed across populations with different Se levels intake. It is known that homocysteine is an emerging risk factor for CVD. Homocysteine is a metabolic product of methyl group transfer from the amino acid methionine. After measuring serum Se and plasma homocysteine concentrations in elderly humans [n = 202; 85 males and 117 females] from Asturias (Northern Spain), Gonzalez et al. (2004) reported that blood Se levels should be considered as a potential factor to lower total plasma homocysteine. Specifically, they found an independent inverse association between serum Se and plasma homocysteine (Gonzalez et al., 2004). Thomson (2004) reported that despite significant research, the role Se plays in protection against CVD remains inconclusive. Se protection found in some studies is consistent with an apparent risk threshold of about 79 μg/l in plasma, which corresponds with the level required to maximize antioxidant GPx. Although recent studies provide hopeful results, they do not unequivocally conclude that higher Se intake decreases risk for CVD. Although Se shows potential as an antioxidant and its role in prevention of CVD is promising, additional longterm intervention trials are necessary. Therefore, despite its antioxidant action and its intervention in regulating the human immune system, indiscriminate Se supplementation still cannot be recommended for the prevention of CVDs.

10.3.

Selenium metabolism in cancers

Solid evidence based on epidemiological studies conducted in the last 50 years show an inverse relationship between Se intake and cancer mortality. Thus the anticarcinogenic effect of Se against leukaemia and cancers of the colon, rectum, pancreas, breast ovaries, prostate, bladder, lung and skin seems clear under at least some conditions (Sunde, 2000). Trumbo (2005) after doing an FDA review of the evidence for Se and cancer concluded that some evidence permits a qualified health claim for Se and cancer. Specifically, of the 36 observational studies reviewed, approximately half supported an association with all cancers. However, the greatest consistency was noted for breast and prostate cancers

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(Trumbo, 2005). Silvera and Rohan (2007) also reported evidence to support an inverse relationship between Se exposure and prostate cancer risk, and possibly a reduction in risk with respect to lung cancer, although additional study is needed. Nevertheless, these authors reported that most studies reported no association between Se and risk of breast, colorectal and stomach cancer (Silvera and Rohan, 2007) Donaldson (2004) reports Se as an antioxidant nutrient and a protective element in a cancer prevention diet along with others like folic acid, vitamin B12, vitamin D, chlorophyll and other antioxidants such as carotenoids. In 2000, our group reviewed and compared 17 studies measuring Se levels in serum or plasma from patients with different types of cancer and in healthy adult controls (Navarro-Alarcon and LópezMartínez, 2000). Fourteen of the studies showed significantly lower Se levels in the cancer patients compared to the control group. Low serum Se also correlates to higher cancer risk. Moreover, Czeczot et al. (2006) found a decrease of the GPx activity in hepatocellular carcinoma tissue compared to adjacent normal liver tissue. This diminishment might cause the intensification of lipid peroxidation and the enhancement of final peroxidation products such as malonaldehyde (MDA). Concomitantly, increase of MDA levels in cancer tissue was also found. Therefore, some researchers recommend Se as a nutritional prophylaxis against cancer at a dose of 50 to100 μg Se/day (Simonoff and Simonoff, 1991). Se has also been recommended as a co-adjuvant to chemotherapy in cancer treatment at a higher dose of 200 μg Se/day (Simonoff and Simonoff, 1991). This dose is considerably higher than that necessary to reach the maximum GPx activity. The anticarcinogenic effect of Se has been attributed to several mechanisms: (a) modulation of cell division; (b) metabolic alteration of some carcinogens; (c) cell protection against oxidative damage by increasing TR activity (Karunasinghe et al., 2006); (d) stimulation of the immune system; (e) inhibition of activation of hepatic enzymes whose metabolic activities enhance the production of toxic substances that lead to cancer genesis.; (f) activation of the detoxifying liver enzymes, etc. In a study of mortality from oesophageal squamous cell carcinoma (ESCC) and gastric cardia cancer (GCC) in Linxian (China), a significant inverse relationship between baseline serum Se and death from these cancers was found (p b 0.05) (Wei et al., 2004). These researchers found a mean serum Se concentration of 73 μg/l, which corresponds to the Se amount present in maximally expressed plasma selenoproteins and to the upper limits of GPx responses to Se supplements in healthy people. On the basis of this criterion, 69% of the subjects were Se deficient (Wei et al., 2004). They concluded that population-wide Se supplements in regions of China with low serum Se and high incidences of ESCC and GCC merits serious consideration. Concomitantly with this finding, Kim et al. (2005) found that the sera of prostate cancer subjects, after Se supplementation, exhibited the same proteomic pattern as prostate cancer-free subjects. Contrarily, Peters et al. (2008) in a cohort study of long-term intake of vitamin E and Se (10-y average intake) found no relationship with overall prostate cancer risk. Additionally, the risk of clinically significant advanced prostate cancer was not reduced with long-term Se supplements.

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Connelli-Frost et al. (2006) found that high body Se was associated with a reduced prevalence of colorectal adenoma. Nevertheless, apoptosis did not seem to be the mechanism by which Se was related to adenoma prevalence. They recommended future clinical trials for Se as a potential chemopreventive agent for colon adenomas and colon cancer. Peters et al. (2006) studied the association of serum Se and advanced colorectal carcinoma and concluded that Se may reduce the risk of developing advanced colorectal adenoma, particularly among the high risk group of smokers. Other studies have also found a significant Se protective effect against total and prostate cancer incidence in men at daily dose of 200 μg Se/day via selenized yeast (Duffield-Lillico et al., 2002). Similarly, Karunasinghe et al. (2006) demonstrated that 6 months of Se supplements in men at high prostate cancer risk (200 or 400 μg Se/day with selenoyeast) increased significantly TR activity from 0.390 ± 0.050 mU/mg Hb at baseline to 6.490 ± 0.261 mU/mg Hb by the end of the supplementation period. However, McNaughton et al. (2005) did a review of 26 studies of human basal cell cancer (BCC) and squamous cell cancer (SCC) of the skin. These studies were critically reviewed and confirmed that the evidence for association between Se, vitamin E and vitamin C and both BCC and SCC is weak. These authors concluded that further well-designed and implemented studies are required to clarify the role of diet Se in skin cancer. Ferguson et al. (2006) stated that biomarker approaches appear useful in assessing antioxidant activity of dietary components like Se and may provide information relevant to cancer protection. In some studies, it is now questioned whether the antioxidant properties or other effects of Se provide cancer protection. Se is significantly accumulated in colorectal polyps (an early stage in colon cancer development) compared to healthy tissues (Alimonti et al., 2008). This finding is probably related to the significant drop in serum Se in patients with gastrointestinal cancers, most of which were colorectal cancers (Navarro-Alarcon et al., 1998) (Table 5).

10.4. Influence of selenium supplementation trials on the prevention and progression of some diseases and body limitations associated with ageing Lately, various studies have been performed (Table 6) concerning the influence of Se supplementation (alone or with other antioxidant vitamins and minerals) on the prevention of pathologies associated with oxidative stress and inflammatory processes (Tomkins, 2003) like cancer, cardiovascular diseases, rheumatoid arthritis, hepatopathies, etc. The influence of Se on the loss of body capability due to ageing is also being studied. One study of Chinese men concludes that the maximum dietary Se required to maximize GPx activity is 41 μg Se/day (11 μg Se/day from normal dietary intake plus a supplement of 30 μg Se/day as Se-Met). A dose of 53 μg Se/day is extrapolated for the for the higher body weight of USA and Europe residents (Thomson, 2004). Nevertheless, some research proposes that Se intakes higher than recommended and higher than normal plasma Se concentrations may protect against cancer, cardiovascular diseases, hepatopathies, and arthritis or provide other additional health benefits. Despite this, it is known that Se plasma and GPx levels are

normally significantly lower in patients with different types of cancer, cardiovascular diseases, hepatopathies, rheumatoid arthritis and osteoarthritis, etc., (Navarro-Alarcon and LópezMartínez, 2000; Navarro-Alarcon et al., 2002; Czeczot et al., 2006; Flores-Mateo et al., 2006). However, most reviews and studies report no disease prevention, protection, or treatment benefits from antioxidant supplements including Se or Se alone (Duffield-Lillico et al., 2003; Lacour et al., 2004; Bleys et al., 2006; Flores-Mateo et al., 2006; Stranges et al., 2006; You et al., 2006; Canter et al., 2007; Stewart et al., 2007). Contrarily, Etminan et al. (2005) in a systematic review and meta-analysis of Se in the prevention of prostate cancer concluded that Se may reduce the risk of prostate cancer. Nevertheless, these authors are awaiting the results of ongoing larger randomized controlled trials to confirm these findings and definitively answer this question. Flores-Mateo et al. (2006) after performing a meta-analysis of Se supplementation and coronary heart disease concluded that the randomized trials performed up until now are still inconclusive. On the other hand, Wei et al. (2004) previously reported an inverse association between pre-diagnostic serum Se concentrations and the risk of oesophageal squamous cell carcinoma (ESCC) and gastric cardiac cancer (GCC). Additionally, they found significant inverse associations between baseline serum Se and death from ESCC after a 15year follow-up. These researchers concluded that populationwide Se supplementation in China areas with low serum Se and high incidences of ESCC and GCC merits serious consideration. Bleys et al. (2006) did a meta-analysis of randomized controlled trials (RCT) (n = 16) of the effect of vitamin– mineral supplementation on atherosclerosis progression. Nevertheless, only 2 trials employed antioxidants with Se as supplements. These authors concluded that antioxidant supplements provide no protection against atherosclerosis, thus providing an explanation for their lack of effect on clinical cardiovascular events (Bleys et al., 2006). Contrarily, Vernardos and Kaye (2007) did a review summarizing the role of myocardial antioxidant enzymes (GPx and TR). These authors found that dietary Se supplements may provide a safe and convenient method for increasing antioxidant protection in aged individuals, particularly those at risk of ischemic heart disease or undergoing clinical procedures involving transient periods of myocardial hypoxia (Vernardos and Kaye, 2007). Other authors (Geoghegan et al., 2006) reported that patients with critical illnesses were supplemented with widely varying doses of Se (between 200 and 1000 μg) used alone or in combination with other antioxidants. They documented a decrease in the length of hospital stay, rate of infection, and need or haemodialysis in these patients. Nevertheless, no trial has demonstrated a statistically significant improvement in mortality, despite a recent meta-analysis suggesting a trend towards reduced mortality with Se supplementation (Geoghegan et al., 2006). In recent years, genomic and proteomic science is growing rapidly. Because of the need to define the capacity of nutrients like Se these sciences concern the study of nutrients like Se to facilitate the up- or down-regulation of specific genes and therefore to enhance or diminish protein synthesis. In this sense,

Table 6 – Supplementation studies with Se alone or with other antioxidant vitamins and minerals Disease or status

Group

n (sex)

Age (years)

Design and intervention

Antioxidant dose

Results

Reference

Country

1706 1705

39–69 35–69

39-month double-blind, RCT

500 mg vitamin C, 200 IU vitamin E, 15 mg β-carotene, 75 μg Se

Antioxidant group Placebo group

1677 1688

35–64 35–64

7.3-year double-blind, RCT

Nonmelanoma skin cancer

Selenium group Placebo group

621 629

10-year double-blind, RCT

250 mg vitamin C, 100 IU vitamin E, 37,5 μg Se from yeast 200 μg Se/day as Se-enriched yeast

Prostate cancer

Selenium group Placebo group

32,400 M for 62.4 selenium and placebo groups

7–12 year double-blind, RCT

200 μg Se/day form L-Se-Met and/or 400 UI/day vitamin E

Men at high prostate cancer risk Cardiovascular disease incidence and mortality

Selenium group Placebo group Selenium group free of cardiovascular disease at baseline Placebo group free of carviovascular disease at baseline Antioxidant group

29 M 14 M 504 (357 M, 147 F)

6-month double-blind, RCT 7.6-year double-blind, RCT

200 or 400 μg Se/day as seleno yeast 200 μg Se/day as high Se baker's yeast table

3.0-year double-blind, RCT

Change in coronary minimal luminal diameter

Brown et al. (2001)

USA and Canada

Placebo group

100 mg vitamin C, 800 IU vitamin E, 100 μg Se, 25 mg β-carotene

7.2-year double-blind, RCT

120 mg vitamin C, 33 IU vitamin E, 100 μg Se, 6 mg β-carotene, 20 mg zinc 100, 200 or 300 mg Se/day as high Se-yeast

Carotid intima-media thickness

Zureik et al. (2004)

France

Selenium group Placebo group

28 (7 M, 21 F) 27 (7 M, 20 F)

61 ± 13 60 ± 13

Rheumatoid arthritis

Selenium group Placebo group

35 30

Precancerous gastric lesions

Antioxidant group Placebo group

Precancerous gastric lesions

50–75 62.5

62.1

79 (71 M, 8 F)

53 53

Mood and quality of life Selenium group Placebo group of elderly individuals

67 (60 M, 7 F) 599 (300 M, 299 F) 563 (281 M, 282 F) 336 112

Acute alcoholic hepatitis

Antioxidant group Placebo group

Chronic hepatitis C virus-infected patients

Selenium group Placebo group

Prevention of the progression of atherosclerosis Prevention of the progression of atherosclerosis

Antioxidant group Placebo group

53 53 60–74 60–74

2-year double-blind, RCT

36 (20 M, 16 F) 34 (18 M, 16 F)

44 44

6-month double-blind, RCT

12 11

43 45

6-month double-blind, RCT

Unknown results by the moment

Peretz et al. (2001)

Belgium

Heinle et al. (1997)

–

You et al. (2001)

Shandong province (China)

You et al. (2006)

Shandong province, China Eastern USA

DuffieldLillico et al. (2003) Lippman et al. (2005)

USA, Puerto Rico and Canada The TR activity of the supplemental group Karunasinghe New measured by 80% relative to baseline et al. (2006) Zealand No overall effect of Se supplementation on Stranges et al. California, the primary prevention of cardiovascular (2006) USA diseases

No justification for increasing Se intake to improve mood in general UK elderly population Vitamin A, vitamin E, Se, Antioxidant therapy alone does not Zn, Mn, Cu, Mg, folic acid, improve 6-mo survival coenzyme Q 500 mg vitamin C. 945 No consistent differences between groups IU vitamin E, 200 μg or changes of activities from the baseline selenium as Se-Met of the GPx, SOD and catalase enzymes

Rayman et al. United (2006) Kingdom Stewart et al. (2007)

United Kingdom

Groenbaek et al. (2006)

United Kingdom

135

500 (356 M, 144 F)

200 μg Se/day as sodium selenite

For Se group only arm movement and health perception rose significantly (p b 0.05) from 6 test points and clinical outcome measurements No significant differences were found for the 3 test points and clinical outcome measurements No significant differences in total, cancer, gastric cancer and cardiovascular deaths between the placebo and the vitamin–mineral preparation groups No significant favourable effects were seen or the diminishment of the prevalence of precancerous gastric lesions No association between treatment and the incidence of cancer

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200 μg Se/day as Se-enriched yeast

58 ± 13 57 ± 13

90-day double-blind, multicentre randomized controlled trial (RCT) 3-month parallel group double-blind, RCT

Rheumatoid arthritis

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Faure et al. (2004) concluded that in type 2 diabetic patients, activation of NF-κβ measured in peripheral blood monocytes can be reduced by Se supplementation, thus confirming its importance in the prevention of cardiovascular diseases (CVD). In this Se supplement trial, type 2 diabetic patients (n = 48; age range = 49–58 years old) were divided into two groups: 21 individuals were supplemented with 960 μg Se/day during 3 months and 27 received a placebo (Faure et al., 2004). The impact of Se on mood and quality of life in the elderly was studied in a randomized controlled trial by Rayman et al. (2006). These researchers found that there was no evidence that Se supplementation benefited mood or quality of life in these elderly volunteers. They stated that the large sample size and long supplementation period confirms that this is a reliable finding. Contrarily, De Yong et al. (2001) reported that New Zealand women aged 75 ± 3 years old in the highest third of functional capacity index (n = 33; plasma Se = 77.4 ± 23.7 μg/l) had significantly higher biochemical Se values than those in the lowest third (64.7 ± 15.0 μg/l). They concluded that suboptimal trace element levels may be more common among those with poor physical function, therefore promoting consumption of high Se foods or supplements to improve Se levels in elderly women in New Zealand may be beneficial (De Yong et al., 2001). Consequently, Se supplements should not be recommended for the prevention of disease considering that until now few randomized controlled trials have been conducted. Randomized trials are inconclusive concerning the effect of Se supplementation. Therefore, the population should be warned against the employment of Se supplements for the prevention of hepatopathies, rheumatoid arthritis, cardiovascular or cancer, as the benefits are still uncertain and their indiscriminate use could generate an increased risk of toxicity.

11.

Conclusions

In the last two decades there has been much progress in our knowledge and understanding of the biological roles of Se and its importance in human nutrition. The current knowledge of the role of Se in health and disease is important in order to assess the health risk associated with low population Se levels. Diet is the major source of Se for the general population and its bioavailability comes mainly from Se organic forms (generally more than 80%). The influence of other dietary factors such as total protein, fat and heavy metal presence, have been also described. Soil content clearly determines the food Se content and consequently the average total Se intake. High Se values for soil are reflected in high Se concentrations in local animals and plants and finally in body fluids as biomarkers of the nutritional status of the population. A widely variability between Se total dietary intakes among different countries has been found. Despite this, healthy individuals who usually have a balanced and varied diet should have the appropriate nutritional level of Se and hence, do not need a supranutritional intake of this element, with the exception of those living in geographical areas of low environmental Se concentrations. Another topic of concern is the effect of technological processing and cooking of food prior to consumption which generally diminishes Se concentration due to volatility and solubility. However, some researchers did

not report any effect of these processes on final Se content in foods and meals. On the other hand few in vivo and in vitro studies have been conducted on the influence of food technology on Se species in prepared food and, consequently, on Se bioavailability. Therefore, we consider that more research is necessary in the supplementation field in order to have a better knowledge of the amount of Se biologically available for the human organism from Se supplements used nowadays. Efforts to characterize Se species can be subdivided into the analyses of the macromolecules (peptides and proteins) and small molecules (amino acids, selenate, and selenite) normally associated with Se in food (except in regions of low endemic soil Se concentrations). Generally, biomarker levels of nutritional Se status diminish significantly in individuals with cardiopathies, hepatopathies and several cancer types. Nevertheless, it is still not clear if this low Se is a pre-existing factor promoting the disease's genesis, or is a consequence of the disease itself. Another conclusion is that additional scientific evidence is needed through large high-quality RCT and observational studies with population groups of different Se and health levels. In addition to epidemiologic studies, basic science research is necessary to detect mechanisms and evaluate disease chemopreventive potential in food Se. Until that moment, the efficacy of Se as a disease preventive agent, Se disease health claim for specific hepatopathies, cardiopathies, cancer, rheumatoid arthritis, etc., cannot be condoned and additional study is required. Nowadays, our understanding of the mechanisms involved in the genesis of hepatopathies, cardiopathies and different cancers is increasing rapidly based on new findings in disease-related functional genomics and proteomics. Therefore, basic and translation research using these findings and new technology will contribute to the definition of molecular and genomic biomarkers that can be employed to evaluate disease risk in cohorts and surrogate endpoints in clinical studies.

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