AJCN. First published ahead of print June 23, 2010 as doi: 10.3945/ajcn.2010.29642.
Optimization of selenoprotein P and other plasma selenium biomarkers
for the assessment of the selenium nutritional requirement: a
placebo-controlled double-blind study of selenomethionine
supplementation in selenium-deficient Chinese subjects1–4
Yiming Xia, Kristina E Hill, Ping Li, Jiayuan Xu, Dingyou Zhou, Amy K Motley, Li Wang, Daniel W Byrne,
and Raymond F Burk
ABSTRACT
Background: The intake of selenium needed for optimal health has
not been established. Selenoproteins perform the functions of selenium, and the selenium intake needed for their full expression is not
known.
Objective: This study sought to determine the intake of selenium
required to optimize plasma selenoprotein P (SEPP1) and to compare SEPP1 with other plasma selenium biomarkers.
Design: A 40-wk placebo-controlled, double-blind study of selenium
repletion was carried out in 98 healthy Chinese subjects who had
a daily dietary selenium intake of 14 lg. Fourteen subjects each were
assigned randomly to daily dose groups of 0, 21, 35, 55, 79, 102, and
125 lg Se as L-selenomethionine. Plasma glutathione peroxidase
(GPX) activity, SEPP1, and selenium were measured. A biomarker
was considered to be optimized when its value was not different from
the mean value of the subjects receiving larger supplements.
Results: The SEPP1 concentration was optimized at 40 wk by the
35-lg supplement, which indicated that 49 lg/d could optimize it.
GPX activity was optimized by 21 lg (total ingestion: 35 lg/d). The
selenium concentration showed no tendency to become optimized.
Conclusions: The present results indicate that SEPP1 concentration
is the best plasma biomarker studied for assessing optimal expression of all selenoproteins, because its optimization required a larger
intake of selenium than did GPX activity. On the basis of the selenium intake needed for SEPP1 optimization with adjustments for
body weight and individual variation, ’75 lg Se/d as selenomethionine is postulated to allow full expression of selenoproteins in
US residents. This trial was registered at clinicaltrials.gov as
NCT00428649.
Am J Clin Nutr doi: 10.3945/ajcn.2010.29642.
INTRODUCTION
Selenium is an essential micronutrient that is toxic when
ingested in excess. Severe selenium deficiency, as it occurred in
parts of China until the 1980s, allowed the development of
a childhood cardiomyopathy known as Keshan disease (1–3).
Moderate selenium deficiency persists in some areas of China,
and milder deficiency occurs in Europe and other parts of the
world. The health significance of these less-than-severe deficiencies is not clear.
Despite a lack of evidence that even mild selenium deficiency
occurs in the United States, there has been enthusiasm for se-
lenium supplementation with the aim of preventing cancer and
other diseases. This has led to inclusion of selenium in multivitamin products at levels higher than the Recommended Dietary
Allowance (RDA) and its addition at even higher levels to nutritional supplements that are marketed directly to consumers.
Outbreaks of selenium poisoning have apparently been caused by
errors in the formulation of these products (4, 5). In addition, it
has been suggested that long-term selenium supplementation
might have adverse health effects (6, 7).
To determine the selenium intake that supports optimal health,
intervention trials with health-related endpoints are needed.
SELECT, a trial in which selenium-replete men received selenium supplements, was such a trial (8). Its primary endpoint was
the development of prostate cancer, and selenium did not affect
that endpoint. Arguments have been made, however, that men
with lower plasma selenium concentrations should have been
studied or that different chemical forms of selenium should have
been administered (9, 10). Trials such as SELECT are complex
and expensive. Therefore, knowledge of selenium biology and
biomarkers is needed for their design.
Selenium exerts its biological functions through selenoproteins. In the human genome, 25 genes encode selenoproteins that
have a variety of functions (11). Two selenoproteins, seleno1
From the Sichuan Provincial Center for Disease Control and Prevention,
Chengdu, Sichuan Province, China (YX, PL, and DZ); the Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (KEH, AKM, and RFB);
the Center for Disease Control and Prevention at Mianning County, Liangshan
Yi Autonomous Prefecture, Sichuan Province, China (JX); and the Department of Biostatistics, Vanderbilt University School of Medicine, Nashville,
TN (LW and DWB).
2
A preliminary report of this study was presented at Experimental Biology, New Orleans, LA, on April 20, 2009 and was published in abstract
form (FASEB J 2009;23:346.1).
3
Supported by NIH grant R01 DK58763 and supported in part by the
Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. L-Selenomethionine
was a gift from V Badmaev of Sabinsa Corp (Piscataway, NJ).
4
Address correspondence to RF Burk, 1030C Medical Research Building
IV, Vanderbilt Medical Center, Nashville, TN 37232-0252. E-mail: raymond.
[email protected].
Received April 7, 2010. Accepted for publication May 29, 2010.
doi: 10.3945/ajcn.2010.29642.
Am J Clin Nutr doi: 10.3945/ajcn.2010.29642. Printed in USA. Ó 2010 American Society for Nutrition
Copyright (C) 2010 by the American Society for Nutrition
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XIA ET AL
protein P (SEPP1) and glutathione peroxidase-3 (GPX3), are
present in plasma and can be used as biomarkers of selenium
nutritional status (12, 13).
In 2001, we carried out a study in a low-selenium area of China
with the aim of determining the minimum selenium intake
needed to optimize selenoproteins. We used plasma SEPP1
concentration and glutathione peroxidase (GPX) activity as
biomarkers for the selenoproteins in the body (14). Plasma GPX
activity was optimized by the intake of 47 lg Se/d for 20 wk,
supporting the results of a Chinese study in which optimization
had been observed at an intake of 41 lg/d (15). That Chinese
study had been used to set the present US RDA for selenium at
55 lg (16).
Despite selenium intakes as high as 71 lg/d for 20 wk, optimization of SEPP1 was not achieved in the 2001 study (14).
Because one of the plasma biomarkers had not been optimized,
it could not have been expected that all other selenoproteins in
the body had been optimized. Thus, it was clear that a higher
dose of selenium or a longer supplementation period was needed
to optimize SEPP1.
Because the results of the 2001 study were compatible with the
need for a higher selenium RDA but did not allow its estimation,
we performed another repletion study in 2007 and report on it
here. The new trial achieved optimization of SEPP1. It showed
the responses of each plasma selenium biomarker to supplementation and, importantly, provided data suitable for estimating
the human selenium requirement.
predicted. The selenium intakes obtained with these 2 methods
differ only slightly, and their average is 14 lg/d. This value was
used as the dietary selenium intake of the subjects.
Selenium supplements
The form of selenium administered was L-selenomethionine,
henceforth referred to as selenomethionine. It was a gift from V
Badmaev of Sabinsa Corp (Piscataway, NJ). Richard B Moon of
Pharmacy Innovations (Jamestown, NY) compounded the tablets with a filler of magnesium stearate 1%, tablet premix 99%,
and a trace amount of FD&C yellow number 5. The tablet
premix consisted of colloidal silicon dioxide 2% and fine-grade
microcrystalline cellulose 98%. The amounts of selenium intended to be in the supplements were 0, 20, 40, 60, 80, 100, and
120 lg per tablet. Ten tablets of each dose were assayed in our
laboratory, and they contained a mean (6SD) of 0, 21 6 2.7,
35 6 2.7, 55 6 6.5, 79 6 3.9, 102 6 7.2, and 125 6 11 lg Se.
Each dose-amount group was assigned 14 subjects. Ten bottles
containing 28 tablets each were prepared for each subject and
labeled with a subject number chosen by using shuffled cards, on
each of which was written a subject number. A document that
linked subject numbers with selenium doses was prepared and
sealed by 2 persons who were otherwise not involved in the
study. The document was not opened until all assays had been
performed.
Study protocol
SUBJECTS AND METHODS
Study subjects
The subjects in this study were farmers in Mianning County
(2006 population: 342,824) of Liangshan Prefecture in Sichuan
Province. This county has a long history of selenium deficiency
and was the site in 1974–1976 of a study showing that selenium
supplementation prevents Keshan disease (17).
Village staff announced the study, and 186 volunteers contributed blood samples in November 2006. Selenium concentrations in plasma, measured at the Sichuan Center for Disease
Control and Prevention in Chengdu, ranged from 18 to 130 lg/L
with outliers of 300 and 335 lg/L. Subjects with plasma selenium concentrations .79 lg/L and 2 volunteers with chronic
health problems, as determined by medical history and physical
examinations, were removed from consideration; 98 healthy
subjects were chosen from the remaining 175 subjects for study
based on the locations of their dwellings to facilitate tablet delivery. Informed consent was obtained, and subjects were paid
when they completed the study.
Dietary selenium intake
A nutrition survey of a sample of the study subjects was carried
out in November 2006 by using a food-frequency questionnaire
and local food tables. The survey estimated daily dietary selenium intakes of 16.5 6 3.0 lg for men (n = 17) and 13.4 6
2.8 lg for women (n = 23). An additional estimation of selenium
intake was made by using a formula relating whole-blood selenium to intake (18). Selenium intakes of 13.3 6 3.1 lg for
men (n = 45) and 12.6 6 2.8 lg for women (n = 53) were
The study was conducted from 18 March through 24 December 2007. The subjects were brought from their villages to the
Center for Disease Control and Prevention in Mianning City on
18 March 2007 (the initiation of the study) and 4, 8, 12, 16, 20, 24,
32, and 40 wk later. All subjects were studied on the same day at
each time point. On the first visit, subjects were assigned numbers
from 1 to 98 that determined which selenium supplement they
would receive for the entire 40 wk. Height, weight, and blood
pressure were determined and recorded along with age and sex.
Blood (20 mL) was sampled by venipuncture at each visit
before the daily study tablet was administered. The blood was
treated with 1 mg disodium EDTA/mL, and plasma was separated
by centrifugation for 15 min at 2000 · g. Plasma was frozen at
liquid nitrogen temperature and transported to Chengdu, where
it was stored at 270°C until it was shipped to Nashville on dry
ice. In Nashville, the de-identified samples were maintained at
280°C until the assays were carried out.
Between visits, tablets were administered each day by 3 village
residents under the supervision of a staff member of the Mianning
Center for Disease Control and Prevention. This method was
adopted to ensure compliance and safety. No important adverse
effects were detected. The Ethical Review Committee (Institutional Review Board) of the Sichuan Center for Disease
Control and Prevention and the Institutional Review Board at
Vanderbilt University approved this protocol.
Assays
Plasma samples stored at 280°C were thawed and used the
same day for measurement of SEPP1 and GPX activity. SEPP1
concentrations were measured by using an enzyme-linked immunosorbent assay developed in our laboratory (19). Plasma
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OPTIMIZATION OF SELENOPROTEIN P IN CHINESE SUBJECTS
GPX activity was measured by determining the rate of NADPH
oxidation in the presence of 0.25 mmol H2O2/L (20). Plasma
selenium concentrations were measured by using the fluorometric assay described by Koh and Benson (21). The preliminary selenium assays in China were performed by using
a similar method (22).
Sample size and statistical analysis
The goal of this study was to determine the daily selenium
requirement of healthy persons. The primary endpoint was
prespecified as the mean plasma SEPP1 concentration after 40 wk
of selenium supplementation. We planned to compare this
endpoint among 7 groups randomly assigned to receive different
amounts of selenium. Our previous research (14) suggested that
there would be a plateau in the plasma SEPP1 concentration for
the participants receiving high doses.
The sample size required to detect a statistically significant
difference at 40 wk was predetermined on the basis of our
previous study (14, 23). We estimated that, in the participants
with the lowest dose that provided optimization of plasma
SEPP1, the mean would be 5.6 mg/L with an SD of 1.0 mg/L. For
the next lowest dose, we were interested in detecting a 25%
decrease in plasma SEPP1 concentrations, which was 4.2 mg/L.
A sample size of 11 in each group was required to detect a statistically significant difference in means of 1.4, on the assumption
that the common SD is 1.0 with a 2-group t test with a 2-sided
significance level of 0.05 and 87% power. To account for potential dropouts in each group, we estimated that 14 persons in
each of the 7 arms of the study, or 98 in all, would be required.
Of the 98 randomly assigned subjects, one had initial selenium
biomarkers .2 SD above the mean of the group and was excluded from the analysis before the code was broken. Another
subject became pregnant, and a third moved from the study area.
Thus, results from 95 subjects were analyzed.
After the code was broken, we compared baseline selenium
biomarkers and other characteristics of the participants to assess
the effectiveness of the randomization (Table 1). No significant
differences were found for these baseline factors between the 7
groups.
A Pearson’s chi-square test was used to assess categorical
comparisons between groups. Differences in the mean values for
GPX activity, selenium concentration, SEPP1, and other continuous variables were compared by using the nonparametric
Kruskal-Wallis test. A general linear model with a Helmert
contrast was used to assess the difference between each supplement amount and all higher amounts. In addition, we used
a mixed-effects model to assess the optimal dose (24). This model
was created by using the R package glsD (25), with SEPP1 as the
dependent variable and baseline SEPP1, time, sex, supplement
dose, and the interaction term of time and supplement dose as
independent factors. An AR1 correlation structure and a restricted maximum likelihood method were used. P values ,0.05
were considered statistically significant, and all tests were 2tailed. Statistical analyses were performed with the SPSS
package for Windows (version 18.0; SPSS Inc, Chicago, IL) and
R (25).
RESULTS
Characteristics and initial selenium status of subjects
The 95 study subjects in the analysis were healthy farmers. aged
20–50 y with a mean (6SD) body mass index (in kg/m2) of 22.1 6
2.2 (Table 2). The mean initial plasma selenium concentration
was 30% of the corresponding value in a US study (Table 3). The
SEPP1 concentration was 36%, and the GPX activity was 42% of
the respective US values. No selenium biomarker value was
different between women and men. These biomarker results
confirm that the subjects were selenium deficient.
Seasonal variation of selenium biomarkers
The 40-wk supplementation trial began in late winter and
ended as the following winter began, which allowed observation
of selenium biomarkers in the placebo group for almost 1 y. A
trend was apparent for all biomarkers to decline from winter to
summer and to rise again as winter approached (Figures 1 and 2).
Also, the GPX and SEPP1 values of the supplemented groups
that had reached their maximal values tended to follow the same
TABLE 1
Baseline comparison of intervention and control groups by selenium dose1
Selenium dose
21 lg/d
(n = 14)
Placebo
(n = 14)
Age (y)
Female (%)
Height (cm)
Weight (kg)
Hematocrit (%)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Plasma selenium (lg/L)
SEPP1 (mg/L)
Plasma GPX activity (U/L)
1
2
3
4
37.7 6
64
161.4 6
57.4 6
40.3 6
112 6
73 6
37.3 6
1.96 6
67 6
2
6.6
8.2
9.1
3.2
12
8.9
9.8
0.73
16
39.8 6
43
162.2 6
57.0 6
41.4 6
118 6
73 6
37.8 6
1.92 6
76 6
6.1
7.2
9.1
3.0
10
7.7
8.5
0.59
19
35 lg/d
(n = 14)
35.2 6
50
163.2 6
58.4 6
41.0 6
111 6
73 6
35.4 6
1.81 6
67 6
7.1
8.5
9.0
3.2
12
8.8
7.7
0.47
16
55 lg/d
(n = 13)
35.9 6
54
160.8 6
59.3 6
42.7 6
116 6
75 6
34.9 6
1.86 6
57 6
BP, blood pressure; SEPP1, selenoprotein P; GPX, glutathione peroxidase.
Mean 6 SD (all such values).
Kruskal-Wallis test.
Pearson’s chi-square test.
7.6
8.4
5.6
3.0
10
7.8
7.2
0.76
16
79 lg/d
(n = 12)
37.9 6
50
160.4 6
57.5 6
40.8 6
118 6
74 6
40.9 6
2.08 6
65 6
7.9
6.8
7.6
4.7
15
10
7.2
0.71
20
102 lg/d
(n = 14)
36.1 6
50
163.1 6
58.2 6
40.9 6
117 6
75 6
35.3 6
1.80 6
61 6
6.2
6.8
6.7
3.9
19
9.7
6.3
0.48
14
125 lg/d
(n = 14)
36.0 6
71
159.4 6
56.7 6
39.9 6
111 6
72 6
38.5 6
1.96 6
70 6
4.2
7.3
6.8
3.4
9.3
8.1
6.5
0.64
12
P value
0.623
0.784
0.903
0.983
0.663
0.603
0.993
0.373
0.923
0.143
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XIA ET AL
TABLE 2
Characteristics of participants at the beginning of the study1
Value
(n = 52 F, 43 M)
Characteristic
Age (y)
Height (cm)
Weight (kg)
Hematocrit (%)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
1
37
162
58
41
115
73
6
6
6
6
6
6
7
8
8
4
13
9
All values are means 6 SDs.
pattern. Thus, it is not clear whether the seasonal variation was
caused by differences in selenium intake or by other factors.
Responses of plasma selenoproteins to supplementation
Plasma GPX activity, which reflects the activity of GPX3, was
more variable than the other biomarkers, especially at the initial
time point (Figure 1A; see supplemental Table S1 under “Supplemental data” in the online issue). All supplement groups were
indistinguishable statistically at 20 wk and beyond, however.
Thus, this biomarker was optimized by 21 lg Se/d—the smallest
supplement that was used. Combining that supplement with
a dietary intake of 14 lg Se/d allows the conclusion that 35 lg
Se/d optimized this selenium-dependent activity. Earlier studies
using this activity as an end-point had similar outcomes (14, 15).
SEPP1 optimization required higher selenium doses and longer
supplementation times than did optimization of GPX activity
(Figure 1B; see supplemental Table S2 under “Supplemental
data” in the online issue). SEPP1 concentrations in subjects who
received the highest 3 doses, 79–125 lg, increased rapidly into
the range of values of selenium-replete US residents and were not
different from one another at 8 wk (Figure 1B). SEPP1 concentrations in the groups receiving lower doses increased with time
so that by the end of the trial only the placebo and 21-lg groups
remained significantly different from the higher dose groups.
At 40 wk, the average SEPP1 concentration for the group who
received the 35-lg selenium supplement was not significantly
different from the concentrations of groups who received higher
doses of selenium. Thus, a total daily intake of 49 lg Se for
40 wk optimized plasma SEPP1 concentration in the study
subjects. If the trial had been terminated at 32 wk, the lowest
total intake optimizing SEPP1 would have been 69 lg Se and at
16 wk it would have been 93 lg. These results indicate that the
length of the supplementation period as well as the dose of
selenium affects the optimization of SEPP1.
FIGURE 1. Mean plasma selenoprotein concentrations in 12–14
selenium-deficient subjects supplemented for 40 wk with selenium as
selenomethionine or with placebo. Variation is shown in Figure 3 and in
supplemental Tables S1 and S2 under “Supplemental data” in the online
issue. A: Plasma glutathione peroxidase activity. One unit (U) is 1 lmol
NADPH oxidized per minute. The supplemented groups were not significantly
different from one another at 20 wk and at later time points. B: Plasma
selenoprotein P (SEPP1) concentrations. Arrowheads indicate the last time
point at which the SEPP1 value was significantly different from the mean
value of subjects who received larger supplements. The statistical methods
used are described in Subjects and Methods. The shaded area indicates the
mean 6 SD of SEPP1 concentrations in US subjects from another study
(Table 2). The values used to construct these figures and their SDs are shown
in Tables S1 and S2 under “Supplemental data” in the online issue.
Response of plasma selenium concentration to
supplementation
The plasma selenium concentration responded differently to
supplementation than did selenoprotein values. The plasma selenium values reflected the supplementation dose at all time
points, with no indication of optimization (Figure 2 and Figure
3; see supplemental Table S3 under “Supplemental data” in the
TABLE 3
Plasma biomarkers of selenium status at the beginning of the study1
Selenoprotein P (mg/L)
Glutathione peroxidase activity (U/L)
Selenium (lg/L)
1
2
3
4
5
Women
Men
P2
All
subjects
Nashville
subjects3
Percentage4
1.9 6 0.75
68 6 17
37 6 8
2.0 6 0.6
64 6 17
37 6 7
0.21
0.23
0.72
1.9 6 0.6
66 6 17
37 6 8
5.3 6 0.9
159 6 32
122 6 13
36
42
30
n values as shown in Table 1.
Comparisons between men and women were made by using Wilcoxon’s rank-sum test.
Values taken from reference 19; n = 81 for selenoprotein P and selenium and 62 for glutathione peroxidase activity.
Values in the present study as a percentage of the values in the Nashville study.
Mean 6 SD (all such values).
OPTIMIZATION OF SELENOPROTEIN P IN CHINESE SUBJECTS
FIGURE 2. Mean plasma selenium concentrations in 12–14 seleniumdeficient subjects supplemented for 40 wk with selenium as selenomethionine
or with placebo. Variation is shown in Figure 3. At every time point, each group
is significantly different from the mean value of subjects receiving larger
supplements. The values used to construct this figure and their SDs are shown
in Table S3 under “Supplemental data” in the online issue.
online issue). Thus, the plasma selenium concentration did not
become saturated, as did the 2 selenoproteins. This indicated
that the plasma selenium concentration reflects a nonsaturable
pool of selenium in addition to the selenium in SEPP1 and
GPX3 (Figure 4). Because of this, the plasma selenium concentration cannot be used to estimate the selenium intake required to optimize selenoproteins in the body.
DISCUSSION
Optimization of SEPP1 required the intake of more selenium
than did optimization of GPX activity (Figure 1). This difference
reflects selenium metabolism in the tissues that synthesize these
selenoproteins. Kidney proximal tubule cells synthesize most of
the GPX3 in plasma (13). Those cells have a privileged receptormediated supply of selenium (26, 27) and thus are not representative of most tissues in the body. On the other hand, the liver,
which synthesizes most of the SEPP1 in plasma, regulates wholebody selenium transport and homeostasis (28). These physiologic
considerations are compatible with plasma SEPP1 reflecting the
selenium status of the whole organism better than plasma GPX
activity.
The plasma selenium concentration is often used as a selenium
biomarker, but its response to selenium supplementation is different from the response of selenoproteins, as shown in Figures 1
and 2. The plasma selenium concentration includes the selenium of
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the 2 plasma selenoproteins and the selenium in selenomethionine
that substitutes nonspecifically for methionine in proteins (Figure
4). Selenomethionine is not a participant in regulated selenium
metabolism; its contribution to plasma selenium depends largely
on the amount of selenomethionine ingested (29).
When optimized, SEPP1 and GPX3 together contain ’80–
90 lg Se/L plasma (30). Thus, a plasma selenium concentration
,80 lg/L indicates that selenoproteins are not optimized, as
was the case at the beginning of the present study (Table 3).
When the plasma selenium concentration is .90 lg/L, selenoproteins are usually optimized and the selenium in plasma
.90 lg/L reflects selenomethionine (Figures 2 and 4). Therefore, the plasma selenium concentration is a useful biomarker
for the intake of selenomethionine, as illustrated in Figure 2 and
as discussed in detail previously (19). It is not, however, a precise biomarker for selenoproteins.
The values in Figure 1B indicate that both the duration and
dose of supplementation were important in optimizing the SEPP1
concentration. For example, the 3 largest doses optimized SEPP1
by 8 wk. Smaller doses required longer times of supplementation
to achieve optimization and the smallest supplement, 21 lg/d,
did not optimize the SEPP1 concentration. This pattern of increasing SEPP1 concentrations over the course of the study in
subjects receiving the lower-dose supplements is compatible
with the sequential filling of selenium pools—possibly representing sequential optimization of pools of selenoproteins.
There is ample evidence for differential responses of selenoproteins to the supply of selenium. Some tissues, including
brain, testis, and kidney, have receptor-mediated uptake of
selenium (31) and optimize their selenoproteins under lowselenium conditions. Even within tissues, there is a “hierarchy”
of selenoproteins with respect to selenium supply (32). Thus, the
increase in SEPP1 concentration over the entire supplementation period is compatible with its representation of selenoproteins throughout the body, supporting its value as a biomarker
for all selenoproteins.
Supplementation with 35 lg Se/d for 40 wk optimized the
SEPP1 concentration in this healthy selenium-deficient population (Figure 1B). By combining the 35 lg supplement with the
14 lg dietary intake, we concluded that an intake of 49 lg Se/d
optimized the plasma SEPP1 concentration in this population.
GPX activity was optimized by a total intake of 35 lg/d. If SEPP1
is accepted as a biomarker for all selenoproteins and optimization
of selenoproteins is considered to signify that the supply of selenium is adequate, these results will be useful in estimating the
selenium requirement. Adjustment for the difference in weight
between the Chinese subjects (58 kg) and US residents (76 kg) and
FIGURE 3. A–C: Mean (61 SD) plasma selenium biomarkers at 20 wk (h) and 40 wk (s) in 12–14 selenium-deficient subjects. Note the “optimization” of
selenoprotein values with higher doses and lack of optimization of selenium concentration.
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XIA ET AL
REFERENCES
FIGURE 4. Effect of ingested selenomethionine (Semet) on selenium
pools in plasma. Semet enters the methionine pool and is incorporated
into proteins at methionine positions, forming a pool of selenium in
plasma (shaded area). The size of this pool depends on the amount of
Semet ingested and is not subject to physiologic regulation. Selenium is
released from Semet when that molecule is catabolized and enters
“regulated selenium metabolism,” which produces the plasma
selenoproteins selenoprotein P (SEPP1) and glutathione peroxidase-3
(GPX3). Once the synthesis of selenoproteins has been satisfied, additional
selenium is excreted to regulate whole-body selenium. Forms of selenium
other than selenomethionine cannot enter the methionine pool. They bypass
it to enter “regulated selenium metabolism” more directly. Thus, selenium
ingested as selenomethionine contributes to 2 pools of selenium in the
plasma: one saturable and one not saturable. Selenium ingested in other
forms contributes only to the saturable pool.
for variation among individuals would yield a selenium requirement for US adults of ’75 lg/d. Thus, if SEPP1 were used as
the nutritional biomarker for selenium, the RDA would likely be
increased from its present value of 55 lg/d for adults.
Studies in Europe and New Zealand, where daily selenium
intakes are commonly 60 lg or less, have shown that plasma
selenoprotein values are lower than in the United States. In
addition, administration of selenium caused an increase in selenoproteins to US values (33–36), which indicated that selenium intake in those countries is not adequate to optimize
selenoproteins and, therefore, that the people in those countries
are mildly selenium deficient. As shown in this study, people in
some areas of China are even more selenium deficient than
are those in Europe and New Zealand. Thus, mild-to-moderate
selenium deficiency occurs in several parts of the world, and
intervention studies with health-related endpoints need to
be carried out in those areas to assess the need for selenium
supplementation.
Selenoproteins are optimized in residents of the United States
because their dietary selenium intakes are .80 lg/d (16), and
supplementation with selenium does not affect plasma selenoproteins (19). Unless a salutary biological effect of selenium in
addition to supporting selenoprotein synthesis can be identified,
no scientific rationale can be presented for supplementing people in the United States whose selenoproteins are optimized.
The authors’ responsibilities were as follows—RFB: full access to all of the
data and responsibility for the integrity of the data and the accuracy of data
analysis; RFB and YX: study concept and design; PL, JX, DZ, AKM, and
KEH: data acquisition; DWB, LW, YX, RFB, and KEH: data analysis and
interpretation; RFB, YX, KEH, and DWB: drafting of the manuscript; PL,
JX, DZ, AKM, and LW: critical revision of the manuscript for important intellectual content; DWB and LW: statistical analysis; and YX, JX, PL, and
KEH: study supervision. None of the authors had a conflict of interest or financial interest regarding the material reported in this article.
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