Journal of the American College of Nutrition, Vol. 18, No. 5, 462-469 (1999)
Published by the American College of Nutrition
Metabolism of Selenite in Men with Widely Varying Selenium Status
Morteza Janghorbani, PhD,
Yiming Xia, PhD,
Pengcheng Ha, MS,
Philip D. Whanger, PhD,
Judy A. Butler, BS,
John W. Olesik, PhD and
Lizla Daniels, PhD
BioChemAnalysis Corp and the Center for Stable Isotope research Inc, 2201 West Campbell Park Drive, Chicago, Illinois (M.J.)
Chinese Academy of Preventive Medicine, Institute of Nutrition and Food Hygiene, Beijing, People’s Republic of CHINA (Y.X., P.H.)
Department of Agricultural Chemistry, Oregon State University, Corvallis, Oregon (P.D.W., J.A.B.)
Microscopic and Chemical Analysis Research Center, Ohio State University, Columbus, Ohio (J.W.O., L.D.)
Address reprint requests to: P.D. Whanger, Ph.D., Department of Agricultural Chemistry, Oregon State University, Corvallis, OR 97331
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ABSTRACT
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Objective: This study was undertaken to investigate the metabolism of selenite in men with life-long intakes of deficient, adequate and excess selenium.
Methods: Stable isotopes of selenium were infused for five hours into Chinese men living in deficient, adequate or excessive selenium areas, and 24-hour urine and blood samples were collected daily for the next seven days. Stable isotopic selenium excretion was determined in urine and in whole plasma and plasma fractions.
Results: Even though there was a positive correlation of selenium intake with the urinary excretion of this element, this relationship was not linear over the entire range (deficient, adequate, excessive) of selenium intake. When the urine excretion was normalized internally within each group, a sharp increase in the slope of this relationship was found when long-term intake increased to adequate amounts, but the slope reached a plateau when the daily intake exceeded the adequate group. The plasma selenoprotein P fraction was labeled initially, but the incorporation in the glutathione peroxidase fraction subsequently increased by a small amount. A two-month dietary restriction of selenium of the subjects from the excess area did not result in a reduction of urinary excretion of infused selenite.
Conclusion: A complex relationship exists between long-term intake of selenium and selenium status, and subjects living in the excess area are more saturated with selenium than anticipated. More than two months of depletion are required to affect urinary excretion of selenium.
Key words: stable isotopes of selenium, Chinese men, deficient selenium, adequate selenium, excess selenium, selenoprotein P, plasma, urine
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INTRODUCTION
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Long-term selenium (Se) supplementation is under consideration as a potential modality for cancer chemoprevention in humans [1,2]. However, current knowledge about the relationship between Se supplementation parameters and their effect on Se body status is not sufficiently well developed to permit design of safe and efficacious supplementation regimes for long-term applications [1]. This lack of information is especially critical because of the known toxic effects of excess chronic Se intake [3]. Chief among these concerns is the effect of various supplementation parameters on total body Se and generation of biologically active Se, mainly Se2-, in target tissues [4]. Important parameters of supplementation are chemical forms of Se and level of chronic intake [1,5]. Among many chemical forms of Se that may be used for this purpose, selenomethionine (Semet) may be especially suitable because of its ability to provide a stable storage form as Semet containing tissue proteins which upon degradation generate biologically active Se species [1,6]. Chronic intake levels suitable for supplementation purposes have not been established, but values of several hundred micrograms per day have been suggested for American adults who already consume approximately 100 µg Se/day in the diet [1].
If Semet-containing Se-supplements, such as selenized yeast, are to be likely candidates for long-term supplementation [2], then the relationship between parameters of supplementation and the consequent tissue flux of biologically active Se needs to be understood over a wide range of chronic Se intake. A simplified model is described (Fig. 1), which is a synthesis of the currently known features of Se metabolism [4]. When dietary intake of Se is deficient, most absorbed Se, regardless of chemical form, is used for synthesis of selenoproteins such as glutathione peroxidase (GPX [4,8]), contributing to the selenite-exchangeable pool, but none to the Semet pool unless this is the dietary form, or to methylation and excretion [9,10]. As dietary intake is increased, the selenite-exchangeable pool reaches saturation, the rate of methylation and excretion is increased and the amount of Semet converted to this pool is influenced by the methionine intake [11].
While the specific chemical form of tissue Se with chemopreventive potency is not known, it is thought to be Se2- or a derivative thereof [5,9,10]. Thus, the ideal index of Se metabolism relevant to chemopreventive studies may be whole body flux of Se2-. Since this labile species cannot be measured directly, its excretory methylated derivatives may be the most suitable surrogate if the quantitative relationship between whole body flux of Se2- and excretion rate of methylated derivatives could be established over the range of Se intake relevant to supplementation studies. Selenoproteins such as plasma GPX [4] and selenoprotein-P (SeP [12,13]) are not likely good surrogates because they do not respond to increasing flux of Se2- over a wide range of supplementations. A potentially suitable alternative strategy is to identify subject groups whose members for their entire lives have consumed foods containing Semet as a major source of their daily Se intake over a wide range of chronic Se intake and examine the behavior of methylated excretory products. Research workers have identified such groups whose members have life-long intakes of Se over the range from deficient to excess [14,15]. In this manuscript, we report some of our initial observations focusing on the relationship between variations in life-long Se intake and several potential indices of biologically active Se.
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EXPERIMENTAL METHODS
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Protocol
Ten adult male volunteers from each of three areas of the People’s Republic of China known to be deficient (Xichang), adequate (Beijing), or high (Enshi) in food-Se were recruited for this study. Detailed descriptions of the residents of these three areas have been presented [14]. The protocol was approved by the Oregon State University Committee for the Protection of Human Subjects and by a special Institutional Review Board convened at the Chinese Academy of Preventive Medicine in Beijing. The baseline parameters of Se for the three groups are shown in Table 1. The day after baseline samples were obtained, each subject received an infusion in the antecubital vein of selenite labeled with the stable isotope of selenium (Na274SeO3), which was prepared specifically for intravenous administration (see below), by adding the stable isotope solution to a 500-mL bag of 5% intravenous glucose solution. Infusion rate was adjusted (by gravity) to last for five hours (0700–1200). Total amounts of Se infused in each subject were 52.5 µg for the Lo-Se group, and 105 µg for the other two groups. Complete 24-hour urine samples for each of the seven days following the infusion were collected from subjects in the Lo-Se and Adeq-Se groups, during which they consumed the locally grown food providing the following daily Se intake: Lo-Se 30 µg Se/d, Adeq-Se 110 µg Se/d and high-Se 480 µg Se/day. Blood samples (15 mL) were obtained at 0700 of each of the seven days; plasma was separated by centrifugation and frozen for later analysis. After the first infusion of high Se subjects, they were moved to Changping Village (Lichuan County, Hubei Province) some 300 km from their native village where they stayed for 70 days. This village is in the Keshan disease area, which during the 1969–1983 period had incidence mortality rates of 103/100,000 and 45.2%, respectively. During their 70-day stay, they consumed locally grown food which provided about 43 µg Se/day based on three-day dietary survey. The procedures for dietary survey have been described in detail [16]. These include the objectives of the survey, subjects of the survey, schedule of the survey, organization and implementation, forms and questionnaires, methods and scope of sampling, personnel selection and training, methods of data collection, data entry and report, data analysis and the quality of survey. In these subjects an identical infusion was conducted again on day 64 after the transfer, with the exception that the total amount of Se infused was 113 µg. Following the second infusion, 24-hour urine samples and blood samples were collected for seven days, obtained and processed as before. The two infusion periods for this group will be referred to as Hi-Se-1 and Hi-Se-2 for the first and second periods, respectively.
Preparation of Stable Isotope for Infusion
Elemental Se (13.6 mg) enriched with the stable isotope of selenium (74Se 54.4 weight%; 77Se 4.406; R74/77 12.35 by weight; the corresponding values for unenriched Se are 0.815, 7.38 and 0.110 respectively) was dissolved in 2–3 mL concentrated HNO3. The resulting solution was heated gently until almost dry. The remaining liquid was transferred with deionized water into an acid-washed plastic container and volume adjusted with deionized water. This solution had a Se-concentration of 99.83 µg/mL, pH 3.0. A measured portion of this solution was prepared for infusion as follows. Solution pH was adjusted with NaOH to 7.4 and diluted with 0.9% saline solution. It was then filtered through 0.45 µm filter and 2.0-mL portions dispensed into sterile glass ampoules. All ampoules were then sterilized by autoclaving at 120°C for 20 minutes. Three of the ampoules were analyzed for Se (52.5 µg/2-mL ampoule). Freedom from pyrogenicity was tested in five rabbits with three randomly selected ampoules using standard procedures. A similar batch was prepared for the second infusion with a final Se concentration of 56.6 µg/2-mL ampoule.
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ANALYTICAL PROCEDURES
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Urine Samples
The volume of 24-hour urine collection was determined, and measured aliquots were processed for the measurement of total Se (urine-Se: Seu) using HNO3/HClO4 digestion [14]. In addition, measured aliquots of urine from the Hi-Se group were processed for the isolation of trimethyl selenonium chloride (TMSe) using the KOH-thermolysis procedure [17]. Each resulting solution was then analyzed for Se content with the fluorometric method [14] and the isotope ratio for 74Se/77Se (R74/77) with hydride generation-inductively coupled plasma mass spectrometry (HG/ICP-MS) [18]. The instrument used for these measurements was a Perkin-Elmer Model 6000 inductively coupled plasma mass spectrometer equipped with a home-made hydride generation system similar to that described previously [18]. Instrumental parameters were optimized for each set of measurements and the measured ion beam intensity ratios corrected for blank were converted to isotope ratios using a set of standards of known isotope ratios.
Plasma Samples
Total Se was measured with the fluorometric procedure on a measured portion of each plasma sample [14]. In addition, a measured volume of each plasma sample from the Hi-Se group was fractionated for three Se-containing fractions using tandem-column chromatography as described previously [19]. Each resulting fraction was then processed for the measurement of Se (fluorometric method [14]) and R74/77 (HG/ICP-MS).
Calculations
Experimental data for each sample for Se and R74/77 were combined to calculate that portion of Se in the sample originating from the enriched infusate, according to Eqs (1)–(3):
 | ((1)) |
 | ((2)) |
R74/77: measured isotope ratio in sample (on weight/weight basis)
Se: Se content of sample, measured fluorometrically
Se°: Se content of sample of unenriched origin
Se*: Se content of sample of enriched origin
Constants: appropriate weight fractions of each isotope in either unenriched Se, or infusate Se
Simultaneous solution of the above two equations yields the desired quantity:
 | ((3)) |
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RESULTS
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Relation between Estimated Long-term Intake and Urine Excretion of Se
Long-term intake of Se was estimated for all subjects from the expression log[Se-intake (µg/d)]=1.64xlog[plasma-Se (µg/mL)]+3.389 [15]. We observed no identifiable temporal pattern in daily urine excretion for the initial seven days for any of the subjects. Thus, we examined three expressions of urine Se excretion in order to minimize day-to-day variations: 24-hour excretion for day 0, mean of seven days for days 1 to 7, and mean of six days for days 2 to 7 (Fig. 2).
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Fig. 2. Comparison of low Se subjects with high Se ones for the measurement of urine Se originating from endogenous Se turnover. The data are presented as 24-hour excretion for day 0, mean of 7 days for days 1 to 7 and mean of 6 days for days 2 to 7.
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As seen from the data, both mean values were comparable (error bars, shown only for days 1 to 7 data, were also comparable for both sets). Day-0 urine excretions appeared more variable (Fig. 2). Because data for days 2 to 7 would include less contribution from the immediate clearance of infused selenite, we have used them as most representative of urine elimination of endogenous Se.
The quantitative relationship between estimated long-term Se intake and urine excretion of endogenous Se (mean excretion for days 2 to 7) for all 30 subjects is shown in Fig. 3. While increasing long-term intake clearly leads to increased urine Se, the relationship is not linear over the wide range of intake observed in these subjects. The relationship for the low-to-adequate range is shown in Fig. 3B. There is little increase in urine excretion over the range of long-term intake for the Lo-Se group, but for the Adeq-Se group the slope is larger. The true change in the slope of the relationship should be even more dramatic when consideration is given to the fact that, because of the unavoidable significance of Se intake during the protocol for the Lo-Se group, dietary Se most likely had a larger contribution to its urine-Se than for the other two groups.
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Fig. 3. Observed quantitative relationship between estimated long-term Se intake and daily urinary excretion of endogenous origin using all subjects (A) as compared to low and adequate subjects (B).
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Relation between Se Status and Retention of Infused Selenite
The kinetics of excretion of the infused selenite are presented in Fig. 4 for all groups, and all showed the expected exponential elimination kinetics for selenite [20,21]. The fraction of the infused dose eliminated was much higher for the Hi-Se group compared with the Adeq-Se and the Lo-Se groups, but identical for both infusion periods within the Hi-Se group (p<0.05).
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Fig. 4. Urine excretion kinetics of infused selenite in the three experimental groups of low selenium, adequate selenium and high selenium (first and second infusions).
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The observed relation between the seven-day cumulative excretion in urine of the infused selenite and daily excretion of endogenous Se (average for days 2 to 7) is shown in Fig. 5. The Lo-Se subjects excreted 4.3±0.38% of the infused dose during the seven days following infusion, the Adeq-Se subjects 12.4±2.2%, and the Hi-Se subjects 29.8±3.2% after the first infusion and 28.8±3.4% after the second infusion. The relationship between urine excretion of infused selenite and daily urine excretion of Se appeared to approach an asymptote, indicating that the Hi-Se group eliminated a smaller fraction of infused selenite via the kidneys for both infusion periods compared with both the Lo-Se and the Adeq-Se groups. The nonlinear relationship between the two variables of Fig. 5 is maintained even if the data of the second infusion period for the Hi-Se group [Hi-Se (2)] are not included.
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Fig. 5. Observed relationship between 5-day (2 to 7) cumulative urinary excretion of infused selenite and daily excretion of endogenous Se.
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The relationship between daily urine excretion of endogenous Se (average of days 2 to 7), or the seven-day cumulative excretion of labeled selenite, and the estimated long-term Se intake of each subject is shown in Fig. 6. Urine excretion data have been normalized internally within each set in order to permit their superposition in a single graph. Both sets of data show a similar behavior in response to the estimated long-term intake. There is a sharp increase in the slope of the relationship when long-term intake increases beyond the Lo-Se group, but the slope then levels off as daily intake exceeds that for the Adeq-Se group.
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Fig. 6. Plot of individual data for each subject showing the relationship between daily excretion in urine of endogenous, or labeled Se, and estimated long-term Se intake.
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Plasma Distribution of Labeled Selenite
Changes in plasma concentration of selenite label are shown for the four groups in Fig. 7A. Data have been normalized to the concentration on day one for the applicable group. Each data point corresponds to mean of 4 to 5 subjects. Except for values for Hi-Se-1 on days four and possibly five, visual inspection of the data does not reveal major differences among the four groups. Thus, using averages for all groups, we have plotted the logarithm of normalized plasma concentrations against time in Fig. 7B. Chromatography of plasma from subjects in all three areas showed that initially plasma label was primarily associated with the SeP fraction and that incorporation in the GPX fraction increased during the latter times of the experiment but no incorporation occurred in the albumin (data not shown). This is consistent with our prior data [22]. Qualitatively, the semilogarithmic plot of Fig. 7B is consistent with a two-compartment model consisting of SeP and GPX. Unfortunately, there are not sufficient experimental data to permit resolution of these data into both their components. However, taking the last 3 to 4 points as representing the degradation kinetics of labeled plasma GPX, a half-life of 3.9 to 4.1 days is obtained.
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Fig. 7. Kinetics of turnover of plasma label for each group (A) and a plot of the semilogrithim of pooled data (B).
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DISCUSSION
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Clearly, the consequences of long-term supplementation with different chemical forms of Se and various supplemental levels require a much better understanding than is currently available [1]. An important aspect of this general problem is the relationship between total body Se resulting from various supplemental regimes and tissue level of Se2- [4,7]. If the simplified model of selenium metabolism based on the existence of two metabolically distinct pools (Fig. 1), a Semet-containing compartment and a selenite-exchangeable one [7], where each comprises a heterogeneous variety of chemical forms, is accepted, the shorter whole body turnover of the latter compared with the former (half-life of 100 vs. 250 days [1]) requires that consumption of a relatively constant dietary Se results in achievement of a steady state earlier in life for the selenite-exchangeable pool than for the Semet-containing proteins. In addition, consumption of normal foods with a significant Semet component (especially foods of plant origin) or Semet-containing supplements such as selenized yeast [2] is expected to lead eventually to saturation of both pools except with a much higher Se content of the Semet-containing proteins. Evidence has been presented that the main dietary form of selenium consumed by the residents of Enshi is Semet [23]. Therein may lie both the storage potential of Semet-containing supplements and their potential toxicity. It should be noted that, as the Se content of the Semet-containing pool is increased from increasing intake of Semet, any factors that increase the catabolism of body proteins would be expected to result in increased flux of Se from this pool to the selenite-exchangeable pool. This could result in excess Se turnover.
As long-term daily intake of food-Se increases from the nutritionally deficient range to supra-nutritional intakes, a general rise in tissue fluxes of Se2- would be expected. Since this labile species either supplies Se for tissue selenospecies like SeP and GPX or for excretory metabolites such as dimethylselenide (DMSe) and trimethylselenium, changes in its tissue fluxes resulting from variations in Se body status should be reflected in some metabolic aspects of these end-products. Thus, some of these end-products may provide useful indices of whole body Se2- flux and an understanding of the relationship between body Se status and changes in these indices is important.
Total Se excreted in urine may provide a suitable index, if its relationship to whole body turnover of endogenous Se over a wide range of chronic intake could be elucidated. The first step in examining this relationship is to determine the contribution of newly absorbed dietary Se to urine Se. Data summarized in Fig. 2 show that average daily urine excretion over several days following reduced Se intake does not indicate a systematic pattern and thus may represent Se catabolized from rapidly turning-over endogenous pools. Data depicted in Fig. 3 clearly demonstrate the nonlinear nature of daily urine excretion of endogenous Se as a function of body Se status. At the nutritionally deficient end, increasing long-term dietary intake leads to little increase in urine excretion due to the body need for synthesis of such important proteins as GPX, consistent with early observations by Burk et al. [24]. Once a threshold of excretion [24] is exceeded, a larger fraction of body’s endogenous Se is used for generation of urinary metabolites (Fig. 3B). However, continued increases in Se body status beyond nutritional range of intake may not result in proportional increments in urine excretion as seen from the decreasing slope of Fig. 3A for the supra-nutritional range of intake. This can be explained readily by invoking a scenario for increased excretion of excretory metabolites by routes other than urine and is consistent with published observations in animals which have succumbed to toxic intakes of Se with elimination of DMSe in expired air [7]. Thus, over such a wide range of long-term Se intake as observed for our subjects or subjects reported by Yang et al. [15], a strictly linear correlation between urine Se and Se intake should not be expected, contrary to conclusions by Yang, et al. [15]. Even under moderately high chronic intake, para-renal excretion may be significant (Fig. 6). In an earlier study with Chinese subjects a linear response was obtained with renal clearance on Se status of the subjects [14] and the regression of renal clearance with plasma Se levels was highly significant.
As seen from the data presented in Fig. 4, daily excretion of infused selenite is strongly influenced by body Se status over the range of deficient-to-adequate intake, consistent with several previous reports [20,21]. For instance, the Lo-Se group excreted 4.3±0.4% of the infused dose during the seven days of observation, while the comparative figure for the Adeq-Se group was 12.4±2.2% and that for the Hi-Se-1 group, 29.8±3.2% (Fig. 5). However, a two-month dietary Se-restriction (Hi-Se-2) did not result in a reduction in urine excretion of infused selenite (28.8% for Hi-Se-2 vs. 29.8% for Hi-Se-1). Two mechanisms may be invoked to explain this observation. First, it may be that the subjects in Hi-Se-1 possessed such high amounts of Semet-containing proteins that the tissue fluxes of Se2- resulting from whole-body protein turnover during the two-months of Se restriction were more than adequate to keep the selenite-exchangeable pool saturated, leading to no change in urine excretion of infused selenite before and after Se restriction. Alternatively, it may be that two months of Se restriction did actually result in changes in whole-body Se2- flux, but that this change was not reflected in urine excretion of the label. As seen from the data of Fig. 5, the relationship between seven-day urine excretion of labeled selenite and daily urine excretion of endogenous Se is nonlinear; this may reflect an increasing contribution of other excretory mechanisms, for example, DMSe in expired air for the elimination of labeled selenite in Hi-Se subjects. Data shown in Fig. 6 for excretion of infused selenite further support this suggestion. Clearly, resolution of this is important to our understanding of the consequences of long-term Se intake.
The dynamics of plasma turnover of infused selenite do not appear to be influenced by Se status (Fig. 7). The majority of the infused selenite is initially incorporated into SeP (data not shown) followed by small increases in GPX; this is in agreement with our prior work [22]. The form of Se in albumin is Semet [25], and since animals cannot synthesize Semet from inorganic selenium, the lack of deposition of Se from selenite in albumin is not unexpected. Chromatography of the plasma revealed that the majority of the Se was in the SeP fraction in plasma from subjects living in the deficient or adequate areas, but in contrast the majority of the Se was in the albumin fraction in plasma from subjects living in high Se area (Enshi). This is consistent with our earlier work [26]. If SeP and GPX are secretory proteins synthesized mostly in the liver with Se integral to the proteins [12,13], then their plasma turnover could only be altered by processes affecting protein turnover in plasma. Increasing whole-body Se status may not be such a factor. Total retention of labeled selenite in the plasma pool is apparently not influenced by Se status, but could not be definitely measured in our experiment because of unknown components in urine. From the data obtained in this investigation, a very complex relationship exists, and further work is needed to elucidate these interactions.
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ACKNOWLEDGMENTS
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The work reported here was supported by Public Health Service grant number DK 38341 from the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases to Oregon State University (PDW).
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FOOTNOTES
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Presented at the Annual Meetings of Experimental Biology 98 held in San Francisco, CA, and published in abstract form: FASEB J. 12:A 524, 1998.
Published with the approval of the Oregon State University Agricultural Experiment Station as Technical Paper Number 11, 384.
Received January 1, 1999.
Accepted May 1, 1999.
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TOP
ABSTRACT
INTRODUCTION
