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Review

Selenium in food and the human body: A review

Miguel Navarro-Alarcon ⁎, Carmen Cabrera-ViqueDepartment of Nutrition and Food Science, University of Granada, 18071-Granada, Spain

A R T I C L E I N F O

⁎ Corresponding author. Tel.: +34 958 243865;E-mail address: [email protected] (M. Navar

0048-9697/$ – see front matter © 2008 Elsevidoi:10.1016/j.scitotenv.2008.06.024

A B S T R A C T

Article history:Received 27 March 2008Received in revised form16 June 2008Accepted 16 June 2008Available online 26 July 2008

Selenium levels in soil generally reflect its presence in food and the Se levels in humanpopulations. Se food content is influenced by geographical location, seasonal changes,protein content and food processing. Periodic monitoring of Se levels in soil and food isnecessary. Diet is the major Se source and approximately 80% of dietary Se is absorbeddepending on the type of food consumed. Se bioavailability varies according to the Se sourceand nutritional status of the subject, being significantly higher for organic forms of Se. Sesupplements can be beneficial for subjects living in regions with very low environmentallevels of Se. Several strategies have been followed: (1) employment of Se-enriched fertilizers;(2) supplementation of farm animals with Se; (3) consumption of multimicronutrientsupplements with Se. Nevertheless, detailed investigations of possible interactions betweenSe supplements and other food components and their influence on Se bioavailability areneeded. Suppliers also need to provide more information on the specific type of Se used insupplements. In addition, research is lacking on the mechanisms through which Se isinvolved in hepatocyte damage during hepatopathies. Although Se potential as anantioxidant for the prevention of cardiovascular diseases (CVD) is promising, additionallong-term intervention trials are necessary. As a result, indiscriminate Se supplementscannot be reliably recommended for the prevention of CVD in human beings. Someinteresting findings reported an association of Se intake with a reduced prevalence and riskfor prostate and colon cancer. However, random trials for other cancer types areinconclusive. As a final conclusion, the general population should be warned against theemployment of Se supplements for prevention of hepatopathies, cardiovascular or cancerdiseases, because benefits of Se supplementation are still uncertain, and theirindiscriminate use could generate an increased risk of Se toxicity.

© 2008 Elsevier B.V. All rights reserved.

Keywords:SeleniumDietary intakeBioavailabilitySupplementationBiomarkersDisease prevention

Contents

1. Selenium content in foods and beverages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161.1. Meat, chicken, fish and eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181.2. Milk and dairy products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181.3. Fruits and vegetables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181.4. Legumes, nuts, cereals and by-products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181.5. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

fax: +34 958 249577.ro-Alarcon).

er B.V. All rights reserved.

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http://dx.doi.org/10.1016/j.scitotenv.2008.06.024

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2. Selenium bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193. Selenium total dietary intake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1204. Selenium supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205. Physiological role of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226. Assessment of body nutritional status on selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237. Selenium metabolism and pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1268. Selenium deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289. Toxicity of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

10. Body seleniummetabolism in several diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12910.1. Selenium metabolism in hepatopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12910.2. Selenium metabolism in cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13210.3. Selenium metabolism in cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13310.4. Influence of selenium supplementation trials on the prevention and progression of some diseases

and body limitations associated with ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13411. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

1. Selenium content in foods and beverages

Se content in food and beverages varies geographically bothwithin and between countries. The Se content of animalproducts reflects the Se levels in their consumed diet (Barclayet al., 1995), whereas the Se content of plants is directlyaffected by Se levels in the soil in which are grown. Se in theform of selenate or selenite is taken up by plants and mainlytransformed into Se-Met in cereal grains (Sathe et al., 1992).Plant absorption of Se principally depends on the concentra-tion and physicochemical forms existing in the soil. Factorssuch as the type of rocks, pH and redox potential in the soil, theexistence of some organic and inorganic compounds, soilmoisture and salinity, soil sulphate concentration, plantspecies, soil-management practices, oxidation state of theelement (the absorption of Se6+ is higher than that of Se4+),nature of drainingwaters, and climatic conditions all influencethe distribution, status and availability of this element (Aroet al., 1995; Barclay et al., 1995; Combs, 2001). In acid soils Se ismainly present as selenite which has very low solubility andplant availability. In alkaline soils, Se is oxidized to selenate,which is more soluble and more available for uptake in thecrops. In many regions of the world Se soil levels generallyreflect the Se status in human populations (Goyer andClarkson, 2001; Burk and Levander, 2002). There are somezones where Se levels in soil are very low (b0.05 ppm), such asparts of China, Finland and New Zealand. In these regions,diseases caused by Se deficiency in livestock and the effect onhumanhealth arewell known. Nevertheless, in regions of highSe soil concentrations (N5 ppm), there is a net excess of thiselement as observed in Canada, Ireland, some regions of thewestern USA, and some zones of China, France, Germany, etc.(Simonoff and Simonoff, 1991; Aro et al., 1995). McNaughtonand Marks (2002) reported that foods from the USA generallyhave higher Se levels than Australian foods, and that foodsfrom United Kingdom and New Zealand have lower levels.Efforts have beenmade to increase the Se content in plants byadding Se to the soil.

Food protein content is another important factor influen-cing Se presence in food since Se can replace sulphur in the

amino acids as selenomethionine (Se-Met), selenocysteine(Se-Cys) and selenocystathionine due to their physicochem-ical similarity (Simonoff and Simonoff, 1991; Navarro-Alar-con and López-Martínez, 2000). Further, selenocompoundswould be used in the synthesis of Se-amino acids (mainly, Se-Met and Se-Cys), and finally incorporated in vegetableproteins. Thus, the Se forms included in the vegetableproteins of animal feed would ultimately be employed inthe synthesis of the animal's own proteins, facilitating theiraccumulation in livestock. Most plants do not have the abilityto accumulate large amounts of Se (concentrations rarelyexceed 100 μg/g, dry weight). However, various plant speciessuch as garlic (Allium sativum), Indian mustard (Brassicajuncea), canola (Brassica napus), and some mushrooms havebeen recognized as Se accumulators. They have the ability totake up large amounts of Se (N1000 mg Se/kg) withoutexhibiting any negative effects (Dumont et al., 2006). This ismainly due to the reduction of the intracellular Se concen-tration of Se-Cys and Se-Met which are normally incorpo-rated into proteins. When consumed in appropriateamounts, these foods can be a significant food source of Se(Dumont et al., 2006).

Industrial and agricultural activity has hastened therelease of Se compounds from geologic sources, makingthem available to fish and wildlife in aquatic and terrestrialecosystems around the globe. In recent years, the results ofmany investigations on contaminant Se conclude that Seexhibits its toxicity in animals primarily through the foodchain (Lemly, 1999; DeForest et al., 1999; Hamilton, 2004).Agricultural drain water, sewage sludge, fly ash from coal-fired power plants, oil refineries, and mining of phosphatesand metal ores are all sources of Se contamination in theaquatic environment. Specifically, bivalves (being filter-fee-ders) have been identified as the most sensitive indicators ofSe contamination (Hamilton, 2004). Fish can take up Se fromwater, plants, or by eating othermarine species. Accumulationof Se in marine animals from dietary sources (phytoplanktonad zooplankton) is more important than that accumulateddirectly from the water. In addition, Se compounds are widelyused in glass manufacture, electronic applications, photocopy

Table 1 – Se content in foods and beverages according toseveral authors

Type ofsample

Origin Se content(ng/g)

Reference

Milk and dairy productsCow's milk Greece 13.1–21.9 Pappa et al. (2006)

Ireland 14–18 Murphy andCashman (2001)

Gouda cheese Greece 85.4±10.0 Pappa et al. (2006)Yoghurt Greece 21.9–26.9 Pappa et al. (2006)

Croatia 29.9 Klapec et al. (2004)Spain 50.0±30.0 Cabrera et al. (1996)

Butter Greece 4.4–13.8 Pappa et al. (2006)Australia 0.7–14.2 Fardy et al. (1994)

Condensed milk Spain 75.0±25.0 Cabrera et al. (1996)Ice-cream Spain 100.0±40.0 Cabrera et al. (1996)

UK 15.0–17.0 Barclay et al. (1995)Fresh buffalo milk Egypt 53 Akl et al. (2006)

Fruits and vegetablesApple Australia 4.5 McNaughton and

Marks (2002)Australia 30.0–50.0 Marro (1996)

Kiwi Greece 1.4±0.2 Pappa et al. (2006)Grapes Australia 40.0–76.0 Marro (1996)Sharon fruit Greece 3.9±0.5 Pappa et al. (2006)Mango Greece 2.6±0.6 Pappa et al. (2006)Orange Australia 5.00 Marro (1996)Potato Australia 30.0–70.0 Marro (1996)

Greece 4.6±1.4 Pappa et al. (2006)Garlic Slovakia 3.5 Kadrabova et al.

(1997)Greece 13.4–13.7 Pappa et al. (2006)

Celery Australia 9.3–14.2 Marro (1996)Lettuce Australia 3.0–22.8 Marro (1996)Onion India 127 Singh and Garg

(2006)Green peas India 180 Singh and Garg

(2006)Pepper India 150 Singh and Garg

(2006)Greece 4.2±0.3 Pappa et al. (2006)

Legumes, nuts, cereals and derivativesLentils USA 28.0 USDA (1999)

New Zealand 18.0 NZ-ICFRL (2000)Bread Greece 70.0–131.8 Pappa et al. (2006)Pasta Greece 5.8±0.2 Pappa et al. (2006)Pasta, boiled Australia 35.6–50.0 Marro (1996)Rice Greece 19.1±1.4 Pappa et al. (2006)

Italy 20.1±45.3 Panigati et al.(2007)

Peanuts USA 75.0 USDA (1999)

Meat, chicken, fish and eggsBeef, steak Australia 80–200 Tinggi (1999)Lamb Spain 27–30 Díaz-Alarcon et al.

(1996a)Rabbit Spain 74–106 Díaz-Alarcon et al.

(1996a)Pork USA 144–450 USDA (1999)Pork kidney Spain 849–1543 Díaz-Alarcon et al.

(1996a)Pork liver Spain 256–800 Díaz-Alarcon et al.

(1996a)Ham Australia 200 Tinggi (1999)Oyster Australia 770 Marro (1996)

843000(continued on next page)

Table 1 (continued)

Type ofsample

Origin Se content(ng/g)

Reference

Meat, chicken, fishSalmon Australia 270–368 Marro (1996)Tuna (in oil)a Egypt 810.0 Akl et al. (2006)Sardines Australia 570 Fardy et al. (1994)Eggs Greece 172.8 Pappa et al. (2006)

Australia 0.7–14.2 Marro (1996)

MiscellaneousApple juice Australia 0.7–5.1 Marro (1996)Beer Australia 5.00 Marro (1996)Cornflakes Greece 19.7±0.6 Pappa et al. (2006)

Australia 62.9 Marro (1996)Extra virginolive oil

Greece 1.1±0.6 Pappa et al. (2006)

Olive oil Australia 5.30 Marro (1996)Honey Greece 1.7±0.004 Pappa et al. (2006)Herbal tea India 190±18 Manjusha et al.

(2007)Tea infusionb Australia 5.00 Marro (1996)Cardamon India 80±4 Manjusha et al.

(2007)Mustard seeds India 248±15 Manjusha et al.

(2007)Black pepper India 116 Singh and Garg

(2006)Vinegar Spain 0.653–2.344 Díaz et al. (1997)Tap water Greece 2.2±0.7c Pappa et al. (2006)Sugar, raw USA 69.0 Marro (1996)Chocolate UK 41.0 Barclay et al. (1995)

USA 39.0 USDA (1999)Margarine Australia 0.71–18.6 Marro (1996)

USA Ndd-10 USDA (1999)New Zealand 6.00–16.0 NZ-ICFRL (2000)

Data are referred to wet weight.aProcessed fishery food.bTea, brewed 5 min.cData expressed as μg/l.dnd, Not detectable.

Meat, chicken, fish and eggs

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machines, inorganic pigments, rubbers, ceramics, plastics andlubricants (Akl et al., 2006).

Food processing such as cooking (boiling, baking or grilling)could decrease Se food content by volatilization (Dumontet al., 2006; Sager, 2006). For example, Se losses of 40% inasparagus and mushrooms were observed when boiled forsome minutes (Navarro-Alarcon and López-Martínez, 2000;Dumont et al., 2006). Some Se losses have also been notedwhen 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 orlyophilization significantly increases Se content in all food(Zhang et al., 1993). Considering the disparate results found inthe many studies we considered, more research in this areashould be performed to clarify the specific influence thatdifferent cooking processes exert on Se content of food.

Therefore, we concluded that the content of trace elementsin food should not be based exclusively on food tables, butshould take into account loss during food processing andpreparation, variation due to seasonal changes or geographi-cal location, as well as food habits. Consequently, thorough


and periodic determinations of trace elements such as Se isadvisable. In addition, lack of data for some foods mayintroduce errors into the estimate of dietary intake of essentialelements such as Se.

1.1. 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 containinghigh levels of Se (Klapec et al., 2004; Sirichakwal et al., 2005). Inthese food groups, Ventura et al. (2007) encountered Se levelsranging from 87.6 to 737 ng/g. Fish and eggs showed thehighest Se concentration (Pappa et al., 2006; Haratake et al.,2007). Meat, fish and eggs contribute the major part of dietarySe in several countries such as Greece, Portugal and Japan(Pappa et al., 2006; Haratake et al., 2007; Ventura et al., 2007). InJapan, fish was the greatest Se contributor (up to 60% of dailytotal intake) rather than the staple foods (rice and vegetables)(Haratake et al., 2007). Literature on Se content in fish fromdifferent locations ranged between 62.7 and 506.7 ng/g inGreece (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 Australiato have a mean concentration of 90 ng/g in white and 260 ng/gin yolk (boiled eggs). Marzec et al. (2002) reported that Se levelsin meat products ranged from 55.0 to 329 ng/g. These valueswere higher than those for the other food groups. Meatshowed large variations in Se concentration, reflecting thedifferences in Se concentrations of the feed consumed by theanimals (McNaughton and Marks, 2002; Pappa et al., 2006).According to Pappa et al. (2006), mean concentrations of Se inmeat from Greece ranged from 48.8 to 94.1 ng/g, with porkmeasuring significantly higher beef. In sausages from Spain,Diaz-Alarcon et al. (1996a) encountered Se levels ranging from89.0 to 739 ng/g. These authors concluded that meat productsand cereals (mostly bread) are the main contributors to dailySe intake in healthy individuals from South-eastern Spain. Atotal of 55% of daily Se intake came from these two foodgroups due to their high Se concentrations and/or consump-tion. These findings are in agreement with other researchers(Srikumar et al., 1992; Donovan et al., 1992) who conclude thatvegetarians and lactovegetarians suffer significantlydecreased daily Se intake, which could contribute to anutritional Se deficiency.

1.2. Milk and dairy products

It has been found that Se concentrations inmilk fromdifferentanimal species decreases in the following order: humanN

sheepNgoatNcow milk. It is known that Se concentrations inmilk are negatively correlated with its fat content (Pappa et al.,2006). A similar trend was observed by Barclay et al. (1995) incheeses. A survey of Se content of Australian cowmilk showeda 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 awide variability among the data due to the different concen-trations of Se present in milk, eggs, cereal, fruit and otherfoodstuffs used in their manufacture. These authors agree

with others such as McNaughton and Marks (2002), and Pappaet al. (2006) who all consider that milk and dairy productscontribute a considerable fraction of the total dietary intake ofSe, particularly for infants.

1.3. Fruits and vegetables

Fruit contains low concentrations of Se (Table 1). This factcould be explained by the low protein fraction (and therefore,the high water content) of these products. Similarly, freshvegetables were also shown to be poor sources of Se(Sirichakwal et al., 2005). Ventura et al. (2007) reported similarSe 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 thebetter known species of the Brassica genus (broccoli, Brusselsprouts, cabbage, cauliflower, collards, kohlrabi, mustards andkale), garlic, chives and onions tend to have higher Seconcentrations and the extent to which they are consumedis 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 contain-ing amino acids and their derivatives, but they also containother sulphur compounds like glycosinolates or sulfoxides.Adequate analogues of these can be formed by substitution ofsulphur 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. Further-more, their intake does not result in excess accumulation of Sein tissues; nor could any perturbation in the action of Seenzymes be observed, even at high Se intakes (Dumont et al.,2006). Similarly, Manjusha et al. (2007) found high Se contentin mushrooms (1340 ng/g). Some, but not all mushrooms tendto accumulate Se because they are another vegetable specieswith a high content of sulphur containing compounds. Agari-cus bisporus is one of the most commonly studied mushroomsfor Se speciation purposes and is also the most commonlyconsumed mushroom in Europe and the USA. Other mush-rooms that accumulate Se are Boletus edulis and B. macrolepiota(Dumont et al., 2006). Plants that accumulate Se may be usedas a natural source of mineral supplements for both animalsand 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 fromGreece ranged from 24.4 to 443.9 ng/g, with a mean value of165.2ng/g, lentilspresenting thehighest concentration (Table1).They encountered Se concentrations between 7.0 and 32.27ng/gin nuts. Pistachios proved to be the richest, whereas almondswere 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 of3800 ng/g. Brazil nuts (Bertholletia excelsa) are known for theirhighSe concentrationandonesingleBrazil nut could exceed theRDA for Se (Dumont et al., 2006). The proteins found in Brazilnuts are very high in Se-containing amino acids,mainly Se-Met.Dumont et al. (2006), in a wide review of the literature, reportedlevels of Se in cereals of 10.0–550.0 ng/g (referred to freshweight). Marro (1996) encountered Se levels in white bread of


80.0–109.0 ng/g (mean of 92.6 ng/g) and in whole meal bread of100.0–152.0ng/g (meanof125.0ng/g). Tinggietal. (1992) reportedthat the major source of Se in Australia comes from wheatproducts 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 from70.0 to 131.8 ng/g. The differences of Se content between brown,whole-wheat and white bread were not statistically significant(pN0.01), although brown bread seemed to be much richer in Sethan the others.

1.5. Miscellaneous

Water Se content is usually trivial compared to the content ofthis element in food (Food and Nutrition Board—Institute ofMedicine, 2000). Diaz et al. (1997) indicated that drinks andpotable water are generally poor sources of Se (Table 1).Molnar et al. (1995) analyzed Se content in fast food from theUK and encountered the highest levels in products based oncertain mushrooms, spinach and fish. Generally, foodsproduced from Se-rich raw ingredients were themselveshigh in Se. They remarked that the Se content of food variesfrom sample to sample, even in cases of the same product. Inbaby foods from Spain such as sole with vegetables or withpotatoes, angler fish with vegetables and hake with rice, Viñaset al. (2000) detected Se levels that ranged from 21.5±1.3 to72.8±5.3 ng/g. Roca et al. (2000) determined Se levels in virginolive oil, olive oil and marc oil produced in Southern Spainranging from undetectable to 178.51 ng/g. No statisticallysignificant differences were found between the three types ofoil. Singh and Garg (2006) determined Se content in Indianspices and condiments ranging from 12 to 670 ng/g. Thehighest levels were detected in turmeric (500 ng/g) and sweetneem (670 ng/g).

Additional Se food content data from other studies andlocations are summarized in Table 1.

2. Selenium bioavailability

Selenium is one micronutrient whose deficiency and toxicconcentrations are very close each other. Therefore, it isimportant to know its abundance or deficiency in food anddiet and to determine the correct balance of Se in humanbeings and animals. In general, estimates of the total elementcontent of a given food are unreliable and the bioavailability ofthe nutrient must be considered. It is a priority to know theelement bioavailability or amount absorbed and used by theorganism, because usually only a fraction is absorbed andtransformed into a biologically available form (Cabrera et al.,1996; Cabañero et al., 2007). Ideally, a complete evaluation ofbioavailability should involve measurements of total nutrientcontent, absorbable fraction, amount actually absorbed, andpercent utilized by the organism. In vivo bioaccessibilitystudies are both expensive and laborious, and the possibilityof measuring certain parameters during the experiments isoften limited (Cabañero et al., 2007). In vitro bioaccessibilitymethods of simulated digestion are an alternative to in vivobioavailability procedures for calculating the percentage of anelement that is transformed into absorbable forms in the

digestive tract. The results of such bioaccessibility studies areusually expressed as the soluble fraction of the element undergiven experimental conditions of pH, enzyme addition,temperature, and duration of contact (Cabañero et al., 2007).These bioaccessibility methods comprise a two-phase simula-tion of gastrointestinal physiology: the stomach and intestinalphases. In vitro bioaccessibility analytical procedures are oftenuseful because they are simple, rapid, inexpensive, and allowindividual experimental variables to be easily controlled(Cabrera et al., 1996). Consequently, bioaccessibility experi-ments offer an appealing alternative to human and animalstudies (Cabañero et al., 2007; Velasco-Reynold et al., 2008).

Se bioavailability strongly depends on the chemical formof Se found in the food. Specifically, selenocompoundsidentified in plants include selenate, selenite, selenocystine,Se-Met, selenohomocysteine, Se-methylselenocysteine, γ-glutamil-selenocystathionine, Se-Met selenoxide, γ-glutamyl-Se-methylselenocysteine, selenocysteineselenic acid, Se-proponylselenocysteineselenoxide,Se-methylselenomethionine,selenocystathionine, dimethyl diselenide, selenosinigrin, seleno-peptideandselenowax.However, thepresenceofSe-Cys inplantsis still controversial (Whanger, 2002). On the other hand,selenocompounds in animal tissues are Se-Cys, selenotrisulfidesof cystine, selenate and selenite.

Se bioavailability is affected by its chemical form (gener-ally, organic compounds of Se are more bioavailable than theinorganic forms) (Thomson, 2004). The influence of otherdietary factors such as total protein, fat, and the presence ofheavy metals has been also described. Se interacts withseveral trace elements, and these interactions can be additive,antagonistic, or synergistic, and in some cases they reversethe interaction, i.e. antagonism changed to synergism (Hamil-ton, 2004; Akl et al., 2006). Perhaps one of the most reportedinteractions between inorganic elements is the antagonisticinteraction betweenHg and Se. Se is recognized to decrease Hgtoxicity when both elements are simultaneously admini-strated (Caurant et al., 1996; Cabañero et al., 2007).

Approximately 80% of dietary Se is absorbed, although thisfigure depends on the types of food consumed. Overallabsorption of all forms of Se is relatively high (70–95%), butvaries 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,comparedwith Se salts, Se in these foods is highly bioavailable(Finley, 2006). Several studies have shown that Se bioavail-ability in meat is high because Se forms in foods of animalorigin aremostly 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 itis known to be highly bioavailable. It is absorbed in the smallintestine, being incorporated into the long-term body reserves(Hinojosa et al., 2006). Although Se content in fish is high, insome cases fish is a poor source of available Se, due in part toits high Hg content and other heavy metals, which bind to Seforming insoluble inorganic complexes (Van der Torre et al.,1991; Pappa et al., 2006). However, when looking at thebioavailability of Se in fish, source and species are important.For example, existing data shows high Se availability fromsalmon (Ornsrud and Lorentzen, 2002). Dumont et al. (2006)reported that the order of bioavailability for Se species of


Atlantic salmon is: Se-MetNseleniteNSe-CysN fish meal.Absorption of Se from fish by humans is comparable to thatfromplants. Fox et al. (2004) indicated that Se in fish is a highlybioavailable source of dietary Se, and that cooking the fish didnot affect Se absorption or retention. These authors alsoobserved that Se from yeast is less bioavailable. Finley (2006)observed that reports on Se bioavailability from yeast aremixed; one group reported that Se from yeast was effective forincreasing the concentration of Se in red blood cells, butcompared with selenite and selenate, was ineffective forincreasing GPx activity. Contrarily, another group reportedthat Se from yeast was almost twice as bioavailable as Se fromselenite and selenate for restoration of depleted GPx activity.These discrepancies may reflect differences in the studypopulations as well as a difference in the chemical speciationof Se in yeast. Cabrera et al. (1996) reported a mean absorbablefraction of Se of 80.0±10.0% in dairy products such as yogurt,custard, cream cheese, curd, crème caramel, ice-cream, andcondensed milk. Barrionuevo et al. (2003) indicated that thegoat-milk has an important and beneficial effect on the Sebioavailability. Finley et al. (2004) concluded that the chemicalforms of Se species also differ among foods. For example, inbroccoli, which is a Se-accumulating plant that containsmanymethylated forms of Se, its bioavailability has been reported tobe low. However, red meats such as pork or beef couldaccumulate Se when the animal is fed high Se diets, and Sefrom such meats has been reported to be highly bioavailablefor selenoprotein synthesis.

Lacour et al. (2004) reviewed 1290 valid studies providingreliable evidence of the therapeutic benefits of Se supple-ments in environmentally associated health disorders. Theyconcluded that none of the studies showed evidence oftherapeutic benefits from Se supplementation in environmen-tally associated health disorders. Several pharmacologicalfactors of human Se supplements influence Se bioavailabilitysuch as the physicochemical form, interactions with othermicronutrients in the supplement, interaction with othermedications being taken, taking the supplements in fasting ormeal conditions, and finally timing, dose and scheduling ofsupplementation. These factors are very interesting becausemost studies focus on the influence of dietary factors on Sebioavailability from supplements such as fibre content,presence of oxalate, phytate, protein, polysaccharides, andamino acids, etc (Lacour et al., 2004). Several studies have beenconducted on the bioavailability of various Se forms (Lacouret al., 2004; Stibilj et al., 2005). In general, animal trialsdemonstrated that bioavailability of organic Se (Se-Met andSe-yeast) was higher than inorganic forms (selenite andselenate). 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 essentialelement depends on its concentration in food and amount offood consumed (Navarro-Alarcon et al., 2005). Combs (2001)indicated that an adequate adult diet should have at least40 μg/day of Se to support the maximum expression of Seenzymes and perhaps as much as 300 μg/day to reduce cancer

risk. Deprivation of Se is associated with reduced antioxidantprotection, redox regulation and energy production as aconsequence of suboptimal expression of one or more of theSe-containing enzymes (Thomson, 2004). At the same time,supranutritional intakes of Se (more than required for Se-Cysenzyme expression) appear to reduce cancer risk (Combs et al.,2001). Hamilton (2004) reported the existence of three Se levelsof biological activity: (1) trace concentrations are required fornormal growth and development; (2) moderate concentrationscan be stored and homeostatic functions maintained; and (3)elevated concentrations can result in toxic effects. Accord-ingly, low Se status is likely to contribute to morbidity andmortality due to infectious as well as chronic diseases, andincreasing Se intakes in all parts of the world can be expectedto reduce cancer rates (Tinggi, 2003). The RecommendedDietary Allowance (RDA) for Se for both men and woman is55 μg/day (0.7 μmol/day) (Food and Nutrition Board—USAInstitute of Medicine, 2000). This recommendation is based onthe amount needed to maximize synthesis of the selenopro-tein glutathione peroxidase (GPx), as assessed by the plateauin the activity of the plasma isoform of this enzyme. TheTolerable 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 selenatesignificantly increased the daily dietary intake of Se from 39 to92 μg per person per day (Varo et al., 1988). In Denmark the Sedietary intake has been estimated to 343 μg/week, and meat,fish, egg, milk, cheese and cereals have been identified as themost important sources (Johansen et al., 2000). Marzec et al.(2002) evaluated the average daily intake of Se in Poland to beless than or near recommended levels, but concluded that Sefood supplements are unnecessary. Several researchers (Sri-kumar et al., 1992; Donovan et al., 1992) revealed thatvegetarians and lactovegetarians significantly decrease dailySe intake, and consequently could induce a deficient Senutritional status. Benemariya et al. (1993) determined thedaily dietary intake of Se in Burundi, Africa as 17 μg, andconcluded that rural populations risk Se deficiency. However,data for most parts of Africa, Southern Asia, and SouthAmerica are scarce or absent. Table 2 shows the daily intakeof Se from selected countries. These data demonstrate thewide variability between countries. But we consider thathealthy individuals with a balanced and varied diet shouldhave an appropriate Se nutritional level and do not need asupranutritional intake of this element.

4. Selenium supplementation

Several authors considered that Se supplementation can bebeneficial for individuals in regions with very low environ-mental 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 popula-tion with sufficient Se:

(1) Use of Se-enriched fertilizers: In order to reach Se RDAs,some countries like Finland, for example, decided in 1984to add sodium selenate to farmlands (Varo et al., 1988).

Table 2 – Estimated Se intakes (μg/day) from selectedcountries

Country Se (μg/day) Reference

Belgium 28–61 Robberecht et al. (1994)Canada 98–224 Gissel-Nielsen (1998)China (Keshan area) 3–11 Dumont et al. (2006)FinlandBefore using Sefertilizer

25 Aro et al. (1995)

After using Se fertilizer 67–110 Anttolainen et al. (1996)Greece 39.3 Pappa et al. (2006)Libya 13–44 El-Ghawi et al. (2005)Lithuania 100 Golubkina et al. (1992)México 61–73 Valentine et al. (1994)Netherlands 67 Foster and Sumar (1997)New Guinea 20 Donovan et al. (1992)Norway 80 Meltzer et al. (1992)Scotland, United Kingdom 30–60 MacPherson et al. (1997)Sweden 38 Dumont et al. (2006)Switzerland 70 Dumont et al. (2006)Spain (South-eastern) 72.6 Díaz-Alarcon et al.

(1996a)Turkey 30 Dumont et al. (2006)United Kingdom 34 Barclay et al. (1995)USA 60–160 Longnecker et al. (1991)


Hartikainen (2005) indicated that this supplement posi-tively affects not only the nutritive value of the entirefood chain (soil to plants to animals to humans) but alsoimproves plant yields. The level of Se addition provedoptimal and no abnormally high concentrations in thefood chain were observed. In fact, plants act as effectivebuffers, because their growth is reduced at high Se levels.They also tend to synthesize volatile compounds in orderto reduce excess Se. Thus, supplementing fertilizers withSe can be considered a very effective and readilycontrolled way to increase the average daily Se intakenationwide. In 1985, the first results were observed,showing increased Se levels inmilk, meat, and eggs from7 to 8, 4 to 5, and 2 to 3 times, respectively (Varo et al.,1988). According to Hartikainen (2005), in meat and meatproducts from Finland, Se increased 13-fold from 1985to1991, and fertilization induced drastic changes in Seconcentrations of agricultural products. For instance, inspring cereals the increase was generally 20–30 foldduring the first years of supplementation. Milk has beenthe most sensitive indicator, and was the first to revealchanges in food quality induced by Se fertilization. Sesupplementation of fertilizers has substantially affectedaverage Se intake. Higher values of total Se intake inJapan, Australia, Finland, and the USA are partly due toSe-enriched fertilizers (Aro et al., 1995; Anttolainen et al.,1996; Dumont et al., 2006). In China, Se supplementationhas beenwidely used to control Keshan and Kashin–Beckdiseases (Tan et al., 1987), even though the latter diseaseprobably is a combined result of deficiencies of two traceelements, Se and iodine. Hartikainen (2005) reported thatthe impact of Se fertilization on the occurrence of humandiseases is difficult to judge. Furthermore, areas withseleniferious soil (concentrationsN1 mg/kg) become

exploited for the production of Se-rich plants meantfor export to other countries. Agricultural products are arather sensitive indicator of available Se in soil (Hartikai-nen, 2005). Experiments with tomatoes have shown thatSe levels can be increased by a factor of 100 by using Se-enriched fertilizer (Aro et al., 1995). Certain fertilizers,however, (sulphate, phosphorus and nitrogen) can lowerSe uptake and modify the synthesis of Se-containingamino acids (Aro et al., 1995). This technology needsfurther investigation since there are no data available onthe effect of Se-fertilizers on microbial population of thesoil (Surai, 2006).

(2) Supplementation of farmanimalswith Se. The need for Se hasresulted in the rise of direct Se enrichment of certainfoods, such as using Se-enriched fertilizer. However,part of the Se in these food products is lost (volatiliza-tion, degradation) during harvesting and manipulationprior to consumption (Dumont et al., 2006). In Australia,subclinical Se deficiency has largely been eliminated asa result of intervention programs which give Se supple-ments to animals. Tinggi (2003) reported a number ofAustralian Se supplement strategies to increase Se infarm animals. These strategies include: a) direct appli-cation of Se to pastures to increase Se uptake by plantsfor animal feed; b) supply of sodium selenite or selenateincorporated into salt blocks or licks; c) direct adminis-tration of Se to animals by drenching with Se saltsolutions such as sodium selenite; and d) the use of Sepellets that slowly release Se in the animal's gut.Recently, a technological process to produce Se-enriched eggs, meat and milk has been developed andsuccessfully introduced in various countries worldwide(Surai, 2006). Indeed, Se-enriched eggs are produced inmore than 25 countries worldwide. Se-pork and Se-milkare on the market shelves in Korea. Such products candeliver 50% RDA of Se with a single egg or portion (80–100 g) of Se-pork or Se-chicken. Recently, a new brand ofSe-enriched eggs called Vi-Omega-3 was developed inGreece delivering 22 μg Se with a single egg (Pappa et al.,2006). Bourre and Galea (2006) described a new naturalmulti-enriched egg as an important source of omega-3fatty acids, vitamins D and E, carotenoids, iodine, andselenium (45% RDA). These authors remarked that theseeggs are beneficial for everyone and particularly appro-priate for older people. Muñiz-Naveiro et al. (2006)indicated that it is possible to obtain Se-enriched cowmilk at different concentrations without altering theoriginal composition of the milk. Lyons et al. (2007)remarked that optimizing Se nutrition for poultry andfarm animals increased efficiency of egg, meat andmilkproduction and, more importantly, improved quality.Recent advances in genomics and proteomics, alongwith newly described selenoproteins, will be a drivingforce in reconsidering old approaches to Se nutrition(Kellof et al., 2000). Grashorn (2006) described theproduction of poultry enriched with conjugated linoleicacid, omega-3 fatty acids and selenium in such a waythat 100 g of enriched tissue provides 3 to 11%, 60 to 70%and/or 200% and 60% of the RDA for humans, respec-tively. However, these authors indicated that some


observed aberrations in meat quality make moreresearch necessary. Detailed investigations on possibleinteractions between other nutrients in Se-enrichedfood are still missing. Several investigations are inprogress by various research groups to measure Sebioavailability and organoleptical properties of foodenhanced by this element (Finley, 2006).

(3) Human intake of multimicronutrient supplements containingSe. During the last decade, the pharmaceutical marketbecame overwhelmed with nutritional supplements or‘nutraceuticals’ based on Se. Two different types can bedistinguished: a) multi-vitamin and multi-mineral pre-parations containing inorganic Se, other trace elementsand vitamins, and b) supplements based on Saccharo-myces cerevisiae yeast. Se-enriched yeast supplementshave been widely studied (Dumont et al., 2006). Sele-nized yeast has been the primary Se dietary supplementand is themost attractive source of Se-Met due to its lowcost and ability to act as a precursor for Se-containingprotein synthesis (Hinojosa et al., 2006). Se-yeast can beconsumed in food or as a nutritional supplement.Another possibility is to use selenized yeast instead ofconventional yeast for baking bread. The use of Se-yeastfor this purpose could result in higher population Seintake since bread is such a commonly consumedproduct. Moreover, Se in Se-yeast is stable even athigher temperatures (Dumont et al., 2006). S. cerevisiaehas a high protein content which improves Se absorp-tion. Mostly, Se is added to the growth medium asNa2SeO3, and Se is mainly incorporated as Se-Met inproteins. S. cerevisiae may assimilate up to 3000 μg Se/g.Moreover, the production of Se-enriched yeast is moremanageable than the production of Se-enriched plants(Dumont et al., 2006). Data on toxicity of Se from Se-yeast are rather scarce (Dumont et al., 2006). Theseauthors remarked that the overall production of Sesupplements urgently needs control because suppliersprovide information on total Se concentration, but littleor no information on the Se species present.

Stibilj et al. (2005) investigated the advertised values of Sein food supplements, and discovered that the differencebetween the advertised and measured Se values varied by10% in 9 out of 13 supplements. Furthermore, 2 of the 14supplements did not comply with the recommendationsstated in the 27th edition of the USA Pharmacopoeia, whichstates that minerals and vitamins in food supplements shouldbe within the range 90 to 200% of the declared value. B'Hymerand Caruso (2000) evaluated six different brands of yeast-based Se food supplements obtained from local stores in theUSA. All Se supplements were found to have near label valuesbased on total Se, and had reasonable uniformity in tablet totablet content. Nevertheless, each brand had dramaticallydifferent profiles for the chemical form of Se present withinthe supplement.

In recent years, our habits have been strongly influenced bypublicity about the necessity of multimicronutrient supple-ments in the normal diet as a method of fortifying inadequatediets with micronutrients such as Se. Different populationgroups are considered a higher risk of deficiency, such as

infants, the elderly, athletes, and healthy people with a highconcern for diet and fitness. There is a belief that physicalactivity increased vitamin and mineral requirements, mainlythose relatedwith the oxidative stress such as Se. This could bean important reason why a majority of athletes ingest largedoses of micronutrient supplements (Navarro-Alarcon andLópez-Martínez, 2000). Additionally, the relationship betweenSe, disease and degenerative pathologies related to aging hasalso contributed to an increase in consumption of supplements.

5. Physiological role of selenium

Selenium is a component of several selenoproteins withessential biological functions (Van Cauwenbergh et al., 2004)(Table 3). This element acts as a cofactor of the GPx family ofenzymes which protect against oxidative stress. Specifically,Se-dependent GPx enzyme recycles glutathione, reducing lipidperoxidation by catalyzing the reduction of peroxides, includ-ing hydrogen peroxide (Fig. 1). In general all these enzymes attheir reduced state catalyse the breakdown of lipid hydroper-oxides and hydrogen peroxides in human cells (Navarro-Alarcon and López-Martínez, 2000; Van Cauwenbergh et al.,2004; Hartikainen, 2005; Navarro-Alarcon et al., 2005). From allthese associated enzymes, GPx and selenoprotein P are alsoinvolved in the regulation of the inflammatory response (VanCauwenbergh et al., 2004).

Moreover, the antioxidative function of Se can help toameliorate the damage induced by the ultraviolet-β radiationin humans. In farm animals diseases associated with Sedeficiency have been an important problem. White muscledisease is a nutritional muscular dystrophy that is the mostcommon Se deficiency disease (Peter and Costa, 1992). Usuallyactively growing animals suffer from this disease, showingsymptoms weakness, problems with feeding, and cardiacimplications that very often produce death. On the other hand,subclinical deficiency levels are associated with poor growth,impairment of animal production, and decrease in immuneefficiency (Peter and Costa, 1992).

On the other hand, the selenoprotein P is a plasma proteinwhose source is the liver and kidney. This protein constitutesthe main plasma Se carrier carrying more than 60% of plasmaSe. Besides, it is known that the protein levels depend on thebody's Se status, such that it has been used as a biomarker ofbody Se content. Particularly, the selenoprotein P acts as anextra cellular antioxidant associated with the vascularendothelium which diminishes the peroxinitrile (ONOO−)level that represents reactive nitrogen specie (Li et al., 2007).

Iodothyronine-50-deiodinases (IDIs) are enzymes that con-vert thehormone tetraiodine thyroxin (T4) to triiodine thyroxin(T3) during the thyroid hormone metabolism (Table 3). Conse-quently, these enzymes are involved in the synthesis ofthyroid sulphated hormones (Navarro-Alarcon et al., 2005).An association between Se status and low plasma T3 levelsshowing diminished IDI function has been reported by severalresearchers (Strain et al., 1997). There exist three types of IDIscalled type I, II and III with different physiological activities:type I ismainly responsible for the T3 levels in the blood streamand is specifically inhibited by the propyl thiomecile. IDI type IIalso participates in the transformation of T4 to T3 when the

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(gastro intestinal), GPx3 (in plasma or extracellular) and GPx4(phospholipid hidroperoxide or intracellular)]

Antioxidant enzymes that protect against the oxidative stress byscavenging of hydrogen peroxide and lipid and phospolipidichydroperoxides. Finally, H202 and a wide range of organichydroperoxides are transformed to water and corresponding alcohols,respectively.

Iodothyronine deidodinases (three isoforms: type I in liver, kidney andthyroid gland; type II in encephalon; and type III inactivant)

Synthesis and metabolic regulation of thyroid sulphated hormones (T3,T4 and T2).

Thioredoxin reductases (also three isoforms) Reduction of intracellular substrates like dehydroascorbic being relatedwith anticancer effects. Specifically it participates in the reduction ofnucleotides in the DNA synthesis as well as in the regulation of geneexpression by redox control of binding of transcription factors to DNA.

Selenoprotein P Extracellular antioxidant associated to the vascular endothelium thatprotects endothelial cells against damage from peroxynitrite.

Selenoprotein W Although it is necessary for muscle function its biological function isstill 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 onecomposed of two Se atoms. Finally the IDI type III catalyses thechange from T4 to inverse T3 and from T3 to T2 protecting thebrain from possible plasma Se concentrations lower than67 μg/l, which have been related to diminished peripheralcapacity 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 intracellularsubstrates (Table 3). When rats were administered consider-ably higher Se amounts than the RDA, their TR activity wasdirectly enhanced (Allan et al., 1999, Thorne, 2003). For someforms of Se at very high doses, the TR enzyme has beenassociated with anticancer effects (Ganther, 1999).

Several studies have also found that Se protects animalsagainst toxicity associated with high exposure and/or intakeof 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 etal., 2007; Mousa et al., 2007). Experimental findings havereported that Se-deficient rodents are susceptible to theprenatal toxicity of methyl mercury. In this sense, importantchanges of selenoenzymes activity, namely GPx and IDIs, havebeen found in neonates (Watanabe, 2001). Kibriya et al. (2007)suggested that long-term Se supplements may revert some ofthe gene expression changes presumably induced by chronicAs exposure in individuals with pre-malignant skin lesions. Inrecent years, genomic and proteomic concerns have beenconsiderably raised. For example, Kibriya et al. (2007) foundthat in one study that many genes, after Se supplementation,were upregulated. However, previously, these authors, insubjects with As induced skin lesions, found the same genesto be down-regulated. Consequently, these findings could helpto define the biological effect of Se supplementation in

humans. Similarly, Mousa et al. (2007) also discovered thatthe pro-angiogenesis action of sodium arsenite or stimulationof basic fibroblast growth factor (b-FGF) was originated by theactivation of the extracellular signal-regulated kinases 1 and 2(ERK-1/2) pathway. However, this pathway was significantlyblocked (pb0.01) by different Se compounds (dimethyl sele-none, diphenyl selenone, sodium selenite or Se-Methyl Se-Cys) demonstrating that pro-angiogenesis As action wasreversed by Se-derived compounds (Mousa et al., 2007).

Wangher et al. (2001) also reported that Se even counter-acts the neurotoxicity of Hg, Cd, Pb and V by amechanism thatcauses their accumulation in the brain, presumably in a nontoxic complex.

6. Assessment of body nutritional status onselenium

When a Se deficiency is established, the activity of Se-dependent enzymes diminishes depending on the enzymetype and body tissue. Of all the enzymes, the activities of theplasmatic and hepatic GPxs are the most dependent on the Sesupply. Therefore, they are employed as evaluation indices ofnutritional Se status. Specifically, GPx appears as 4 isoforms ofwhich the presence of classic or citosolic-GPx in plasma is agood Se status indicator in humans (Persson-Moschos et al.,1995). Additionally, several human fluids and tissues (wholeblood, plasma, serum, hair and toenails) can also be used toassess the nutritional Se status. In fact, in most studies the Sestatus has been assessed by measuring the element either inserum or plasma erythrocytes, platelets or whole blood, andby determining the GPx activity in whole blood or platelets.Recently, levels of selenoprotein P, a Se-rich protein mainlypresent in plasma, have also been used as good Se indicator in

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-phosphatedeshidrogenase. SOD: superoxide dismutase.


human beings (Persson-Moschos et al., 1995). Human nailclippings have also been employed in epidemiological studiesas indicators of Se exposure (Slotnick and Nriagu, 2006). It isbelieved that nail clippings show the exposure that occurredover the past 6 to 12 months. On the contrary, blood and urinearemarkers of shorter exposure periods (Navarro-Alarcon andLópez-Martínez, 2000; Slotnick and Nriagu, 2006). In fact, urineand blood Se levels show recent intake for no longer thanseveral days for urine or several weeks for blood-basedmeasurements, respectively.

From all biomarkers previously reported, blood, plasmaand serum Se levels are usually employed to evaluate Sestatus and intake (Thomson, 2004; Batáriová et al., 2005). Forlong-term Se status, toenails and hair levels are oftenemployed as markers (Mannisto et al., 2000; Slotnick andNriagu, 2006). Collecting them is non-invasive and it is easy tostore samples long-term (Slotnick and Nriagu, 2006). However,highly variable intra hair biology and pharmacokinetics

(Harkins and Susten, 2003) as well as contamination by Se-containing shampoos affect hair sample suitability. Nails, onthe contrary, have less external contamination and growthrates are less variable (Slotnick and Nriagu, 2006).

On the other hand, Se urinary excretion is closelycorrelated with plasma and serum and could be used tomonitor recent dietary intake of Se. Thomson (1998) reportedthat Se urinary excretion constitutes between 50 and 60%of the total amount excreted, so dietary intake could beestimated simply by multiplying by two the daily urinaryexcretion of Se.

Despite everything previously stated, tissue Se concentra-tion may not accurately show functional activity, which variesdepending on the Se specie ingested. Therefore, more accurateand reliable biomarkers of element status should show the Seamounts available for functional selenoproteins (Thomson,2004). In certain circumstances, it is also necessary to concur-rently measure the concentration of several selenoproteins. In


this sense GPx activity (GPx3 and GPx1) (Table 3) is used toassess the effect of different Se species supplementation aswellas monitoring element status in population groups (Zacharaet al., 2006) assuming that maximum enzyme activity is notreached [approximately at 100 μg Se/l of blood (Nève, 1991;Thomson, 2004)]. Taking into account everything previouslystated, platelet GPx seems to be a more sensitive indicator ofincreased Se intake during supplementation trials, showingenhancements in its activity after 1 to 2 weeks. Due to the factthat Se deficiency diminishes levels of selenoproteins, they arebeing used nowadays [namely selenoprotein P, tyroxine (T4) totri-iodothyronine (T3) ratios, TR] to monitor body Se nutritionalstatus (Persson-Moschos et al., 1995; Tinggi, 2003; Thomson,2004; Xi et al., 2005; Karunasinghe et al., 2006). It has beenreported that the use of GPx as an index of Se statusmay not beappropriate (Xi et al., 2005). They also found that the fullexpression of selenoprotein P requires a greater Se dietaryexposure than that for plasma GPx activity. Consequently, Xiet al. (2005) concluded that selenoprotein P is a better indicatorof Se nutritional status. Nevertheless, Wang (2006) stated thatdue to the fact that selenoprotein P does not adequately focus

Table 4 –Mean serum, plasma and whole blood Se levels meas

Population group(age and characteristics)

n (sex) Mean(μg/

Health adult individuals 130 (56 M, 74 F) 74.9±27

General population 126.0Pregnant women 158 F 76.6

Healthy individuals from 6 to 75 years old 395 (187 M, 208 F) 74.7±25

Adult population (20–40 years old) 201 (66 M, 135 F) 100.0

Healthy volunteers aged 19–74 years old 40 (20 M, 20 F) 67.4±38

Healthy adult subject aged 24–45 years old 50 89.5±15

Healthy volunteers (mean age: 39.6 years) 30 (23 M, 7 F) 73.2±9.9

Individuals of the NHANES III (1988–1994) 14,619 (7,102 M,7,517 F)

124.5±0122.0±0

Healthy Caucasian volunteers sampledonce a month during 1 year (23–69 years)

26 (13 M, 13 F) 84.3

Healthy volunteers recruited fromblood donor aged 43.2±1.7 years old

31 (17 M, 14 F) 216.2±7

Healthy individuals aged N16 years old 160 (106 M, 24 F) 100.6±1

Healthy adult blood donorsaged 20–45 years old

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

84.2±20

Elderly women aged 60–70 years old 187 F 92.4±17

Healthy individuals aged 18–65 years old 153 (81 M, 78 F) 85.9±24

Institutionalized elderly peopleaged 60–80 years old

205(80 M, 125 W)

86.2±17

Healthy adult individualsaged 48.5±13.2 years old

50 (25 M, 25 F) 129.0±2

Subjects aged ≥15 year old and that havebeen living in their own for over 5 years

401(128 M, 272 F)

75.0±28

Healthy adult women 41 F 105.0

on the clinical specificities of different Se-responsive diseases,the adoption of selenoprotein P as the principal standard for Sestatus evaluation would not be appropriate. Therefore, biomar-kers should be selected tomatch the characteristics of differentSe-responsive diseases (Wang, 2006).

Table 4 summarizesmean and range of serum, plasma andwhole blood Se levels measured in healthy individuals fromdifferent countries as biomarkers of Se nutritional status ofdefined population groups. As a general tendency, Se con-centrations in serum and plasma were lower in females thanin males but not at a statistically significant level (pN0.05), aswas previously reported (Navarro-Alarcon and López-Martí-nez, 2000; Van Cauwenbergh et al., 2004). Most of the studiescollected in Table 4 (≅63%) reported “normal” Se concentra-tions: serumor plasma Se levels ranging from61–99 μg/l (Nève,1991). Large geographical variation in Se intake due to varyingsoil Se levels has been found, which correlates to the highvariability in Se serum and plasma levels measured indifferent countries. This variability depends on geographicallocation, climatological characteristics like annual rain, Sespecies existing in soils, soil pH, type of plants cultivated, diet

ured in healthy individuals from different countries

Sel)

Se range(μg/l)

Area (country) Reference

.3 30.2–175.0 Granada(South-eastern Spain)

Navarro et al.(1995)

Singapore Hughes et al. (1998)46.2–106.9 Valencia

(Eastern Spain)Ferrer et al. (1999)

.2 7.9–182.3 Canary Islands(Spain)

Díaz-Romero et al.(2001)

35.8–185.6 Mumbai (India) Raghunath et al.(2002)

.6 20.0–129.8 Lower Silesian region(Poland)

Luty-Frackiewiczet al. (2002)

.6 Bydgoszc (Poland) Czuczejko et al.(2003)

56.5–94.5 Rio de Janeiro(Brazil)

Da Cunha et al.(2003)

.2 (M) – USA Kafai and Ganjii(2003).2 (F) –

51.4–121.7 Antwerp region(Belgium)

Van Cauwenberghet al. (2004)

.4 Taiwan (China) Ko et al. (2005)

3.0 75.0–134.0 Tehran (Iran) Safaralizadeh et al.(2005)

.2 b40.0–N120.0 Czech Republic Batáriová et al. (2005)

.4 – Hannover(Germany)

Wolters et al. (2006)

.0 41.7–183.0 Vienna (Austria) Gundacker et al.(2006)

.0 Asturias(Northern Spain)

González et al. (2006)

1.5 Taiwan (China) Lin et al. (2006)

.3 35.2–160.4 Zhou Koudian(China)

Li et al. (2007)

66.4–137.0 Helsingborgh(Southern Sweden)

Rossborg et al. (2007)


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

7. Seleniummetabolism and pharmacokinetics

Although it has been reported that Se metabolism in the bodyis not completely understood, it is known that Se-Cys is themajor selenocompound present in selenoproteins of bodytissues (Sunde, 2000).

The total amount of Se in the human body varies from 10 to20 mg. Fifty percent of body Se is located in the skeletalmuscles, although organs like the kidneys, testes and liverhave the highest relative concentration of Se. On the otherhand, cells that reveal a higher consumption of Se are those ofthe immune system, erythrocytes and platelets. Se is mainlyeliminated from the body by urine, although significant lossesvia faeces also occurs (Burk and Levander, 2002). Additionally,low amounts of Se are lost through the skin and respiration. Itis known that several Se species present in foods are usuallywell absorbed in the gut of human beings (the usualabsorption rate ranges from 50 to 100%) (Sunde, 2000;Navarro-Alarcon et al., 2005).

Se-Met is absorbed by the same active transportmechanismused by methionine because Se can substitute for sulphideatoms due to its similar ionic radius. The selenate is activelyabsorbed by a mechanism common to sulphate, depending onthe Na+ gradient and maintained by the Na+/K+ ATPase. On theother hand, Se-Cys and selenite are not absorbed by activetransport and their capture is not inhibited by similar sulphurcompoundsor bybodySe status (MataixVerduandLlopis, 2002).

Several selenocompounds exist in animal and plant tissues(Fig. 2) (Gammelgaard et al., 2008). Specifically, selenate is themajor inorganic selenocompound found in both animal andplant tissues (Whanger, 2002). On the other hand, Se-Met isthe predominant selenocompound in cereal grains, grassland,legumes and soybeans, and, in some cases, Se-enriched yeast.Finally, Se-methylselenocysteine is the major selenocom-pound in Se enriched plants such as garlic, onions, broccoliflowers 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 methio-nine amino acid during the synthesis of Se-containingproteins (Fig. 2). On the other hand, selenate and seleniteincorporate directly into the Se pool when used in synthesis ofspecific selenoproteins and Se-containing proteins, indepen-dent of their origin (animal or vegetable) (Brody, 1999; MataixVerdu and Llopis, 2002; Navarro-Alarcon et al., 2005).

In general, the human body metabolizes the various Seforms into selenide as HSe− (Fig. 2) which seems to be thecommonpoint for regulating Semetabolism (Brody, 1999; Burkand Levander, 2002; Mataix Verdu and Llopis, 2002; Navarro-Alarcon et al., 2005). It has been found that animals synthesizemany different intermediary metabolites during the conver-sion of inorganic Se to organic forms or vice versa (Ganther,1999). As mentioned above, HSe− ion is a key metaboliteformed from inorganic sodium selenite via selenodiglu-tathione through reduction by thiols and NADPH-dependentreductases and released from Se-Cys by liase action (Bjorn-

stedt et al., 1992). Although the main pathway in animals ismethylation, demethylation back to inorganic Se can alsooccur. Hydrogen selenide (by a previous activation to seleno-phosphate) provides Se for synthesis of selenoproteins(Ganther, 1999). After the catabolism of Se-containing proteinsand, subsequently, component amino acids, the Se of the Se-Met is finally available for its specific use. In this sense, Seentered into the upregulated metabolism and could beincorporated in macromolecules to be transported to otherorgans or even excreted (Burk and Levander, 2002).

Serum and plasma Se levels depend on the Se bioavailablefraction present in diet. In plasma, two selenoproteins havebeen cited as extracellular carriers of Se, namely selenoproteinP and GPx-3. However both of these selenoproteins contain Seas Se-Cys making neither of them likely carriers of Se.Nevertheless, low molecular weight forms of Se have beenidentified as possible Se carriers in plasma. Of all the organs,the liver and kidneys show the highest capacity to accumulatethis element. High Se levels found in the liver counteractmethyl mercury toxicity by facilitating its accumulation asmercuric selenide (Caurant et al., 1996).

Although the mechanism that regulates production ofexcretory metabolites has not still been discovered, urineexcretion has been reported to be the body's mechanism formaintaining Se homeostasis (Mataix Verdu and Llopis, 2002).Therefore, under physiological conditions, Se homeostasis isnot regulated by absorption but rather by urinary excretion(Gammelgaard et al., 2008). Despite this, the transporters,receptors and enzymes involved in the absorption or move-ment of Se across membranes of intestinal cells are generallyunknown (Sunde, 2002).

Intestinal excretion of Se is a secondarypath of elimination.It has also been observed that when the body Se status is low,urinary Se excretion is diminished to keep element home-ostasis in a narrow range, as reported for patients withcardiovascular diseases (Navarro-Alarcon et al., 1999). How-ever, when large amounts have to be excreted, respiration canalso contain volatile Se compounds, usually in the form ofdimethyl selenide (Fig. 2). In a studyof healthymenconfined toametabolic research unit and fed diets naturally high or low inSe,Hawkes et al. (2003) reported that urinary Semeasurementsresponded rapidly to changes in Se intake. These researchersremarked that urinary excretion rose rapidly in the high Segroup, but decreased only with severe Se restriction demon-strating a lowadaptation to Se excretion. Additionally, Hawkeset al. (2003) reported that fecal excretion decreased by half inthe low Se group, a finding that indicates an underappreciatedrole in metabolic adaptation to low Se. Zachara et al. (2006)reported that losses in urine represent 50–78% of the ingestedelement. These researchers also confirmed that the level of Seexcretion in urine was proportional to the level of Se intake.

Various selenocompounds are claimed to be present asurinary Se metabolites such as selenite, selenate, methylse-lenol, mehylselenite, trimethylselenonium ion, Se-Met, sele-nodiglutathione, Se-Cis, selenoethionine, Se-Cys,methylselenomethionine, selenocistamine, selenoadenosyl-Met and selenosgars 1, 2 and 3 (Francesconi and Pannier,2004). Among all of these Se compounds, only the trimethyl-selenonium ion has been found in human urine (Francesconiand Pannier, 2004). Suzuki (2005) and Kuehnelt et al. (2007)

Fig. 2 –Main Se forms in diet and human organism: Se metabolism (adapted from Navarro-Alarcon et al., 2005). 1Although insome vegetables (cereal grains, grassland legumes and soybeans) the Se-Met is themain Se form, however the identification ofselenocysteine in vegetables is still inconclusive. Other Se forms present in vegetals are selenate, selenite, selenocystine,selenomethionine, selenohomocysteine, Se-methylselenocysteine, γ-glutamil-selenocystathionine, selenomethionineselenoxide, 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 inorganicselenocompound followed by selenite. Another organic Se form found in animal tissues is selenotrisulfide of cystine. 3Secompound eliminated in the expired air in element overdosing that originates a typical garlic stink in breath. 4Selenopersulfide.5GS-Seleno-N-acetyl-galactosamine. 6,7,8Se-methylseleno-N-acetylgalactosamine, Se-methylseleno-N-acetylglucosamine,Se-methylseleno- galactosamine, respectively. Additional ways of excretion. 9Trimethylselenonium.10Se-Methylselenocystein. 11γ-glutamil-Se-methylselenocysteine11.



reported that new Se-containing selenosugars are the majorurinary metabolites in humans, the trimethylselenonium ionbeing less significant. Specifically, the metabolite methyl-2-acetamido-2-deoxy-1-seleno-β-D-galactopyranoside (calledselenosugar 2) has been identified (Francesconi and Pannier,2004; Suzuki, 2005). Similarly to that stated above, Kuehneltet al. (2006) found during a Se supplement trial using selenite(200 μg of Se) that selenocompounds are converted byunknown mechanisms into trymethylselenonium and sele-nosugars as urine metabolites in a percentage ranging from 1to 5% and from 20 to 53% of urinary total Se, respectively.Nevertheless, Francesconi and Pannier (2004) concluded thateven though available data shows that selenite, selenosugar 2and selenosugar 3 (methyl 2-amino-2-deoxy-1-seleno-βD-galactopyranoside) constitute three of the typical urinaryspecies, there are still species that remain unknown. Futureresearch is required to determine how factors such asnutritional status and biological and chemical effects influ-ence the type and concentration of Se urinary metabolites(Francesconi and Pannier, 2004).

8. Selenium deficiency

Selenium is an essential mineral in human nutrition closelyassociatedwith the population health. The element essentialityin mammals was not discovered until 1979 due to its over-lapping function with vitamin E (Strain and Cashman, 2002).LowSe intake fromagricultural products has negative effects onhuman health. Serious health consequences have beenreported in low Se areas of China and Eastern Siberia, whereSe deficiency causes endemic Keshan disease in the Keshanregion of China. This pathology is an endemic juvenilecardiomiopathy with myocardial insufficiency that primarilyaffects children aged 2 to 10 years old, and to some extentwomen of child-bearing age (Hartikainen, 2005). This disease iscausedby lowsoil Se levels inKeshan (meanSecontent 0.125μg/g). Consequently, a very lowSe intake fromadiet ofKeshan foodproducts was found, in some cases, lower than 10 μg Se/day.Additionally, Se deficiency in other regions of China caused atype of osteoarthritis called Kashin–Beck disease (Li et al., 2007).This endemic disease is a human rheumatoid state resulting inenlarged joints, shortened fingers and toes and dwarfism inextreme cases (Hartikainen, 2005). In this disease, oxidativedamage attacks cartilage leading to deformation of the bonestructure (Ge and Yang, 1993). Kashin–Beck disease affectschildrenaged from5 to13years old in certain areasof Chinaandthe former Soviet Union. This pathology is amultiple degenera-tion and necrosis of the hyaline cartilage, although Se's role inthe formation of this connective tissue is still unknown.However, the interaction between the metabolism of thyroidhormones and Se can help treat this deficiency (Nève, 1999) inareas where the soil is Se deficient as it occurs in Zaire.

Both endemic diseases are mainly confined to the North-east part of China. The principal characteristics of the zone aredark brown and black soils very low in bioavailable Se aswater-soluble element fractions (Tan et al., 1994). Low Seintake by inhabitants from these areas is caused by insuffi-cient 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+), elementspecie that seems to form strong inner sphere complexes withFe 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 bio-available for plants and its levels increase with the alkalinityof soils (Diaz-Alarcon et al., 1996c).

Supplementation of farmland with Se salts such as sodiumselenite in China and Finland significantly diminished theincidence of disorders reported. This Se supplementationexerted a prophylactic effect, raising from 2 to 8 times the Selevels in milk, eggs, meats, etc. (Hartikainen, 2005). Since 1970,Se in human serum has been periodically monitored inhealthy adults from Finland due to the fact that they wereamong the lowest reported in the world (Hartikainen, 2005). Sesupplemented fertilizers were used which significantlyimproved Se intake and serum Se levels in the Finnishpopulation. 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 Cauwenberghet al., 2004; Hartikainen, 2005).

However, there is a seasonal aspect of Keshan diseasedifficult to explain by considering only Se deficiency. Recentliterature describes a certain non-virulent strain of the poxvirusCoxsackie (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 withKeshandisease, because they usually infectwith this virus type.The genome of the virus strain codifies one GPx, whichapparently serves to protect it against the hydrogen peroxideproduced by the host's leucocytes. An absence of this enzymeaffects the virus genome. Therefore, some of the resultingmutations increase the virus' virulence. As previously stated,this deficiency creates somecardiac pathologies likemyocardialnecrosis by injuring cellular membranes and proteins byoxidative stress. Hartikainen (2005) deduced from animalstudies that Keshan disease produced by dietary Se deficiencyhas a second aetiology of infection by enterovirus. Similarly, forthe Kashin–Beck disease, Se deficiency in diet is probablyassociated with iodine intake (Nève, 1999).

9. Toxicity of selenium

Although RDA and upper limits for Se have been established bythe Food and Nutrition Board-Institute of Medicine (2000),controversy still exists about what Se concentrations should beconsidered adequate but not be toxic (Sunde, 2000). This isbecause Se toxicity depends on the Se compound, method ofadministration, 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 (Gold-haber, 2003) characterized byhair loss, fingernails changes andbrittleness, gastrointestinal disturbances, skin rash, garlicbreath, and abnormal functioning of the nervous system.Other related toxic effects are a disruption of endocrinefunction, synthesis of thyroid hormones and growth hor-mones, and an insulin-like growth factor metabolism. Parti-cularly high levels of dietary Se were significantly associated


with diminished T3 levels, impairment of natural killer cellsand hepatotoxicity (Goldhaber, 2003). Other researchers statethat high Se levels catalyse hydrosulphide oxidation whichexerts an inhibitory effect on protein synthesis or an enhancedrisk of the cancer (Villa Eliaza et al., 1999). These toxicsymptoms are associated with Se intakes of 3200 to 6700 μgSe/day.Milder symptomssuchas fingernail changeshavebeenreported for Se intakes of 1260 μg Se/day (Sunde, 2000). In onestudy of 400 Chinese with Se intakes up to 853 μg Se/day, andanother study of 142 subjects living in high Se areas of SouthDakota and Wyoming with Se intakes up to 724 μg Se/day, noevidence of Se poisoningwas reported (Sunde, 2000). But, otherresearchers did report selenosis with Se intakes of ≥850 μg Se/day. Consequently, the Environmental Protection Agency ofUSA set a reference dose of 5 μg Se/kg/day, taking into accountan epidemiological study of 400 Chinese in which selenosiswas observed in 5. This agency defined 1262 μg Se/day as theelement intake at which clinical selenosis appeared, whichwas related to awhole 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 intakethat is likely to pose no risk of adverse health effects in almostall 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 workerswho manufacture Se rectifiers. Additionally, high accidentalingestion of Se has been related with vomiting, diarrhoea,mottling of the teeth as well as neurological disturbances likeacroparesthesias, weakness, convulsion, etc., (Sunde, 2000;Mataix Verdu and Llopis, 2002; Tinggi, 2003). In any event, thetoxicity of Se depends on many factors like the Se species,amount ingested, age, physiological status, and dietary inter-action 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), highlevels of Se dietary supplements should be considered withcaution. This conclusion correlates with other researcherswho found that Se dietary intakes of about 300 μg Se/day couldhave toxic effects on growth hormone and insulin-like growthfactor-1metabolism, as well as synthesis of thyroid hormones(Kaprara and Krassas, 2006).

10. Bodyseleniummetabolisminseveraldiseases

10.1. Selenium metabolism in hepatopathies

Se deficiency has been associated with hepatocyte damageand necrosis similar to that caused by excessive alcoholconsumption. This effect usually occurs concurrently with lowbody vitamin E concentrations. Therefore, microsomal perox-idation of hepatocytes is induced by the endoplasmic reticulechanges (Simonoff and Simonoff, 1991; Navarro-Alarcon et al.,2002).

However, the pathologic mechanism of liver injury inchronic alcoholic liver disease has not yet been defined(Jablonska-Kaszewska et al., 2003). But, it seems that onepossible mechanism involves free radical reactions which

produce lipid, nucleic acid andproteinperoxidation (Czuczejkoet al., 2003; Pemberton et al., 2005; Czeczot et al., 2006).Specifically, alcohol metabolism in the hepatocytes increasesthe lipidic oxidation of cell membranes provoking a chronictransient state characterized by leukocyte infiltration and arise in collagen formation. In fact, one of the most effectivedefence mechanisms is associated with the activity of severalantioxidative enzymes among which GPx has to be recognized(Pemberton et al., 2005). This enzyme, with Se as significantcofactor, is directly involved in numerous reactions whichprotect the human organism, and specifically liver cells, fromoxidative stress. During the progression of alcoholic hepaticdisease, the liver has an initial steatosis, then it changes tohepatitis and finally, in the last step of this process cirrhosisdevelops. Cirrhosis damage is non-reversible due to intensehepatocyte damage creating loss of liver function, compromis-ing metabolism and overall health (Czeczot et al., 2006).Nevertheless, the pathologic mechanisms are not well under-stood and medical assays have generated controversialresults. However, it is known that alcohol consumptionenhances free radical production and the resulting oxidativestress is directly implied in the disease (Pemberton et al., 2005;Manzanares, 2007). Specifically, ethanol causes microsomalproliferation and reactive oxygen species (ROS) like superoxide(O2">U) andhydrogenperoxide (H2O2) generatedby the ethanol-cytochrome P450 2E1 (CYP 2E1). Additionally, the action ofaldehyde oxidase on acetaldehyde (first metabolite in ethanolmetabolism in the liver) can also produce superoxides. TheseROS, by means of the catalysed Fenton and Harber–Weissreaction, lead to the formation of highly reactive hydroxylradicals (OH">U) which have the capacity to generate 1-hydroxy-ethyl radicals CH3–CH2O· directly from ethanol (Pem-berton et al., 2005). Accumulation of all these alcohol-inducedROS can overwhelm antioxidant defences causing, amongother oxidant actions, peroxidative damage to phospholipidsof membranes. ROS are capable of attacking proteins, poly-saccharides, nucleic acids and polyunsaturated fatty acids,resulting in cellular injury and death (Geoghegan et al., 2006).These oxidant species may also trigger the cytokine releasefrom immune cells, activate inflammatory cascades andincrease the expression of adhesionmolecules. The accumula-tion of granulocytes in organs leads to enhanced generation ofROS that amplifies the inflammatory response and tissueinjury (Geoghegan et al., 2006).

Contrarily, Bonnefont-Rousselot et al. (2006) report thatroutine blood oxidative stress markers are not sensitiveindices of oxidative stress in the liver and are therefore notgood predictive markers of hepatic steatosis. However,Czeczot et al. (2006) remarked that the antioxidant system ofcirrhosis is severely impaired.

Additionally, chronic alcoholics are frequently malnour-ished and consequently suffer insufficient Se supply due todiminished food intake. Since diet is the primary Se source,excessive alcohol consumption which impairs food intakealso limits Se supply (Navarro-Alarcon et al., 2002). Aconstant Se deficiency characteristic of chronic alcoholicswould develop a decrease in GPx activity and, consequently,of catalytic elimination of hyroperoxides otherwise en-hanced by high alcohol intake. As a result, accumulation oftoxic substances in the liver occurs progressively, along

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

Pathology and/orstatus

Group n (sex) Mean Se(μg/l)

Se range(μg/l)

Age(years)

Statisticaldifferencesa

Sampletype

Area (country) Reference

Hepatophathies Cirrhosis group 12 (8 M, 4 F) 41.0±12.4 17.7–61.5 – Yesb Serum Motril (Spain) Navarro-Alarconet al. (2002)Hepatitis group 38 (23 M, 15 F 52.4±15.6. 15.8–80.5 – Yesb Serum

Control group 130 (56 M, 74 F) 74.9±27.3 30.2–175.0 – SerumChronic liverdiseases

Chronic hepatitis C orC virus infection group

59 48.6±11.8 – 54 Yesb Plasma Poland Czuczejko et al.(2003)66.4±14.1 – 54 Yesb Whole blood

Alcoholic, autoimmune orcryptogenic chronic liverdisease group

64 43.0±13.3 – 52 Yesb Plasma58.4±16.6 – 52 Yesb Whole blood

Healthy controls 50 67.4±11.7 – 42 Plasma89.5±15.6 – 42 Whole blood

Chronichepatitis C

Hepatitis group 33 (20 M, 13 F) 159.1±5.3 – 49.5±2.4 Yesc Plasma China Ko et al. (2005)‘‘ ‘‘ 55.1±3.8 – ‘‘ Yesc ErythrocyteControl group 31 (17 M, 14 F) 216.7±7.4 – 43.2±1.7 Plasma‘‘ ‘‘ 139.1±5.8 – ‘‘ Erythrocyte

Alcoholic liverdisease

Cirrhosis group 24 (14M, 10 F) 46.1 31.9–60.6 46.8±10.0 Yesb Serum United Kingdom Pemberton et al.(2005)Control group 49 (21 M, 28 F) 100.6 92.3–105.4 45.7±14.8 Serum

Hepatopathies Non-alcoholic fatty liverdisease group

17 (15 M, 5 F) 114.5±15.8 – 49.5±3.0 No Plasma Paris (France) Bonnefont-Rousselotet al. (2006)

Viral hepatitis group 47 (36 M, 11 F) 90.8±7.1 – 43.5±1.6 PlasmaViral hepaticdiseases

Hepatitis B virus carriersgroup

50 (25 M, 25 F) 124.3±22.6 – 49.9±12.5 No Serum Taiwan (China) Lin et al. (2006)

Chronic hepatitis B group 40 (20 M, 20 F) 123.5±20.4 – 52.1±11.6 No SerumHepatic cirrhosis group 20 (10 M, 10 F) 117.5±25.3 – 56.3±9.5 No SerumHepatocellular carcinomagroup

18 (9 M, 9 F) 108.5±21.8 – 58.5±10.1 Yesc Serum

Control group 50 (25 M, 25 F) 129.0±21.5 – 48.5±13.1 SerumHepatopathies Cirrhosis group 15 (8 M, 7 F) 0.023±0.008d – 39 No Liver tissue Poland Czeczot et al. (2006)

Hepatocellular carcinomagroup

15 (10 M, 5 F) 0.023±0.008c,d – 58 Yesb Livers tissue

Adjacent healthy liver group 15 (10 M, 5 F) 0.031±0.015d – 58 Liver tissue

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Cancer Respiratory cancer group 3 (3 M) 42.6±2.42 39.8–44.2 – Yesb Serum Motril (Spain) Navarro-Alarconet al. (1998)Digestive cancer group 20 (11 M, 9 F) 51.8±26.6 8.85–100.0 – Yesb Serum

Hematological cancer group 15 (9 M, 6 F) 59.5±20.9 21.3–97.9 – Yesb SerumGynecological cancer group 21 (9 M, 12 F) 55.3±27.3 13.2–112.5 – Yesb SerumControl group 130 (56 M, 74 F) 74.9±27.3 30.2–175.0 – Serum

Acutemyocardialinfarction (AMI)

AMI group 36 (14 M, 22 F) 88.4±16.6 – 53 No Plasma France Coudray et al. (1997)Control group 498 (200 M, 298 F) 85.2±15.0 – 65 Plasma

AMI AMI group 683 M 86.8±15.8 – b70 Yesc Whole blood 8 European countriesand Israel

Kardinaal et al. (1997)Control group 729 M 105.8±13.4 – 53 Whole blood

CVD AMI group 32 (27 M, 5, F) 58.7±27.2 21.6–118.5 – Yesc Serum Motril (Spain) Navarro-Alarconet al. (1999)Ischemic cardiopathy

group50 (38 M, 12 F) 55.5±16.7 19.2–86.0 – Yesc Serum

Control group 130 (56 M, 74 F) 74.9±27.3 30.2–175.0 –AMI AMI group 27 63.7±12.0 – – Yesc Plasma Turkey Bor et al. (1999)

‘‘ 0.48±0.04 – – No ErythrocytesControl group 24 (20 M, 4 F) 82.2±14.6 – 51 Plasma

‘‘ 0.51±0.03 – 51 ErythrocytesAMI AMI group 49 53.8±18.3 – – No Plasma Poland Zachara et al. (2001)

‘‘ 71.4±18.2 – – No Whole bloodControl group 58 (35 M, 23 F) 52.5±13.6 – 57 Plasma

‘‘ 73.1±18.1 – 57 Whole bloodMortalitypredictione

Died group 89 F 112.9 109.0–117.6 73.9 Serum Serum Baltimore (USA) Ray et al. (2006)Lived group 543 F 121.6 120.0–124.0 75 Serum Serum Baltimore (USA)

Occurrence ofCV events

Group at baseline 751 (296 M, 456 F) 86.9±15.8 – 65±3 Plasma Nantes (France) Arnaud et al. (2007)Group at the end of thestudy followed for 9 years

751 (296 M, 456 F) 79.0±14.2 – 74±3 Yesb Plasma

aStatistical differences were established when compared Se levels measured in patients with those found in healthy subjects that constitute the control group.bpb0.001.cpb0.05.dSe was measured as μmol Se GPx/min per mg protein.eThe 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%).

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with alcohol toxicity. Czuczejko et al. (2003) found thatdisturbances in antioxidant parameters in the blood ofpatients with chronic liver disease may be the cause of theperoxidative damage of cells.

Several case/control studies of serum, plasma and/orwhole blood Se levels and erythrocyte and/or platelet GPxactivities have been conducted in individuals with differenthepatopathies. A previous review by our research group(Navarro-Alarcon and López-Martínez, 2000) discovered thatin 12 of 13 studies conducted between 1985 and 1998,measured serum or plasma Se levels were significantly lowerthan those of the healthy control group. In this review, sixadditional studies have been discovered (Table 5), four ofwhich report body Se levels significantly lower in patientswith hepatopathies than for healthy subjects. The resultswereindependent of the Se nutritional biomarker employed,namely serum Se (Navarro-Alarcon et al., 2002; Pembertonet al., 2005) plasma and erythrocytes Se (Ko et al., 2005), andplasma and whole blood Se (Czuczejko et al., 2003).

It has also been reported that the reduction of body Selevels are more pronounced with the advance of the disease.Therefore, as hepatitis progresses to cirrhosis, the mostpronounced Se impairment is reached in the final stageswhen the highest liver injury occurs (Navarro-Alarcon et al.,2002). This finding confirms that the severity of liver damageis one of factors affecting the impairment in Se body statusfound in patients with hepatopathies.

However, low peripheral Se levels cannot automatically beconsidered as hepatopathy promoters. In fact, these diminishedSe levels are really the consequence of an impairment of bodymechanisms which control enhanced oxidative stress duringthe genesis and progression of hepatopathies to more severestages likenon-reversible cirrhosis (Navarro-Alarconet al., 2002).

During non-invasive monitoring of oxidative stress in 24alcoholic cirrhosis disease patients, Pemberton et al. (2005)found that the levels of 8-isoprostane and malonaldehyde (asmarkers of lipid peroxidation) were significantly increasedwhen compared with controls (pb0.001). Concomitantly,serum Se GPx, and vitamins A, C and E (as antioxidants)were all significantly diminished (pb0.001). Consequentlythese authors conclude that oxidative stress is a significantfeature of alcoholic cirrhosis as reported for other hepaticdiseases like chronic liver disease (Czuczejko et al., 2003) orhepatocellular 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 existsbetween the appearance of some cardiopathies and low Selevels in the environment, diet, and blood (Navarro-Alarconand López-Martínez, 2000). Extreme dietary deficiencies leadto endemic Keshan and Kashin–Beck disease. Here we review12 serum and plasma Se level studies in patients withcardiovascular diseases (CVDs: myocardial infarction, arterio-sclerosis, congestive heart failure, diverse cardiopathies,cardiomiopathies, arterial hypertension, chronic heart dis-ease, coronary arteriosclerosis and ischemic cardiomiopathy)versus healthy controls. In ten of the studies, Se levels weresignificantly lower than normal (Navarro-Alarcon and López-Martínez, 2000). Additionally, of the five studies showed in

Table 5, only half showed Se biomarker levels were signifi-cantly lower for patients vs. healthy controls (pb0.05). Weiet al. (2004) did a prospective study of serumSe concentrationsand heart disease (HD), stroke, other diseases, and total death.These authors measured baseline serum Se concentrations in1103 individuals from Linxian (China) randomly selected froma larger trial cohort. After examining the relation betweenbaseline serum Se and the subsequent risk of death from HDand stroke over 15 years of follow-up (from 1986–2001). Weiet al. (2004) only found inverse correlation trends between Selevel and death for HD (p=0.07). Contrarily, Lewin et al. (2002)used the human endothelial cell line EAhy 926 to determinethe importance of Se in preventing oxidation damage inducedby test-butyl hydro peroxide or oxidized low density lipopro-tein (LDLox). These researchers showed that cells pre-treatedwith 0.4 nM selenite prior to exposure to 1 μM gold tioglucosewere significantly more resistant to damage from test-BuOOHthan Se-deficient cells. These authors suggested that Sesupplementation, acting through induction of TR and GPxhas the potential to protect the human endothelium fromoxidative damage (Lewin et al., 2002).

In general, these findingsdemonstrate controversial resultsas it still has not been determined if differences are etiologicalor biological consequences of the various cardiopathies.Nevertheless, it has been reported that a serum Se levelb55 μg/l is associated with an increased risk of coronary heartdisease. Moreover, Helmersson et al. (2005) report that low Selevels predict mortality and CVD in some populations. Theseauthors investigated the longitudinal association betweenserum Se and several standard indicators of oxidative stresslike F2-isoprostane and prostaglandin F2α (indicator of cycloox-igenase-mediated inflammation) in a 27 year follow-up ofSwedish men (n=615; 50 years old). Helmersson et al. (2005)concluded that high concentrations of serum Se predictreduced levels of oxidative stress (8-isoprostaglandin F2α) andsubclinical cyclooxigenase-mediated (but no cytokine-mediated) inflammation. Therefore, the association betweenSe, oxidative stress and inflammation may be related to thecardiovascular protective properties of Se (Helmersson et al.,2005)

Ray et al. (2006) performed a 60month longitudinal study of632 women (70–79 years old). They found that high serum Seand carotenoid levels were significantly associated with alower risk of mortality (Table 4). Of the five major causes ofdeath studied, almost half were related to the cardiovascularsystem. HD was the primary cause with 32.6%, and stroke wasin 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 ofan elderly French population, Arnaud et al. (2007) usedmultivariate linear regression models to find the relationbetween plasma Se variability and 11 risk factors (age,education, marital status, smoking, alcohol consumption,obesity, dislipidemia, diabetes, hypertension and personalhistory of CVD). They found that cardiovascular events(p=0.003) and chronic obesity (p=0.02) significantly increasedwith a reduction in plasma Se (Arnaud et al., 2007). By othermeans, Faure et al. (2004) also reported the importance of Sesupplementation in the prevention of CVD in type 2 diabeticpatients. It is known that the enhancement of Se GPx activity


improves the antioxidant system and results in less peroxideformation which is indirectly implicated in the activation ofnuclear factor-kappa B (NF-κB). Activated NF-κB has beenidentified in situ atherosclerotic plaques (Collins and Cybulsky,2001), and has also been linked to development of late diabeticmacro vascular complications in humans. Antioxidants inhi-bit NF-κB activation which, contrarily, is directly activated byhyperglycaemia 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 (pb0.05), reaching thesame level as the non-diabetic control group (n=10).

To the contrary, Navas-Acien et al. (2008) concluded thatcurrent evidence is insufficient to support using Se in the roleof cardiovascular disease prevention. Additionally, theseauthors stated that subjects living in high Se intake regionsshould be aware that Se supplements may increase the risk ofdiabetes and hypercholesterolemia. Navas-Acien et al. (2008)concluded that large, high-quality, randomized controlledtrials (RCTs) and observational studies are needed acrosspopulations with different Se levels intake.

It is known that homocysteine is an emerging risk factor forCVD. Homocysteine is a metabolic product of methyl grouptransfer from the amino acid methionine. After measuringserum Se and plasma homocysteine concentrations in elderlyhumans [n=202; 85 males and 117 females] from Asturias(Northern Spain), Gonzalez et al. (2004) reported that blood Selevels should be considered as a potential factor to lower totalplasma homocysteine. Specifically, they found an indepen-dent inverse association between serum Se and plasmahomocysteine (Gonzalez et al., 2004).

Thomson (2004) reported that despite significant research,the role Se plays in protection against CVD remains incon-clusive. Se protection found in some studies is consistent withan apparent risk threshold of about 79 μg/l in plasma, whichcorresponds with the level required to maximize antioxidantGPx.

Although recent studies provide hopeful results, they donot unequivocally conclude that higher Se intake decreasesrisk for CVD. Although Se shows potential as an antioxidantand its role in prevention of CVD is promising, additional long-term intervention trials are necessary. Therefore, despite itsantioxidant action and its intervention in regulating thehuman immune system, indiscriminate Se supplementationstill cannot be recommended for the prevention of CVDs.

10.3. Selenium metabolism in cancers

Solid evidence based on epidemiological studies conducted inthe last 50 years show an inverse relationship between Seintake and cancer mortality. Thus the anticarcinogenic effectof Se against leukaemia and cancers of the colon, rectum,pancreas, breast ovaries, prostate, bladder, lung and skinseems clear under at least some conditions (Sunde, 2000).Trumbo (2005) after doing an FDA review of the evidence for Seand cancer concluded that some evidence permits a qualifiedhealth claim for Se and cancer. Specifically, of the 36observational studies reviewed, approximately half supportedan association with all cancers. However, the greatestconsistency was noted for breast and prostate cancers

(Trumbo, 2005). Silvera and Rohan (2007) also reportedevidence to support an inverse relationship between Seexposure and prostate cancer risk, and possibly a reductionin risk with respect to lung cancer, although additional studyis needed. Nevertheless, these authors reported that moststudies 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 anda protective element in a cancer prevention diet along withothers like folic acid, vitamin B12, vitamin D, chlorophyll andother antioxidants such as carotenoids. In 2000, our groupreviewed and compared 17 studies measuring Se levels inserum or plasma from patients with different types of cancerand in healthy adult controls (Navarro-Alarcon and López-Martínez, 2000). Fourteen of the studies showed significantlylower Se levels in the cancer patients compared to the controlgroup. Low serum Se also correlates to higher cancer risk.Moreover, Czeczot et al. (2006) found a decrease of the GPxactivity in hepatocellular carcinoma tissue compared toadjacent normal liver tissue. This diminishment might causethe intensification of lipid peroxidation and the enhancementof final peroxidation products such as malonaldehyde (MDA).Concomitantly, increase of MDA levels in cancer tissue wasalso found. Therefore, some researchers recommend Se as anutritional prophylaxis against cancer at a dose of 50 to100 μgSe/day (Simonoff and Simonoff, 1991). Se has also beenrecommended as a co-adjuvant to chemotherapy in cancertreatment at a higher dose of 200 μg Se/day (Simonoff andSimonoff, 1991). This dose is considerably higher than thatnecessary to reach the maximum GPx activity. The antic-arcinogenic effect of Se has been attributed to severalmechanisms: (a) modulation of cell division; (b) metabolicalteration of some carcinogens; (c) cell protection againstoxidative damage by increasing TR activity (Karunasingheet al., 2006); (d) stimulation of the immune system; (e)inhibition of activation of hepatic enzymes whose metabolicactivities enhance the production of toxic substances that leadto cancer genesis.; (f) activation of the detoxifying liverenzymes, etc.

In a study of mortality from oesophageal squamous cellcarcinoma (ESCC) and gastric cardia cancer (GCC) in Linxian(China), a significant inverse relationship between baselineserum Se and death from these cancers was found (pb0.05)(Wei et al., 2004). These researchers found a mean serum Seconcentration of 73 μg/l, which corresponds to the Se amountpresent in maximally expressed plasma selenoproteins and tothe upper limits of GPx responses to Se supplements inhealthy people. On the basis of this criterion, 69% of thesubjects were Se deficient (Wei et al., 2004). They concludedthat population-wide Se supplements in regions of China withlow serum Se and high incidences of ESCC and GCC meritsserious consideration. Concomitantly with this finding, Kim etal. (2005) found that the sera of prostate cancer subjects, afterSe supplementation, exhibited the same proteomic pattern asprostate cancer-free subjects. Contrarily, Peters et al. (2008) ina cohort study of long-term intake of vitamin E and Se (10-yaverage intake) found no relationship with overall prostatecancer risk. Additionally, the risk of clinically significantadvanced prostate cancer was not reduced with long-termSe supplements.


Connelli-Frost et al. (2006) found that high body Se wasassociated with a reduced prevalence of colorectal adenoma.Nevertheless, apoptosis did not seem to be the mechanism bywhich Se was related to adenoma prevalence. They recom-mended future clinical trials for Se as a potential chemopre-ventive agent for colon adenomas and colon cancer. Peterset al. (2006) studied the association of serum Se and advancedcolorectal carcinoma and concluded that Se may reduce therisk of developing advanced colorectal adenoma, particularlyamong the high risk group of smokers.

Other studies have also found a significant Se protectiveeffect against total and prostate cancer incidence in men atdaily dose of 200 μg Se/day via selenized yeast (Duffield-Lillicoet al., 2002). Similarly, Karunasinghe et al. (2006) demonstratedthat 6 months of Se supplements in men at high prostatecancer risk (200 or 400 μg Se/day with selenoyeast) increasedsignificantly TR activity from 0.390±0.050 mU/mg Hb atbaseline to 6.490±0.261 mU/mg Hb by the end of thesupplementation period. However, McNaughton et al. (2005)did a review of 26 studies of human basal cell cancer (BCC) andsquamous cell cancer (SCC) of the skin. These studies werecritically reviewed and confirmed that the evidence forassociation between Se, vitamin E and vitamin C and bothBCC and SCC is weak. These authors concluded that furtherwell-designed and implemented studies are required to clarifythe role of diet Se in skin cancer.

Ferguson et al. (2006) stated that biomarker approachesappear useful in assessing antioxidant activity of dietarycomponents like Se and may provide information relevant tocancer protection. In some studies, it is now questionedwhether the antioxidant properties or other effects of Seprovide cancer protection. Se is significantly accumulated incolorectal polyps (an early stage in colon cancer development)compared to healthy tissues (Alimonti et al., 2008). Thisfinding is probably related to the significant drop in serumSe in patients with gastrointestinal cancers, most of whichwere colorectal cancers (Navarro-Alarcon et al., 1998) (Table 5).

10.4. Influence of selenium supplementation trials on theprevention and progression of some diseases and bodylimitations associated with ageing

Lately, various studies have been performed (Table 6) con-cerning the influence of Se supplementation (alone or withother antioxidant vitamins andminerals) on the prevention ofpathologies associated with oxidative stress and inflamma-tory processes (Tomkins, 2003) like cancer, cardiovasculardiseases, rheumatoid arthritis, hepatopathies, etc. The influ-ence of Se on the loss of body capability due to ageing is alsobeing studied. One study of Chinese men concludes that themaximum dietary Se required to maximize GPx activity is41 μg Se/day (11 μg Se/day from normal dietary intake plus asupplement of 30 μg Se/day as Se-Met). A dose of 53 μg Se/dayis extrapolated for the for the higher body weight of USA andEurope residents (Thomson, 2004). Nevertheless, someresearch proposes that Se intakes higher than recommendedand higher than normal plasma Se concentrations mayprotect against cancer, cardiovascular diseases, hepatopa-thies, 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 ofcancer, cardiovascular diseases, hepatopathies, rheumatoidarthritis and osteoarthritis, etc., (Navarro-Alarcon and López-Martínez, 2000; Navarro-Alarcon et al., 2002; Czeczot et al.,2006; Flores-Mateo et al., 2006).

However, most reviews and studies report no diseaseprevention, protection, or treatment benefits from antioxidantsupplements 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 andmeta-analysis of Se in the prevention of prostate cancerconcluded that Se may reduce the risk of prostate cancer.Nevertheless, these authors are awaiting the results ofongoing larger randomized controlled trials to confirm thesefindings and definitively answer this question. Flores-Mateoet al. (2006) after performing a meta-analysis of Se supple-mentation and coronary heart disease concluded that therandomized trials performed up until now are still incon-clusive. On the other hand, Wei et al. (2004) previouslyreported an inverse association between pre-diagnosticserum Se concentrations and the risk of oesophageal squa-mous cell carcinoma (ESCC) and gastric cardiac cancer (GCC).Additionally, they found significant inverse associationsbetween baseline serum Se and death from ESCC after a 15-year follow-up. These researchers concluded that population-wide Se supplementation in China areas with low serum Seand high incidences of ESCC and GCC merits serious con-sideration. Bleys et al. (2006) did a meta-analysis of rando-mized controlled trials (RCT) (n=16) of the effect of vitamin–mineral supplementation on atherosclerosis progression.Nevertheless, only 2 trials employed antioxidants with Se assupplements. These authors concluded that antioxidantsupplements provide no protection against atherosclerosis,thus providing an explanation for their lack of effect onclinical cardiovascular events (Bleys et al., 2006). Contrarily,Vernardos and Kaye (2007) did a review summarizing the roleof myocardial antioxidant enzymes (GPx and TR). Theseauthors found that dietary Se supplements may provide asafe and convenient method for increasing antioxidantprotection in aged individuals, particularly those at risk ofischemic heart disease or undergoing clinical proceduresinvolving transient periods of myocardial hypoxia (Vernardosand Kaye, 2007).

Other authors (Geoghegan et al., 2006) reported thatpatients with critical illnesseswere supplementedwithwidelyvarying doses of Se (between 200 and 1000 μg) used alone or incombination with other antioxidants. They documented adecrease in the length of hospital stay, rate of infection, andneed or haemodialysis in these patients. Nevertheless, no trialhas demonstrated a statistically significant improvement inmortality, despite a recent meta-analysis suggesting a trendtowards reduced mortality with Se supplementation (Geoghe-gan et al., 2006).

In recent years, genomic and proteomic science is growingrapidly. Because of the need to define the capacity of nutrientslike Se these sciences concern the study of nutrients like Se tofacilitate the up- or down-regulation of specific genes andtherefore toenhanceordiminishproteinsynthesis. 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 andintervention

Antioxidantdose

Results Reference Country

Rheumatoid arthritis Selenium group 28 (7 M, 21 F) 61±13 90-day double-blind,multicentrerandomizedcontrolled trial (RCT)

200 μg Se/day asSe-enriched yeast

For Se group only arm movementand health perception rose significantly(pb0.05) from 6 test points andclinical outcome measurements

Peretz et al.(2001)

BelgiumPlacebo group 27 (7 M, 20 F) 60±13

Rheumatoid arthritis Selenium group 35 58±13 3-month parallelgroup double-blind, RCT

200 μg Se/day assodium selenite

No significant differences were foundfor the 3 test points andclinical outcome measurements

Heinle et al.(1997)

–Placebo group 30 57±13

Precancerousgastric lesions

Antioxidant group 1706 39–69 39-monthdouble-blind, RCT

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

No significant differences in total, cancer,gastric cancer and cardiovascular deathsbetween the placebo and thevitamin–mineral preparation groups

You et al.(2001)

Shandongprovince(China)

Placebo group 1705 35–69

Precancerousgastric lesions

Antioxidant group 1677 35–64 7.3-yeardouble-blind, RCT

250 mg vitamin C,100 IU vitamin E,37,5 μg Se from yeast

No significant favourable effects wereseen or the diminishment of theprevalence of precancerous gastric lesions

You et al.(2006)

Shandongprovince,China

Placebo group 1688 35–64

Nonmelanomaskin cancer

Selenium group 621 10-yeardouble-blind, RCT

200 μg Se/day asSe-enriched yeast

No association between treatmentand the incidence of cancer

Duffield-Lillico et al.(2003)

EasternUSAPlacebo group 629

Prostate cancer Selenium group 32,400 M forselenium andplacebo groups

62.4 7–12 yeardouble-blind, RCT

200 μg Se/day formL-Se-Met and/or400 UI/day vitamin E

Unknown results by the moment Lippman etal. (2005)

USA,PuertoRico andCanada

Placebo group

Men at high prostatecancer risk

Selenium group 29 M 50–75 6-monthdouble-blind, RCT

200 or 400 μg Se/dayas seleno yeast

The TR activity of the supplemental groupmeasured by 80% relative to baseline

Karunasingheet al. (2006)

NewZealandPlacebo group 14 M

Cardiovascular diseaseincidence and mortality

Selenium group freeof cardiovasculardisease at baseline

504(357 M, 147 F)

62.5 7.6-yeardouble-blind, RCT

200 μg Se/day as highSe baker's yeast table

No overall effect of Se supplementation onthe primary prevention of cardiovasculardiseases

Stranges et al.(2006)

California,USA

Placebo group freeof carviovasculardisease at baseline

500(356 M, 144 F)

62.1

Prevention of theprogression ofatherosclerosis

Antioxidant group 79 (71 M, 8 F) 53 3.0-yeardouble-blind, RCT

100 mg vitamin C, 800 IUvitamin E, 100 μg Se,

Change in coronary minimal luminaldiameter

Brown et al.(2001)

USA andCanada

Placebo group 67(60 M, 7 F)

53 25 mg β-carotene

Prevention of theprogression ofatherosclerosis

Antioxidant group 599(300 M, 299 F)

53 7.2-yeardouble-blind, RCT

120 mg vitamin C, 33 IUvitamin E, 100 μg Se,6 mg β-carotene,20 mg zinc

Carotid intima-media thickness Zureik et al.(2004)

France

Placebo group 563(281 M, 282 F)

53

Mood and quality of lifeof elderly individuals

Selenium group 336 60–74 2-yeardouble-blind, RCT

100, 200 or 300 mgSe/day as high Se-yeast

No justification for increasing Se intaketo improve mood in general UK elderlypopulation

Rayman et al.(2006)

UnitedKingdomPlacebo group 112 60–74

Acute alcoholichepatitis

Antioxidant group 36 (20 M, 16 F) 44 6-monthdouble-blind, RCT

Vitamin A, vitamin E, Se,Zn, Mn, Cu, Mg, folic acid,coenzyme Q

Antioxidant therapy alone does notimprove 6-mo survival

Stewart et al.(2007)

UnitedKingdomPlacebo group 34 (18 M, 16 F) 44

Chronic hepatitis Cvirus-infected patients

Selenium group 12 43 6-monthdouble-blind, RCT

500 mg vitamin C. 945IU vitamin E, 200 μgselenium as Se-Met

No consistent differences between groupsor changes of activities from the baselineof the GPx, SOD and catalase enzymes

Groenbaeket al. (2006)

UnitedKingdomPlacebo group 11 45

135SC

IEN

CE

OF

TH

ET

OT

AL

EN

VIR

ON

MEN

T400

(2008)

115–141


Faure et al. (2004) concluded that in type 2 diabetic patients,activationofNF-κβmeasured inperipheral bloodmonocytes canbe reduced by Se supplementation, thus confirming its impor-tance in the prevention of cardiovascular diseases (CVD). In thisSe supplement trial, type 2 diabetic patients (n=48; agerange=49–58 years old) were divided into two groups: 21individuals were supplemented with 960 μg Se/day during3 months and 27 received a placebo (Faure et al., 2004).

The impact of Se on mood and quality of life in the elderlywas studied in a randomized controlled trial by Rayman et al.(2006). These researchers found that there was no evidencethat Se supplementation benefited mood or quality of life inthese elderly volunteers. They stated that the large samplesize and long supplementation period confirms that this is areliable finding. Contrarily, De Yong et al. (2001) reported thatNew Zealand women aged 75±3 years old in the highest thirdof functional capacity index (n=33; plasma Se=77.4±23.7 μg/l)had significantly higher biochemical Se values than those inthe lowest third (64.7±15.0 μg/l). They concluded that sub-optimal trace element levels may be more common amongthose with poor physical function, therefore promotingconsumption of high Se foods or supplements to improve Selevels in elderly women in New Zealand may be beneficial (DeYong et al., 2001).

Consequently, Se supplements should not be recom-mended for the prevention of disease considering that untilnow few randomized controlled trials have been conducted.Randomized trials are inconclusive concerning the effect of Sesupplementation. Therefore, the population should bewarnedagainst the employment of Se supplements for the preventionof hepatopathies, rheumatoid arthritis, cardiovascular orcancer, as the benefits are still uncertain and their indis-criminate use could generate an increased risk of toxicity.

11. Conclusions

In the last two decades there has been much progress in ourknowledgeandunderstandingof thebiological rolesof Seand itsimportance in human nutrition. The current knowledge of theroleofSe inhealthanddisease is important inorder toassess thehealth risk associated with low population Se levels. Diet is themajor source of Se for the general population and its bioavail-ability comesmainly fromSeorganic forms (generallymore than80%). The influence of other dietary factors such as total protein,fat and heavy metal presence, have been also described. Soilcontent clearly determines the food Se content and conse-quently the average total Se intake. High Se values for soil arereflected in high Se concentrations in local animals and plantsand finally in body fluids as biomarkers of the nutritional statusof the population. A widely variability between Se total dietaryintakes among different countries has been found. Despite this,healthy individualswhousually have a balanced and varied dietshouldhave the appropriatenutritional level of Se andhence, donot need a supranutritional intake of this element, with theexception of those living in geographical areas of low environ-mental Se concentrations. Another topic of concern is the effectof technological processing and cooking of food prior toconsumption which generally diminishes Se concentrationdue to volatility and solubility. However, some researchers did

not report any effect of these processes on final Se content infoods and meals. On the other hand few in vivo and in vitrostudieshavebeenconductedon the influenceof food technologyon Se species in prepared food and, consequently, on Sebioavailability. Therefore, we consider that more research isnecessary in the supplementation field in order to have a betterknowledge of the amount of Se biologically available for thehuman organism from Se supplements used nowadays. Effortsto characterize Se species can be subdivided into the analyses ofthe macromolecules (peptides and proteins) and small mole-cules (amino acids, selenate, and selenite) normally associatedwith Se in food (except in regions of low endemic soil Seconcentrations).

Generally, biomarker levels of nutritional Se status dimin-ish significantly in individuals with cardiopathies, hepato-pathies and several cancer types. Nevertheless, it is still notclear if this low Se is a pre-existing factor promoting thedisease's genesis, or is a consequence of the disease itself.Another conclusion is that additional scientific evidence isneeded through large high-quality RCT and observationalstudies with population groups of different Se and healthlevels. In addition to epidemiologic studies, basic scienceresearch is necessary to detect mechanisms and evaluatedisease chemopreventive potential in food Se. Until thatmoment, the efficacy of Se as a disease preventive agent, Sedisease health claim for specific hepatopathies, cardiopa-thies, cancer, rheumatoid arthritis, etc., cannot be condonedand additional study is required. Nowadays, our under-standing of the mechanisms involved in the genesis ofhepatopathies, cardiopathies and different cancers isincreasing rapidly based on new findings in disease-relatedfunctional genomics and proteomics. Therefore, basic andtranslation research using these findings andnew technologywill contribute to the definition of molecular and genomicbiomarkers that can be employed to evaluate disease risk incohorts and surrogate endpoints in clinical studies.

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