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Department of Human Nutrition, University of Otago, Dunedin, New Zealand
2To whom correspondence should be addressed. E-mail: tim.green{at}stonebow.otago.ac.nz
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • homocysteine • selenium supplements • human • glutathione peroxidase • randomized-controlled trial
Plasma total homocysteine (tHcy)3 is determined by genetic, lifestyle and nutritional factors (1
,2
). Although folate, vitamin B-12 and vitamin B-6 are major nutritional determinants of plasma tHcy (3
), other nutrients such as riboflavin (4
) and choline (5
) may also be important. Selenium-deficient rats have lower plasma tHcy concentrations than selenium-adequate rats (6
,7
). Recently, Uthus and co-workers (8
) reported low plasma tHcy concentrations in rats fed a low selenium diet, and tHcy increased incrementally as selenium was added to the diet up to a level of 0.05 µg selenium/g diet. The relevance to humans of these findings in animals is unknown. Nevertheless, the animal studies raise an issue of whether selenium supplementation increases tHcy in humans. An elevated tHcy concentration has been associated with an increased risk of vascular disease (9
), Alzheimer’s disease (10
) and neural tube defects (11
). On the other hand, suboptimal selenium status has been suggested to reduce resistance to infectious diseases and to increase cancer and cardiovascular disease risk (12
). In Western countries where selenium intake is low, fortification has been suggested, and in Finland selenium has been added to fertilizer to protect the Finnish population from the negative effects of a low selenium intake (13
). Any effect of selenium supplementation on plasma tHcy should be most apparent in a population where selenium intake is marginal. Mean plasma selenium levels in New Zealand are typically below the level required for saturation of the selenium-dependent enzyme glutathione peroxidase (Gpx) (14
,15
). Here we present the results of a 20-wk placebo-controlled trial conducted to determine the effect of selenium supplements on homocysteine concentrations in a group of healthy New Zealanders.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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A convenience sample of 189 participants (18–64 y) was recruited from Dunedin, New Zealand. Users of selenium supplements were not eligible to participate. The Human Ethics Committee of the University of Otago approved the study and participants gave written informed consent.
Study design.
The study was a 20-wk placebo-controlled trial. Participants were randomized by sex and assigned to receive daily a placebo or a supplement containing 200 µg selenium as selenomethionine (Pharma Nord, Vejle, Denmark). The supplement and placebo were identical in taste and appearance. Fasting blood samples were drawn at baseline and at 20 wk. Compliance was assessed by counting returned supplements and from completed diary forms.
Biochemical analyses.
Blood was collected in tubes containing EDTA. Plasma was separated within 2 h of collection by centrifugation (1600 x g for 15 min at 4°C). Plasma tHcy and plasma folate were determined on an Abbott IMX analyzer (Abbott Laboratories, Abbott Park, IL) with a between-run CV of <8% for both assays based on the manufacturer’s control samples. Plasma selenium was determined using flow-injection hydride generation atomic absorption spectrometry (AAS) (Perkin–Elmer Model 3100; Perkin Elmer Cetus Instruments, Norwark, CT) (16
), with a between-run CV of 6%. Plasma Gpx activities were measured using a coupled-enzyme procedure with glutathione reductase (17
,18
), automated on the Cobas Fara autoanalyzer with a between-run CV of 10% (Roche Diagnostic Systems, Somerville, NJ). Plasma protein was measured by the standard Biuret method (19
).
Statistics.
Baseline characteristics between treatment groups were compared using a one-way ANOVA for continuous variables and chi-square analyses for categorical variables. Response to the treatments was calculated for each subject as the difference in plasma tHcy, folate, selenium, and Gpx activities between wk 20 and baseline. One-way ANOVA was used to test treatment response. The analyses were conducted using Version 10 of SPSS for Macintosh software (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Sixty-six percent (n = 110) of participants were female. Compliance was high in both groups, with over 90% of participants consuming >90% of their supplements. The mean plasma selenium concentration of the participants at baseline was 1.1 ± 0.2 µmol/L. Two thirds of the participants had plasma selenium concentrations < 1.2 µmol/L, a concentration believed to be around that necessary for full Gpx activity (14
,15
).
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. At 20 wk, plasma selenium concentration increased in the selenium group by 1.2 µmol/L (95% CI: 1.1, 1.3), an amount that was greater than the change in the placebo group (P < 0.001). Gpx activity increased in the supplemented group by 5.1 nkat/g protein (95% CI: 3.7, 6.5). This increase was greater than the change in the placebo group (P < 0.001). There were no differences in the changes in plasma tHcy (P = 0.54) or plasma folate (P = 0.17) between the selenium-treated and placebo groups. Further, there was no difference in the change in plasma tHcy (P = 0.43) between the selenium-treated and placebo groups when the analysis was restricted to participants with a baseline plasma selenium concentration < 1.2 µmol/L.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Our findings are in contrast to a study in rats, in which supplementing rats with selenium raised plasma tHcy concentrations (8
). The lack of an effect of selenium supplements on plasma tHcy in humans may be attributable to a threshold effect. In rats, plasma tHcy increased incrementally as selenium was added to the diet up to a level of 0.05 µg selenium/g diet. However, increasing dietary selenium from 0.05 to 0.1 µg selenium/g diet did not result in a further increase in plasma tHcy (8
). This threshold effect in rats may be related to plasma selenium concentrations required to maximize activity of selenium-dependent enzymes such as Gpx and 5'-deiodinase (Type I). If there is a threshold in humans, then it must occur at a mean plasma selenium concentration < 1.2 µmol/L. However, it is possible that tHcy could be influenced by selenium status in populations with a very low selenium intake, such as in parts of China (21
). In conclusion, our findings show that selenium supplementation does not influence plasma tHcy concentrations in healthy populations in developed countries, whose selenium status is characterized by lower plasma selenium concentrations.
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FOOTNOTES |
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3 Abbreviations used: CI, confidence interval; Gpx, glutathione peroxidase; tHcy, total homocysteine.
Manuscript received 23 September 2002. Initial review completed 22 October 2002. Revision accepted 26 October 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Nygard, O. (1998) Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am. J. Clin. Nutr. 67:263-270.[Abstract]
2. Saw, S. M., Yuan, J. M., Ong, C. N., Arakawa, K., Lee, H. P., Coetzee, G. A. & Yu, M. C. (2001) Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore. Am. J. Clin. Nutr. 73:232-239.
3. Selhub, J., Jacques, P. F., Wilson, P. W., Rush, D. & Rosenberg, I. H. (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J. Am. Med. Assoc. 270:2693-2698.[Abstract]
4. Jacques, P. F., Kalmbach, R., Bagley, P. J., Russo, G. T., Rogers, G., Wilson, P. W., Rosenberg, I. H. & Selhub, J. (2002) The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J. Nutr. 132:283-288.
5. Brouwer, I. A., Verhoef, P. & Urgert, R. (2000) Betaine supplementation and plasma homocysteine in healthy volunteers. Arch. Intern. Med. 160:2546-2547.
6. Davis, C. D., Uthus, E. O. & Finley, J. W. (2000) Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. J. Nutr. 130:2903-2909.
7. Davis, C. D. & Uthus, E. O. (2002) Dietary selenite and azadeoxycytidine treatments affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells. J. Nutr. 132:292-297.
8. Uthus, E. O., Yokoi, K. & Davis, C. D. (2002) Selenium deficiency in Fisher-344 rats decreases plasma and tissue homocysteine concentrations and alters plasma homocysteine and cysteine redox status. J. Nutr. 132:1122-1128.
9. Ford, E. S., Smith, S. J., Stroup, D. F., Steinberg, K. K., Mueller, P. W. & Thacker, S. B. (2002) Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int. J. Epidemiol. 31:59-70.
10. Seshadri, S. A., Beiser, A., Selhub, J., Jacques, P., Rosenberg, I., D’Agostino, R. B., Wilson, P.W.F. & Wolf, P. A. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 346:476-483.
11. Vollset, S. E., Refsum, H., Irgens, L. M., Emblem, B. M., Tverdal, A., Gjessing, H. K., Monsen, A. L. & Ueland, P. M. (2000) Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am. J. Clin. Nutr. 71:962-968.
12. Rayman, M. P. (2000) The importance of selenium to human health. Lancet 356:233-241.[Medline]
13. Varo, P., Alfthan, G., Ekholm, P., Aro, A. & Koivistoinen, P. (1988) Selenium intake and serum selenium in Finland: effects of soil fertilization with selenium. Am. J. Clin. Nutr. 48:324-329.
14. Thomson, C. D., Robinson, M. F., Butler, J. A. & Whanger, P. D. (1993) Long-term supplementation with selenate and selenomethionine: selenium and glutathione peroxidase (EC 1.11.1.9) in blood components of New Zealand women. Br. J. Nutr. 69:577-588.[Medline]
15. Duffield, A. J., Thomson, C. D., Hill, K. E. & Williams, S. (1999) An estimation of selenium requirements for New Zealanders. Am. J. Clin. Nutr. 70:896-903.
16. Tiran, B., Tiran, A., Rossipal, E. & Lorenz, O. (1993) Simple decomposition procedure for determination of selenium in whole blood, serum and urine by hydride generation atomic absorption spectroscopy. J. Trace Elem. Electrolytes Health Dis. 7:211-216.[Medline]
17. Thomson, C. D., Rea, H. M., Doesburg, V. M. & Robinson, M. F. (1977) Selenium concentrations and glutathione peroxidase activities in whole blood of New Zealand residents. Br. J. Nutr. 37:457-460.[Medline]
18. Paglia, D. E. & Valentine, W. N. (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 70:158-169.[Medline]
19. Gornall, A., Bardawill, C. & David, M. (1949) Determination of serum proteins by means of the Biuret reaction. J. Biol. Chem. 177:751-766.
20. Vadhanavikit, S. & Ganther, H. E. (1993) Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. J. Nutr. 123:1124-1128.
21. Diplock, A. T. (1993) Indexes of selenium status in human populations. Am. J. Clin. Nutr. 57:256S-258S.
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