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Department of Medicine, University of Liverpool, Liverpool, L69 3GA, UK
2 To whom correspondence should be addressed. E-mail: mjj{at}liv.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • immune function • selenium-dependent enzymes • viral replication
Selenium is as an essential micronutrient for human health (1). Overt selenium deficiency has been associated with dilated cardiomyopathy, skeletal muscle myopathy, osteoathropathy and cretinism (in iodine-deficient populations), and more marginal deficiencies may contribute to reduced immune function, some cancers and viral diseases [reviewed in (2, 3)]. Many of these functions are associated with selenoproteins that specifically incorporate selenocysteine. It has been suggested that up to 100 selenoproteins may exist in mammalian systems, with 25 of these already partially or fully characterized (4).
Particularly intriguing are the data of Beck and colleagues who reported that selenium deficiency influences the virulence of RNA viruses. In selenium-deficient mice, the harmless Pircorna virus coxsackie B3 becomes cardiotoxic (5, 6). When selenium-deficient or glutathione peroxidase knockout mice were inoculated with the benign strain of the coxsackie virus, mutation occurred in the genome to give a cardiovirulent form of the virus that caused myocarditis. This deficiency-driven evolution of pathogenicity was stable, and daughter coxsackie virus isolates from the selenium-deficient mice retained their newly acquired cardiovirulence. The mechanisms are unclear, but may be due to either an increased replication rate of virus in hosts with impaired immunity or to increased free radical damage to the viral genome (5).
The epidemiological and experimental evidence linking selenium levels to cancer is also compelling. Evidence is based on animal studies, inverse geographic correlations between intake and site-specific cancer incidence, an inverse association between serum selenium and subsequent risk of cancer, and additionally some human intervention studies. This possibility has been considered for three decades and subsequently epidemiological, pharmacological and biochemical investigations supported the importance of dietary selenium to the incidence of cancer (7– 12). There are also a number of animal studies in which selenium compounds have shown antitumorigenic activities (11, 13, 14).
Prospective cohort studies also support an association of selenium levels with the incidence of total cancer as well as various specific cancers, including cancers of the lung, prostate, esophagus, gastrointestinal tract and colon. Cancer mortality rates were found to be significantly lower in areas of the U.S. with intermediate or high selenium levels, compared with areas with low selenium levels (15).
The Nutritional Prevention of Cancer (NPC) trial carried out by Clark and co-workers (12) in the U.S. was a double-blind, placebo-controlled intervention trial in a Western population, designed to test the hypothesis that selenium supplementation could reduce the incidence of cancer. Previous trials in China had given selenium in combination with other nutrients and this trial was the first to evaluate the effects of supplementation with selenium alone in a generally well-nourished U.S. population. These investigators carried out a long-term, double-blind, placebo-controlled study on 1312 individuals, and found that supplementation with 200 µg of selenium per day reduced the incidence of prostate, colorectal and lung cancer by 63%, 58% and 45%, respectively; total cancer mortality was lowered by 50% and total cancer incidence by 37%. Furthermore, they showed that the greatest effect of selenium supplementation was again seen in those individuals whose plasma selenium level was low, below 106 µg/L at the beginning of the trial. In this group, selenium supplementation reduced the risk of cancer by 48%. This trial was conducted in regions of the U.S. where dietary intake is estimated to be 90 µg/d.
Dietary intakes of selenium in the UK are falling
Dietary selenium intakes in the UK have fallen over the last 20 years and recent surveys indicate that the average selenium intake may be as low as 30–40 µg/d (2). Table 1 shows the estimated intake of the UK population since 1974 (16, 17). Current dietary selenium intakes are well below national recommended daily intakes; the UK RNI is 75 µg/d for adult men and 60 µg/d for women. The U.S. recommendation is 55 µg/d for both sexes. The UK intakes are also below those that are found in many other countries such as the U.S. where values ranging 90–250 µg/d have been reported. Specific subgroups of the population may have even lower intakes with vegetarians and the elderly particularly at risk. It is well known that a variety of social and physiological factors may lead to a generalized reduction in food intake and nutrient absorption in the elderly in comparison with young subjects. For nutrients that are present in excess in the diet, this probably has little functional consequence, but in the presence of an already diminished intake of selenium, it may precipitate a body lack of the nutrient. Where studies of the selenium status of elderly subjects have been undertaken, the majority indicate that selenium levels are reduced in the elderly in comparison with young subjects (18– 22), although these are not universal findings (23). Studies of the selenium status of elderly patients with cancer indicate that their serum selenium levels are further depressed (24), although this is not specific to cancer with similar reductions reported in elderly patients with other chronic disorders. In a review of the literature, Richard and Roussel (25) concluded that selenium supplementation in the elderly reversed the biochemical changes associated with selenium lack in all reported studies, and Oliveiri and colleagues (21) presented evidence that the reduction in selenium levels in the elderly had functional consequences. The most recent survey of plasma selenium concentrations in over 1000 elderly subjects in the UK indicated that the mean was 0.9 µmol/L, well below the levels seen 25 years ago (26).
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Relatively few studies have examined the potential effect of repletion of UK selenium intakes to those seen in other countries. Brown and co-workers examined the effect of small selenium supplements on the activity of selenium-dependent enzymes and found an overall increase in activity, although the responses were very variable (27). Whether these biochemical changes are associated with functional changes is currently unclear, although preliminary data from our laboratory indicate that significant changes in immune function accompany an increase in selenium status (28). These data are in line with previous studies that showed selenium supplementation leads to changes in various immune parameters. These included an increased ability of lymphocytes to respond to mitogen, generate cytotoxic lymphocytes, destroy tumor cells, and to stimulate B- and NK-cells. Cytotoxic T cells (CTL) are considered one of the primary effector cell populations in antitumor immunity. Recent studies, however, have demonstrated the critical importance of helper T cells (Th), specifically interferon-
secreting Th1 cells, either by supporting an appropriate CTL environment or by recruiting other effector cells (29).
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Rayman, M. P. (2000) The importance of selenium to human health. Lancet 356: 233–234.[Medline]
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10. Combs, G. F., Jr. (1995) Selenium and cancer. In: Biochemistry and Molecular Biology of Selenium (Wang, Z., ed.). Chinese Academy of Medical Sciences, Bejing.
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13. Burke, K. E., Combs, G. F., Jr., Gross, E. G., Bhuyan, K. C. & Abu-Libdeh, H. (1992) The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation. Nutr. Cancer 17: 123–137.[Medline]
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16. Ministry of Agriculture, Fisheries and Foods. (1999) Total diet study – Aluminium, arsenic, cadmium, chromium, copper, lead, mercury, nickel, selenium, tin and zinc. Food Surveillance Information Sheet no. 191. HMSO.
17. British Nutrition Foundation. (2001) Selenium and Health. British Nutrition Foundation, London.
18. Kivela, S. L., Maenpaa, P., Nissinen, A., Alfthan, G., Punsar, S., Enlund, H. & Puska, P. (1989) Vitamin A, vitamin E and selenium status in an aged Finnish male population. Int. J. Vitam. Nutr. Res. 59: 373–380.[Medline]
19. Berr, C., Nicole, A., Godin, J., Ceballos-Picot, I., Thevenin, M., Dartigues, J. F. & Alperovitch, A. (1993) Selenium and oxygen-metabolizing enzymes in elderly community residents: a pilot epidemiological study. J. Am. Geriatr. Soc. 41: 143–148.[Medline]
20. Olivieri, O., Stanzial, A. M., Girelli, D., Trevisan, M. T., Guarini, P., Terzi, M., Caffi, S., Fontana, F., Casaril, M. & Ferrari, S. (1994) Selenium status, fatty acids, vitamins A and E, and aging: the Nove Study. Am. J. Clin. Nutr. 60: 510–517.
21. Olivieri, O., Girelli, D., Azzini, M., Stanzial, A. M., Russo, C., Ferroni, M. & Corrocher, R. (1995) Low selenium status in the elderly influences thyroid hormones. Clin. Sci. (Lond.) 89: 637–642.[Medline]
22. Chapman, K. M., Ham, J. O. & Pearlman, R. A. (1996) Longitudinal assessment of the nutritional status of elderly veterans. J. Gerontol. A Biol. Sci. Med. Sci. 51: B261–B269.[Abstract]
23. Campbell, D., Bunker, V. W., Thomas, A. J. & Clayton, B. E. (1989) Selenium and vitamin E status of healthy and institutionalized elderly subjects: analysis of plasma, erythrocytes and platelets. Br. J. Nutr. 62: 221–227.[Medline]
24. Navarro-Alarcon, M., Lopez-Ga de la Serrana, H., Perez-Valero, V. & Lopez-Martinez, M. C. (2002) Selenium concentrations in serum of individuals with liver diseases (cirrhosis or hepatitis): relationship with some nutritional and biochemical markers. Sci. Total Environ. 291: 135–141.[Medline]
25. Richard, M. J. & Roussel, A. M. (1999) Micronutrients and ageing: intakes and requirements. Proc. Nutr. Soc. 58: 573–578.[Medline]
26. Bates, C. J., Thane, C. W., Prentice, A. & Delves, H. T. (2002) Selenium status and its correlates in a British national diet and nutrition survey: people aged 65 and over. J. Trace Elem. Med. Biol. 16: 1–8.[Medline]
27. Brown, K. M., Pickard, K., Nicol, F., Beckett, G. J., Duthie, G. G. & Arthur, J. R. (2000) Effects of organic and inorganic selenium supplementation on selenoenzyme activity in blood lymphocytes, granulocytes, platelets and erythrocytes. Clin. Sci. (Lond.) 98: 593–599.[Medline]
28. Broome, C. S., McArdle, F., Kyle, J. A. M., Andrews, F., Hart, C. A., Arthur, J. R. & Jackson, M. J. (2002) Functional effects of selenium supplementation in healthy UK adults. Free Radic. Biol. Med. 33: S261.
29. McKenzie, R. C., Rafferty, T. S. & Beckett, G. J. (1998) Selenium: an essential element for immune function. Immunol. Today 19: 342–345.[Medline]
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