Plasma selenoprotein P levels of healthy males in different selenium status after oral supplementation with different forms of selenium

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1 European Journal of Clinical Nutrition (1998) 52, 363±367 ß 1998 Stockton Press. All rights reserved 0954±3007/98 $ in different selenium status after oral supplementation with different forms of selenium M Persson-Moschos 1, G Alfthan 2 andbaê kesson 1 1 Department of Applied Nutrition and Food Chemistry, Center for Chemistry and Chemical Engineering, PO Box 124, University of Lund, S Lund, Sweden and 2 Department of Nutrition, National Public Health Institute, FIN Helsinki, Finland Objective: To assess changes in selenoprotein P levels in plasma from subjects who had received oral supplements of different selenium forms. Design: The same study group participated in two similar selenium supplementation trials, Trial I in 1981 (Levander et al, 1983) and Trial II in 1987 (Alfthan et al, 1991). During Trial II the mean baseline intake of selenium in Finland was higher compared to that during Trial I (100 and 40 mg/d, respectively), due to a nationwide supplementation of fertilisers which started in Subjects: Fifty healthy Finnish men, 36±60 y old. Intervention: The study group received daily placebo or oral supplements consisting of 200 mg selenium as selenium-enriched yeast, sodium selenate or selenium-enriched wheat (Trial I) or selenium-enriched yeast, sodium selenate or sodium selenite (Trial II). The duration of supplementation periods was 11 (Trial I) and 16 (Trial II) weeks. Results: In Trial I the mean plasma selenoprotein P values in all the supplemented groups increased signi cantly, approaching a plateau at 2 weeks and reaching maxima at 4 weeks (mean increase 34%, P < 0.05). In Trial II the mean selenoprotein P levels of the supplemented groups were not signi cantly different from each other or from the placebo group at the start or at any time point of the supplementation period. Conclusions: At a low selenium status the selenoprotein P levels increased in a similar fashion after supplementation with different forms of selenium, but at a high selenium status no signi cant effects of supplementation with the same amount of selenium were observed. No differences in selenoprotein P levels were observed for inorganic and organic selenium supplements. Sponsorship: This study was supported by The Swedish Council for Forestry and Agricultural Research, the PaÊhlsson Foundation and the Swedish Nutrition Foundation. Descriptors: selenoprotein P; healthy men; selenium supplementation; selenium forms; selenium status Introduction Several chemical forms of selenium are present in the diet, and the major forms are probably the selenium-containing amino acids selenocysteine and selenomethionine bound in proteins. Selenomethionine is likely the dominating form in vegetables, while proteins of animal foods contain both selenomethionine and selenocysteine in varying proportions (Burk, 1986). The inorganic forms selenite and selenate are used in supplements but it is not certain if they occur in foods. Uncharacterised forms occur as well; for instance unknown low molecular-weight selenium compounds were demonstrated in sh (A Ê kesson & Srikumar, 1994). In mammalian tissue the major functional form of selenium is selenocysteine in the primary structure of selenoproteins. At least ten different selenoproteins have been identi ed in mammals. Their concentrations in tissues are dependent on the dietary intake of selenium (Chen et al, 1990; Behne et al, 1991; Marchaluk et al, 1995). The major selenoprotein in human plasma is selenoprotein P, which accounts for about 40% of the total plasma selenium (A Ê kesson et al, 1994; Hill et al, 1996). Its concentration in Correspondence: Dr M Persson-Moschos. Received 2 November 1997; revised 26 January 1998; accepted 31 January 1998 plasma re ects the selenium status in healthy subjects (Marchaluk et al, 1995; Persson-Moschos et al, 1995a; Hill et al, 1996) as well as in patients with low selenium status (Persson-Moschos et al, 1995b; Rannem et al, 1996). Selenoprotein P is a selenium-rich protein, which contains up to ten selenocysteine residues per polypeptide chain, compared to one selenocysteine residue in other characterised selenoproteins. The function of selenoprotein P is unclear, but it is expressed by several tissues and it may serve as an extracellular oxidant defence (Burk & Hill, 1994). Since the level of selenoprotein P may be related to susceptibility to oxidant-induced disease, it is important to know how it is in uenced by different forms of dietary selenium. In this study, selenoprotein P was measured in plasma samples from subjects who had received oral supplementation of different forms of selenium. Two similar supplementation trials have been carried out, and in the second one the same subjects had acquired a higher selenium status through the nation-wide selenium supplementation of fertilisers in Finland (Aro et al, 1997). Methods Study group As described in previous reports (Levander et al, 1983; Alfthan et al, 1991) the study group consisted of healthy

2 364 Finnish men, aged 36±60 y. Fifty men were recruited for the rst supplementation study during 1981±1982 (Trial I) and the same subjects except ve also participated in the second study (Trial II) six years later, when they were divided into the same supplementation groups as before. The mean daily dietary intake of selenium of adults increased from approximately 40 mg in 1981 to 100 mg in 1987 as a result of the country-wide supplementation of fertilisers with selenium starting in Finland in 1985 (Aro et al, 1997). The subjects were divided into one placebo group (n ˆ 15 and 20, respectively) and three treatment groups (n ˆ 10 for each) that received 200 mg selenium per day as seleniumenriched yeast, sodium selenate or selenium-enriched wheat (Trial I) or selenium-enriched yeast, sodium selenate or sodium selenite (Trial II). For analysis of selenoprotein P, plasma samples from Trial I were available at the time points 0 (before intervention), 2, 4, 7 and 11 weeks (supplementation period), and 21 weeks (10 weeks after the end of supplementation period). From Trial II plasma samples at the time points 0 (before intervention), 4, 7 and 16 weeks (supplementation period) were available. Data on plasma and erythrocyte selenium, and plasma and platelet glutathione peroxidase activity were available from previous studies (Levander et al, 1983; Alfthan et al, 1991). Methods Selenoprotein P levels in the plasma samples were measured with a radioimmunoassay (Persson-Moschos et al, 1995a), and the concentration of selenoprotein P was expressed in arbitrary units (au) relative to a standard of pooled plasma. The intra-assay coef cient of variation (cv) was 3.8% and the inter-assay cv was 6.6%. The standard deviations of mean selenoprotein P values of all groups in Trial I varied from 0.09±0.24 au, and in Trial II the s.d. varied from 0.16±0.35 au. Statistics Differences between selenoprotein P mean levels in different groups and their changes after selenium supplementation were evaluated by one-way ANOVA followed by Bonferroni's test and Duncan's multiple range test. P- values < 0.05 were considered statistically signi cant. Correlations were assessed by Pearson's two-tailed signi cance test. The statistical analysis were performed by using SPSS 6.1 for Windows (SPSS Inc, 1994). Results In Trial I the mean levels of selenoprotein P in the supplemented groups (yeast, selenate and wheat) increased signi cantly in a similar way and approached a plateau already after two weeks of supplementation (Figure 1; Table 1). The supplemented groups reached their maximal selenoprotein P value at 4 weeks (1.4 (0.1) au) (mean (s.d.)). The selenoprotein P levels among the supplemented groups were not signi cantly different from each other at any time-point, except at 21 weeks when the group supplemented with selenate had signi cantly lower levels than the group that received yeast (P < 0.05 in Duncan's test) (Figure 1). The more rapid post-supplementational decline in selenoprotein P level in the selenate group is most probably explained by the higher tissue amounts of unspeci cally incorporated selenium which had accumulated in the subjects given organic selenium. During the post-supplementation period more selenium was thus liberated during protein turnover in the subjects given organic selenium than in those given selenate and to some extent utilized for selenoprotein synthesis. The mean selenoprotein P level of the placebo group stayed constant throughout the supplementation period, but in the postsupplementation period it increased by 21% from 11±21 weeks (P < 0.05). The most plausible explanation of this phenomenon is that selenium-rich grain was imported during this period and the selenium intake of the subjects was increased accordingly (Levander et al, 1983; Mutanen & Koivistoinen, 1983), although unknown factors may also be involved. In Trial II the study group had acquired a higher selenium status and the mean concentration of selenoprotein P at baseline (0 weeks) was 74% higher than in Trial I (1.8 (0.3) and 1.0 (0.2)) au, respectively (Figure 1). The Figure 1 Changes in selenoprotein P levels in plasma from healthy Finnish men that had received different forms of selenium supplements (200 mg selenium/d) in two previous studies, Trial l in 1981±1982 (Levander et al, 1983) and Trial II in 1987 (Alfthan et al, 1991). In Trial II the subjects had acquired a higher selenium status through a nation-wide selenium supplementation of fertilisers starting in Supplementation was started at week 0 and stopped at week 11 (Trial I) or at week 16 (Trial II). Each symbol represents the mean selenoprotein P value of nine to twenty subjects (Trial I) or of nine to fteen subjects (Trial II). The standard deviations of mean selenoprotein P values of all groups in Trial I varied from 0.09±0.24 au (arbitrary units), and in Trial II the SD varied from 0.16±0.35 au.

3 Table 1 Percentage change in selenium status variables of healthy men after supplementation with different selenium forms Selenium forms 365 Selenium status variable Wheat Yeast Selenate Selenite Placebo Trial IÐ% change from 0±11 weeks P-Se a. 139***. 144***. 66*** Ð. 10 RBC-Se a. 111***. 113***. 19* Ð. 6 P-GSHPx a. 15*. 10**. 16 Ð. 5 Plat-GSHPx a. 79***. 61***. 106*** Ð. 10 P-SeP. 36***. 27**. 30*** Ð. 2 Trial IIÐ% change from 0±16 weeks P-Se b Ð. 49***. 2* RBC-Se b Ð. 72***. 4* Plat-Se b Ð **. 29***. 3 P-SeP Ð P-Se ˆ plasma selenium; RBC-Se ˆ red blood cell selenium; P-GHSPx ˆ plasma glutathione peroxidase; Plat-GSHPx ˆ platelet glutathione peroxidase; P-SeP ˆ plasma selenoprotein P. a Data were obtained from Levander et al, b Data were obtained from Alfthan et al, Signi cance of changes in selenium status variables: *P < 0.05; **P < 0.01; ***P < (Paired t-test). mean selenoprotein P levels among the supplemented groups (yeast, selenate and selenite) were not at any time point signi cantly different from each other or from that in the placebo group. Plasma selenium and selenoprotein P concentrations in the whole study group were correlated at baseline in both trial I and II (r ˆ 0.34, P ˆ 0.015, and r ˆ 0.30, P ˆ 0.048, respectively). As expected, the correlations between plasma selenium and selenoprotein P increased after supplementation in Trial I, being usually >0.70 (P < 0.001) at different time points. In Trial II the correlations decreased with time from 0.30 (P ˆ 0.048) to 0.16 (not signi cant). In Trial I the correlations between plasma glutathione peroxidase and selenium or selenoprotein P were not signi cant in most cases, r always being < We also calculated the ratio of selenoprotein P/plasma selenium. In Trial I the ratio decreased rapidly during supplementation from approx. 15 to approx. 8 in the wheat and yeast selenium groups but was unchanged in the selenate group the rst four weeks after supplementation, and thereafter it decreased somewhat. In the placebo group selenoprotein P/plasma selenium ratio was constant with time. In Trial II this ratio also decreased in the yeast selenium group from 15 to 11, but was unchanged in the groups supplemented with inorganic selenium. Discussion There are indications that supplementation with selenium or nutrient combinations containing selenium will decrease the incidence of cancer (Blot et al, 1993; Clark et al, 1996). Moreover, selenium supplementation has been shown to have a prophylactic effect on Keshan disease (Ge & Yang, 1993). The number of cases has been radically reduced by selenium enrichment of table salt. Selenium supplementation has been tried in several other disease conditions but usually without preventive or therapeutic effect (Johnsson et al, 1997). It is unknown whether the possible anticarcinogenic effects are mediated by changes in the concentrations or actions of different selenoproteins. Recently several new selenoproteins have been identi ed, and it is important to study the effect of different forms of dietary selenium on the levels of each selenoprotein. Previous results in Trial I showed that the baseline plasma selenium in the study group was moderately low (0.9 mmol/l), and that it increased more when the selenium supplement was yeast (144%) or selenium-rich wheat (139%) compared with selenate (66%) (Levander et al, 1983) (Table 1). In Trial II the study group had acquired a higher basal plasma selenium concentration (1.4 mmol/l) through the nation-wide supplementation of fertilizers (Alfthan et al, 1991). Supplementation with yeast selenium resulted in considerably elevated levels of plasma selenium (49%), and only a small but signi cant increase was observed after supplementation with selenite but not with selenate. In both trials the maximal level of plasma selenium was the same (2.1 mmol/l) in the groups supplemented with yeast selenium. Signi cant increases in plasma selenium following ingestion of selenomethioninecontaining supplements have also been observed in several human (Tarp et al, 1985; NeÁve et al, 1988; Thomson et al, 1993) and animal experiments (Whanger & Butler, 1988; Butler et al, 1990). Since approximately half of the total amount of selenium in the selenium-rich yeast used in the Finnish study was in the form of selenomethionine (Korhola et al, 1986), a likely cause of the large increase in plasma selenium in the groups given these supplements is that selenomethionine is nonspeci cally incorporated into all tissue proteins, in plasma mainly into albumin. Organic selenium forms therefore increase plasma selenium much more than the inorganic forms selenate and selenite which enter the selenide pool and are thereby available only to synthesis of speci c selenoproteins. It is noteworthy that the maximal mean plasma selenium concentration in the selenate-supplemented group was the same in the two trials (1.4 mmol/l). Concerning selenoprotein P, the results in Trial I indicated that the three selenium forms were equally ef cient in increasing its levels in plasma (Figure 1). The maximum levels after supplementation were reached at four weeks at plasma selenium levels in the range 1.2±1.7 mmol/l. However, in Trial II no increase in selenoprotein P levels was observed in any supplemented group. The baseline selenoprotein P levels had probably already reached a maximum level due to the higher initial selenium status of the subjects. A tendency towards plateauing of selenoprotein P levels at plasma selenium concentrations in the range 1.2±1.5 mmol/l was also observed previously in a crosssectional investigation of 414 European subjects (Marchaluk et al, 1995). On the other hand, when Chinese men having a low initial plasma selenium level (0.5 mmol/l) were supplemented with 200 mg selenium per

4 366 day (as selenate) for two weeks, selenoprotein P levels tended to approach a plateau after two weeks at a plasma selenium concentration of only 0.9 mmol/l (Hill et al, 1996). Several factors can in uence the plasma selenium level at which selenoprotein P reaches a plateau. One is that the dietary intake of selenomethionine and its unspeci c incorporation into plasma proteins would be expected to vary in different populations. A subject with a low selenium intake would be expected to have less selenomethionine incorporated in plasma proteins that a subject with a higher selenium intake. If these two subjects are supplemented with saturating amounts of selenate, both would be expected to obtain similar plateaus of selenoprotein P and other selenoproteins since selenate would not be incorporated into selenomethionine. The subject with initially higher selenium intake would likely reach a higher plasma selenium level after supplementation than the subject with initially low selenium intake. Dietary methionine may also in uence the amount of selenium available for synthesis of selenoproteins since it competes with selenomethionine for incorporation into proteins (Luo et al, 1985; Waschulewski & Sunde, 1988; Behne et al, 1991). Since there were no signi cant differences in selenoprotein P levels between subjects given organic and inorganic forms of selenium in Trial I, the methionine supply of the subjects was probably suf cient making possible a high utilisation of selenium from the selenomethionine supplement for synthesis of selenoprotein P. The difference between organic and inorganic selenium supplements can also be interpreted from the selenoprotein/ selenium ratios. Although plasma selenium and selenoprotein P were correlated in Trial I, the selenoprotein P/selenium ratio varied in different supplementation groups with time. Wheat and yeast selenium supplementation increased plasma selenium much more than did selenate supplementation and in these groups the ratios decreased rapidly. The fact that in the selenate group the selenoprotein P/selenium ratio was unchanged in the four rst weeks of the supplementation period is compatible with the interpretation that most of the increase in plasma selenium was due to increases in selenoprotein P and maybe other selenoproteins. An interesting point is that the mean baseline level of selenoprotein P in Trial II (1.8 au) was higher than its mean maximum level after supplementation in Trial I (1.4 au). When Trial I was started, the subjects' basal intake of selenium was 62 mg/d (plasma selenium 0.9 mmol/l), and together with the daily selenium supplements of 200 mg selenium, the total intake was approximately 262 mg/d. When Trial II was started, the basal dietary intake of selenium was approximately 100 mg/d (plasma selenium 1.4 mmol/l), and the subjects had probably had this higher level of selenium intake more than one year before the supplementation study. The nding that selenoprotein P starting levels in Trial II were higher than the plateaus of Trial I is dif cult to interpret, but it may be due to long-term redistribution and accumulation of selenium in different organs which may increase the synthesis of selenoprotein P. The response in selenoprotein P levels after supplementation can be compared to the corresponding responses in other selenoprotein levels. In Trial I platelet glutathione peroxidase activity increased rapidly and reached a plateau at four weeks at a plasma selenium concentration of 1.3± 1.5 mmol/l (Levander et al, 1983). Selenate was more effective supplement in stimulating platelet glutathione peroxidase activity compared to selenium-rich wheat and yeast selenium (Table 1). In Trial II, only selenate and selenite increased the platelet glutathione peroxidase activity which reached a plateau at a plasma selenium concentration of 1.4 mmol/l (Alfthan et al, 1991). NeÁve (1994) summarized the responses in platelet glutathione peroxidase activities in various studies after selenium supplementation. If selenite or selenate was used for supplementation, platelet GSHPx plateaued when the plasma selenium concentration was 1.2±1.5 mmol/l. When organic selenium forms were administered the plateau was reached at a plasma selenium of 1.4±1.7 mmol/l. In Trial I there were no signi cant changes in plasma glutathione peroxidase activity during supplementation (Levander et al, 1983). Similar ndings were observed in Dutch subjects with plasma levels in the same range as the subjects in Trial I, after supplementation with selenium-rich meat or bread (van der Torre et al, 1991). On the other hand, supplementation of New Zealanders with a plasma selenium level of 0.7 mmol/l with 200 mg/d selenium as selenate or selenium-rich yeast, resulted in increased plasma glutathione peroxidase activities plateauing at selenium concentrations of 1.2 mmol/l and 2.5 mmol/l, respectively (Thomson et al, 1993). In Chinese men with a plasma selenium concentration of 0.3 mmol/l, supplementation with 200 mg/d as sodium selenate or selenium-rich yeast resulted in similar increases in plasma glutathionine peroxidase in both groups, reaching plateaus at plasma selenium concentrations of 0.9 mmol/l and 1.4 mmol/l, respectively (Xia et al, 1992). Moreover, when plasma glutathione peroxidase and selenium data from different cross-sectional studies were combined, a tendency towards a plateau of plasma glutathione peroxidase was reached at a plasma selenium concentration of approximately 1 mmol/l (Huang, 1996). It is noteworthy that supplementation with yeast selenium and selenate gives similar responses in erythrocyte and plasma glutathione peroxidase (Thomson et al, 1993) and selenoprotein P (this study), whereas platelet glutathione peroxidase increases much more after selenate than after yeast selenium (Levander et al, 1983; Alfthan et al, 1991; Thomson et al, 1993). This difference remains to be explained. Several mechanisms are involved in the homeostatic regulation of selenoprotein levels both with respect to the rate of change for individual proteins and their maximum concentrations in tissues. Although regulation at the transcriptional level has been observed for selenoproteins (O'Prey et al, 1993), there is little evidence that selenium supply exerts its in uence via such mechanisms (Burk, 1997). The biosynthesis of individual selenoproteins in different selenium states is tissue- and selenoprotein-speci c (Behne et al, 1991), which may be mediated by tissue-speci c changes in selenocysteine trna:s (Diamond et al, 1993) and differences in the selenocysteine insertion sequences (SECIS) for different selenoproteins (Kollmus et al, 1996). Moreover, the response in mrna levels of individual selenoproteins to changes in selenium supply is both tissue-speci c and differs in magnitude and direction (Bermano et al, 1995). Selenium supplementation can also affect non-selenoprotein genes and gene products (Christensen & Pusey, 1994; Nelson et al, 1996). The importance of all these mechanisms in the human body is not yet known. 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