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U.S. Department of Agriculture, ARS, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202 and * Seitoku University Faculty of Humanities, Department of Human Life and Culture, 550 Iwase, Matsudo, Chiba 271-8555, Japan
4To whom correspondence should be addressed. E-mail: euthus{at}gfhnrc.ars.usda.gov.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • selenium • homocysteine • cysteine • glutathione • transsulfuration
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and Halpin and Baker (2
) suggested that selenium deficiency in chicks can influence transsulfuration. Both groups also indicated that, qualitatively, free homocyst(e)ine was decreased in the plasma of selenium-deficient chicks. Bunk and Combs (1
) showed that selenium-deficient chicks had decreased free one-half cystine and cystathionine concentrations in plasma, but no change in methionine.
Halpin and Baker (2
) also reported that selenium-deficient chicks had decreased concentrations of cysteine and cystathionine in plasma, but no change in plasma methionine concentration. Homocystine was detected only in plasma of one strain of chicks fed selenium-adequate diets containing methionine as the source of sulfur amino acid. In two of the three strains of chicks studied, growth was better in the birds fed a diet containing both methionine and cystine compared with chicks fed an isosulfurous amount of methionine alone. This suggested to Halpin and Baker (2
) that transsulfuration efficiency may be impaired by selenium deficiency in some strains of chicks.
In a series of studies, Hill and Burk showed that selenium deficiency affects the metabolism of glutathione. For example, liver glutathione production is increased and plasma glutathione markedly elevated by selenium deficiency (3
–6
). At present, there is no adequate explanation for the increase in glutathione release by liver and concomitant increase in plasma glutathione as a result of selenium deficiency. Burk et al. (7
) speculated that the glutathione peroxidase activity of some nonselenium-dependent glutathione S-transferases is increased in selenium deficiency to compensate for the loss of selenium-dependent glutathione peroxidase activity.
Recently, research by our group (8
,9
) showed that plasma total homocysteine is markedly reduced by selenium deficiency in Fisher-344 rats. The findings that selenium deficiency decreases the plasma concentrations of cysteine, cystathionine and homocysteine, and increases the concentration of plasma and liver glutathione, strongly suggest that selenium deficiency can affect the metabolism of methionine. Thus, this research was designed to confirm the effect of selenium deficiency on homocysteine in laboratory rats and to determine the effect of graded amounts of dietary selenium, ranging from deficient to adequate intakes, on plasma and tissue homocysteine concentrations. A second objective was to determine the effect of selenium deficiency on methionine metabolism. Because selenium plays an important role in providing protection against oxidative damage, we also determined the effects of dietary selenium on redox status of homocysteine and cysteine. Ultimately, we hope to determine the metabolic consequence(s) of decreased homocysteine resulting from selenium deficiency. Also, because plasma homocysteine is used as a risk factor for cardiovascular disease (10
–12
) and as a clinical marker for deficiencies of folate or cobalamin (13
–15
), it is important to determine what influences the concentration and metabolism of plasma homocysteine.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male weanling Fisher-344 rats (Sasco, Omaha, NE) were weighed individually upon arrival. Rats were assigned to each dietary group with no significant difference in initial mean weight among groups. The dietary variable was selenium supplemented to a basal torula yeast-based diet (30% torula yeast), which has been described (8
). The basal diet was supplemented with 0, 0.02, 0.05 or 0.1 µg selenium (as sodium selenite)/g diet, giving a range of selenium intakes from deficient (0 µg/g) to adequate (0.1 µg/g). By analysis, the basal diet contained <2 ng Se/g; the 0.02 diet contained 0.027 µg Se/g; the 0.05 diet contained 0.065 µg Se/g; and the 0.1 diet contained 0.119 µg Se/g. A 30% torula yeast-based diet contains 
9.7 mg folate/kg (2 mg/kg added and 7.7 mg/kg from the yeast). Seven rats were assigned to the group fed the 0.02 µg Se/g diet; all other groups contained 8 rats. The rats were housed individually in stainless steel wire-bottomed cages in a room with controlled temperature (23°C) and humidity (50%). Automatically controlled lighting provided 12 h light. Rats were provided free access to food and deionized water (Super Q Systems, Millipore, Bedford, MA). About 2 wk before termination, the rats were placed in metabolic cages for 20 h and urine was collected on ice in acidified containers (0.8 mL of 2 mol/L HCl). During urine collection no food was given but the rats had free access to water. After 61 d, the rats were food-deprived overnight, weighed and decapitated subsequent to ether anesthesia and cardiac exsanguination with a heparin-coated syringe and needle.
This study was approved by the Animal Care Committee of the Grand Forks Human Nutrition Research Center, and the rats were maintained in accordance with the NIH guidelines for the care and use of laboratory animals.
Selenium status.
Selenium concentrations in the diets and plasma were determined by hydride-generation atomic absorption spectrometry according to Finley et al. (16
). Samples were prepared for analysis by predigestion in nitric acid and hydrogen peroxide, followed by high temperature ashing in the presence of MgNO3 as an aid to prevent selenium volatilization. Glutathione peroxidase activity was determined according to the coupled enzymatic method of Paglia and Valentine (17
) with hydrogen peroxide as the substrate.
Plasma total homocysteine and cysteine.
Total homocysteine and cysteine were determined in heparinized plasma by using HPLC according to the procedure of Durand et al. (18
). Total homocysteine consists of homocysteine, homocystine, mixed disulfides containing a homocysteine residue and protein-bound homocysteine through disulfide bonds. Total cysteine consists of cysteine, cystine, mixed disulfides containing a cysteine residue and protein-bound cysteine through disulfide bonds.
Plasma free reduced and oxidized homocysteine and cysteine.
To determine free (nonprotein bound) reduced homocysteine and cysteine, plasma was deproteinized with sulfosalicylic acid (2 volumes plasma + 1 volume 10% sulfosalicylic acid). The supernatant was used for determination of homocysteine and cysteine (without reduction by tributylphosphine) according to Durand et al. (18
). Free total homocysteine and cysteine were determined as above but with the addition of tributylphosphine. Free oxidized homocysteine and cysteine were determined as the difference between the free total and free reduced forms.
Plasma total free glutathione.
Plasma proteins were precipitated with 10% 5-sulfosalicylic acid and centrifuged (9000 x g, 10 min, 4°C). The supernatant was used for glutathione analysis according to Durand et al. (18
). Plasma total free glutathione consists of reduced glutathione (GSH),5
glutathione disulfide (GSSG) and mixed disulfides containing a glutathione residue.
Kidney and heart homocysteine.
Tissue was homogenized (1 g tissue + 3 mL buffer) in 0.25 mol/L sucrose/0.01 mol/L phosphate buffer, pH 7.4. EDTA (60 µL, 4 mmol/L) was added to a portion of the homogenate (240 µL). Total homocysteine was determined on the EDTA-containing homogenate after the reduction and derivatization procedure of Durand et al. (18
). Kidney and heart homocysteine consist of homocysteine, homocystine, mixed disulfides containing a homocysteine residue and protein-bound homocysteine through disulfide bonds.
Liver glutathione and cysteine.
Liver was homogenized in 5 volumes of cold 0.4 mol/L perchloric acid. After centrifugation (9000 x g, 10 min, 4°C), the supernatant was used for glutathione and cysteine analysis according to Durand et al. (18
). Liver glutathione consists of GSH, GSSG and mixed disulfides containing a glutathione residue. Liver total free cysteine consists of cysteine, cystine and mixed dissulfides containing a cysteine residue.
Urine homocysteine.
Total homocysteine in urine was determined by using the procedure of Durand et al. (18
) after reduction and derivatization. Urine total homocysteine consists of homocysteine, homocystine and mixed disulfides containing a homocysteine residue.
Plasma and liver amino acids.
Plasma amino acids were determined by the HPLC method of Georgi et al. (19
).
Plasma aspartate aminotransferase (GOT), alanine aminotransferase (GPT), and creatine phosphokinase (CPK).
Plasma GOT, GPT and CPK were assayed by using commercially available kits (Sigma Chemical, St. Louis, MO; GOT, #51; GPT, #52; and CK, #520).
Genomic DNA methylation.
The methylation status of CpG sites in genomic DNA was determined by the in vitro methyl acceptance capacity of DNA by using [methyl-3H]SAM as a methyl donor and prokaryotic CpG DNA methyltransferase, as described previously (8
). To control for day-to-day variation, equal numbers of samples (one half) from each dietary treatment were analyzed at the same time. Furthermore, blanks containing no enzyme were analyzed with each sample and consistently yielded <3000 dpm. These values were subtracted from the dpm obtained in the presence of enzyme. We also used one batch of [methyl-3H]SAM that was included in each run. Means and variations between the corresponding groups were compared and were consistently similar.
Liver S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH).
Liver was prepared for SAM and SAH analysis according to Davis et al. (8
) and measured with a Dionex 4000i HPLC (Dionex, Sunnyvale, CA) according to the procedure of Bottiglieri (20
).
Liver enzyme activities.
The activity of betaine-homocysteine methyltransferase (BHMT) was determined according to Finkelstein and Mudd (21
) as modified by Xue and Snoswell (22
). The substrate [methyl-3H]betaine was prepared according to Xue and Snoswell (22
). Liver was prepared by homogenization (1 g liver/4 mL buffer) in 0.04 mol/L potassium phosphate buffer, pH 7.4. The homogenate was centrifuged at 18,000 x g for 15 min at 4°C; the supernatant was used for the assay. Methionine synthase (MS) activity was determined by the method of Sauer (23
). For the MS assay, liver was prepared by homogenization (1 g liver/4 mL buffer) in 0.01 mol/L potassium phosphate buffer, pH 7.5, containing 1 mmol/L GSH. The homogenate was centrifuged at 40,000 x g for 30 min at 4°C; the supernatant was used for the assay. The activity of cystathionine synthase (CS) was determined according to a modified method of Suda et al. (24
) which is based on the method of Mudd et al. (25
). The reaction mixture of Suda et al. (24
) was used but the reaction was stopped with 0.4 mL cold 10% trichloroacetic acid (TCA) and centrifuged. A 0.5-mL aliquot of the TCA-stopped reaction mixture was diluted to 20.5 mL, and 0.01 mL of 0.05 mol/L cystathionine was added. The solution was applied to a Dowex 50-X4(H+) (200–400 mesh) column, 0.9 x 3.0 cm. The column was washed with 18 mL H2O, 35.5 mL of 0.4 mol/L HCl, and then 12 mL H2O; 14C-labeled cystathionine product was then eluted with 6.0 mL of 2 mol/L NH4OH. The eluant (3 mL) was counted for 14C. Liver was homogenized in 0.03 mol/L potassium phosphate buffer, pH 7.0, and centrifuged at 36,000 x g for 10 min at 4°C. The supernatant was used for the assay. S-Adenosylmethionine synthase (SAM-S) activity was determined by the method of Cantoni (26
) with modifications. No glutathione was included in the reaction mix; KCl was added to a final concentration of 0.3 mol/L and all volumes were reduced to one half, resulting in a final volume of 0.5 mL. The reaction was stopped with 0.5 mL of cold 0.4 mol/L perchloric acid. After centrifugation, the supernatant was diluted with H2O and analyzed for SAM by capillary electrophoresis (Uthus, E. O., unpublished). Liver was prepared as outlined for CS. The activity of cystathionase (CTH, cystathionine 
-lyase) was determined by the method of Stipanuk (27
). For CTH, liver was prepared as outlined for CS.
Plasma vitamin B-12, plasma and red cell folate.
Plasma vitamin B-12, plasma and red cell folate were determined by RIA (KVSP2, B-12; and KFSP, folate; Diagnostic Products, Los Angeles, CA).
Statistical analyses.
The data were analyzed by one-way ANOVA by using the statistical package SAS (SAS Version 8.02; SAS Institute, Cary, NC). Tukey’s contrasts were used to differentiate among means for variables that were significantly (P 
0.05) affected by dietary selenium.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Selenium status indicators, plasma selenium and liver glutathione peroxidase activity were markedly depressed by selenium deficiency and generally increased with increasing dietary selenium (Table 1)
.
|
). The concentration of plasma free reduced homocysteine was highest in rats fed 0.1 µg Se/g (Table 2)
. The ratios of free reduced plasma homocysteine to total plasma homocysteine and free reduced plasma homocysteine to free oxidized plasma homocysteine were significantly increased by selenium deficiency. Other researchers found that protein-bound homocysteine accounted for 30–59% of the total homocysteine in rat plasma (28
–30
). Values reported here are at the high end of this range. For example, we found 59% [(6.94 - 2.83)/6.94 x 100] for rats fed 0.1 µg Se/g and 63% [(2.70 - 0.99)/2.70 x 100] for rats fed 0 µg Se/g (values from Table 2
). The effects of dietary treatment on the various forms of plasma cysteine paralleled those of plasma homocysteine except for free reduced cysteine, which was not affected by dietary selenium (Table 3
).
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). Generally, the concentrations of homocysteine in kidney and heart were lower in rats fed the diet containing no supplemental selenium compared with those fed diets containing either 0.05 or 0.1 µg Se/g. The values obtained for kidney and heart homocysteine are somewhat higher than those reported by Svardal et al. (31
) who reported 3.83 and 2.80 nmol/g, for kidney and heart, respectively (7.61 nmol/g for liver). We found (in the selenium adequate groups) 8.97 and 7.72 nmol/g in kidney and heart, respectively. We estimate that the discrepancy between our results and those of Svardal et al. (31
) might stem from the difference in the detection methods of homocysteine and pretreatment of samples. Jacobs et al. (32
) reported a mean value of 9.0 nmol/g for liver total homocysteine. Liver glutathione was elevated in rats fed no supplemental selenium compared with those receiving adequate dietary selenium (0.1 µg Se/g). Plasma total free glutathione was elevated in rats fed no supplemental selenium compared with all other groups (Table 4)
. Urinary total homocysteine tended to be decreased by decreasing dietary selenium (P = 0.06; Table 4
). Liver total free cysteine tended to be decreased in selenium-deprived rats (P = 0.1).
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). The activities of MS, SAM-S, and CS were not affected by dietary selenium; the activity of liver CTH tended to be increased by selenium deficiency (P = 0.09; Table 5
).
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15%) in rats fed the 0 µg Se/g diet compared with the ratios from rats fed 0.02, 0.05 or 0.1 µg Se/g (P < 0.0001, data not shown). Measures of tissue damage (GOT, GPT and CPK) were not affected by selenium status. Also, we found no detectable injury or pathological change in heart apices with histological investigation using hematoxylin-eosin staining (data not shown). Measured plasma amino acids (asparagine, serine, glutamine, glycine, threonine, citrulline, arginine, alanine, taurine, tyrosine, valine, methionine, tryptophan, isoleucine, phenylalanine and leucine) were not affected by dietary selenium (data not shown). Glycine and threonine were the only liver amino acids affected by dietary selenium; both were increased in rats fed the 0 µg Se/g diet (P < 0.001, data not shown; amino acids measured in liver included all those measured in plasma as well as aspartic acid and glutamic acid).
Although the concentration of liver SAM, SAH and the SAM/SAH ratio were not affected (data not shown), dietary selenium did affect DNA methylation. Liver DNA from rats given no supplemental selenium was hypomethylated compared with DNA from rats fed 0.1 µg Se/g (P < 0.018, data not shown).
Plasma vitamin B-12 was lower (P = 0.05) in selenium-deprived rats; this was significant by Tukey’s contrast in rats supplemented with 0.02 µg Se/g compared with rats fed 0.1 µg Se/g. Dietary selenium did not affect red cell or plasma folate (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) reported that approximately half of the intracellular glutathione pool in human liver cells is derived from homocysteine through transsulfuration. The concentrations of plasma homocysteine and cysteine but not glutathione generally correlate with dietary selenium until dietary selenium reaches 0.05–0.1 µg/g. This suggests that these amino acids are sensitive to changes in selenium status. However, we found no change in plasma or liver methionine or taurine. The work by Bunk and Combs (1
) and Halpin and Baker (2
) showed that selenium deficiency results in decreased plasma cystathionine and no change in methionine.
Selenium deficiency decreases plasma total cysteine and increases liver and plasma glutathione. This implies that an enzyme(s) between cysteine and glutathione, and that possibly an enzyme(s) between homocysteine and cysteine, is markedly elevated. Although we did not measure -glutamylcysteine synthetase, Hill and Burk reported that -glutamylcysteine synthetase activity in the selenium-deficient rat liver was twice that of control (3
). Recently it was shown that this rate-limiting enzyme in glutathione biosynthesis is upregulated under oxidative stress conditions (34
). A marked increase in -glutamylcysteine synthetase would suggest a "pull" on transsulfuration (see Fig. 1
) in the direction of glutathione, resulting in the known decreases in plasma cysteine, cystathionine and homocysteine. The activity of liver BHMT was decreased and MS was not affected by selenium deficiency. To account for the decreased homocysteine (substrate for all 3 enzymes) and based on the Km values for these enzymes [(mmol/L) BHMT, 0.002; MS, 0.06; CS, 1–24; from (35
)], one would then possibly expect an increase in the activity of CS. We found no effect of selenium on CS. This implies that the other enzyme between homocysteine and cysteine, CTH, may be increased. We found that the activity of CTH in liver was elevated but not significantly.
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) showed that oxidation of 14CH3-methionine to 14CO2 was increased in selenium-deficient chicks fed an amino acid-based diet with methionine as the sole sulfur source. Supplementation with cystine resulted in lowering the oxidation to values similar to those seen in the selenium-supplemented chicks fed no supplemental cystine. The torula yeast-based diet used in our study is relatively low in methionine and thus is supplemented with 3.0 g DL-methionine/kg diet. Cystine is present, although also at a relatively low concentration. In other words, perhaps the dietary cystine allows for some sparing of methionine and thus, we did not see a great effect of selenium deficiency on methionine cycling.
The kidney plays a major role in the metabolism of homocysteine (30
,37
,38
). House et al. (30
) suggested that because of the normal low rates of homocysteine excretion, most homocysteine is taken up and metabolized by the kidney. Refsum et al. (39
) also reported that the kidney is a very important organ for plasma homocysteine homeostasis. They reported that the major fraction of homocysteine in plasma is derived from the liver and is eliminated or metabolized by the kidneys. Selenium deficiency resulted in an increase in the kidney weight/body weight ratio and a slight decrease in urinary homocysteine excretion. Kidney homocysteine was decreased by selenium deficiency. Plasma GOT, GPT and CPK were not affected by dietary selenium. Although these are not specific markers for kidney damage, the fact that they are not increased indicates that there is little possibility of tissue injury. These results suggest that excretion of homocysteine by the kidney or kidney damage were not the causes of the decreased plasma concentration of homocysteine as a result of inadequate dietary selenium intake. An altered metabolism of homocysteine in kidney, however, cannot be ruled out.
The metabolic importance of decreased plasma and tissue concentrations of homocysteine and increased concentrations of glutathione resulting from low dietary selenium is not known, but may be related to antioxidant defense. Glutathione is an important metabolite in antioxidant defense. Selenium provides protection against oxidative stress (40
,41
). Dietary selenium reduces the formation of carcinogen-induced aberrant crypts in rat colons (42
) and selenium deficiency has been shown to increase global DNA hypomethylation in rat liver (as was also shown in the present study) and colon and in Caco-2 cells (8
). Inadequate selenium intake can result in a compromised oxidative defense. Mosharov et al. (33
) showed that during oxidative stress, methionine metabolism is altered such that more glutathione is synthesized. In vitro work by that group also has shown that under oxidative stress, the activity of MS decreases and CS increases. Their study reported that the expression of CS and MS did not change even though there was an increased flux of homocysteine through CS. They hypothesized that redox regulation is important in modulating the flux of homocysteine through transsulfuration.
Ueland et al. (43
) suggested that changes in the concentration and redox status of one aminothiol may have rapid and remote influence on other sulfhydryl groups, including those essential for the function of enzymes or structural proteins. They also suggested that protein binding may buffer moderate fluctuations in circulating total homocysteine and cysteine. The ratios of free reduced homocysteine/total homocysteine and free reduced cysteine/total cysteine in plasma showed that the redox status of these thiols is altered by selenium deficiency (Tables 2
and 3
). The resultant effects on other sulfhydryl groups (i.e., in enzyme or structural proteins) is unknown. It is possible that the effect of inadequate dietary selenium on BHMT is related to an alteration of thiol redox status. BHMT is a zinc-dependent enzyme in which the binding of zinc is thought to be through several cysteine residues (44
); these cysteine residues are important in the redox regulation of the enzyme (45
). In another report, Ueland et al. (46
) stated that the redox status of aminothiols in plasma is probably an integral part of the extracellular antioxidant defense system and may be linked to intracellular redox status. Stamm and Reynolds (47
) noted that in the folate-adequate individual, the ratio between free-reduced and oxidized homocysteine is tightly regulated, keeping the plasma total homocysteine within a specific and narrow range. As shown in Tables 2
and 3
, these ratios for homocysteine and cysteine were affected by selenium status. Selenium deficiency disrupts the homeostasis that keeps plasma homocysteine tightly regulated, resulting in a marked decrease in plasma homocysteine.
The mechanism leading to a decrease in plasma homocysteine as a result of selenium deficiency remains unknown. The plasma concentration of homocysteine is determined by the metabolism of homocysteine within methionine recycling (48
), its irreversible loss from the methionine cycle through transsulfuration (49
) and its clearance by the kidney (50
). The effects of dietary selenium on plasma homocysteine may involve many tissues. These findings suggest that inadequate selenium intake can affect methionine metabolism, probably through effects on both methionine recycling and transsulfuration. The metabolic consequences of a marked decrease in plasma homocysteine and smaller but significant decreases in tissue homocysteine are not known but possibly could be related to an altered oxidant defense and may be detrimental.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area is an equal opportunity/affirmative action employer and all agency services are available without discrimination.
3 Mention of a trademark or proprietary product does not constitute a guarantee of warranty of the product by the U.S. Department of Agriculture and does not imply its approval to the exclusion of other products that may also be suitable.
5 Abbreviations used: BHMT, betaine homocysteine methyltransferase; CPK, creatine phosphokinase; CS, cystathionine synthase; CTH, cystathionase (cystathione -lyase); GOT, aspartate aminotransferase; GPT, alanine aminotransferase; GSH, reduced glutathione; GSSG, glutathione disulfide; MS, methionine synthase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SAM-S, S-adenosylmethionine synthase; TCA, trichloroacetic acid.
Manuscript received 2 January 2002. Initial review completed 18 January 2002. Revision accepted 5 March 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Bunk, M. J. & Combs, G. F., Jr (1981) Evidence for an impairment in the conversion of methionine to cysteine in selenium-deficient chick. Proc. Soc. Exp. Biol. Med. 167:87-93.[Medline]
2. Halpin, K. M. & Baker, D. H. (1984) Selenium deficiency and transsulfuration in the chick. J. Nutr. 114:606-612.
3.
Hill, K. E. & Burk, R. F. (1982) Effect of selenium deficiency and vitamin E deficiency on glutathione metabolism in isolated rat hepatocytes. J. Biol. Chem. 257:10668-10672.
4. Hill, K. E. & Burk, R. F. (1985) Effect of selenium deficiency on the disposition of plasma glutathione. Arch. Biochem. Biophys. 240:166-171.[Medline]
5. Hill, K. E., Burk, R. F. & Lane, J. M. (1987) Effect of selenium depletion and repletion on plasma glutathione and glutathione-dependent enzymes in the rat. J. Nutr. 117:99-104.
6. Hill, K. E., Taylor, M. A. & Burk, R. F. (1987) Influence of selenium deficiency on glutathione disulfide metabolism in isolated perfused rat heart. Biochim. Biophys. Acta 923:431-435.[Medline]
7. Burk, R. F., Hill, K. E., Awad, J. A., Morrow, J. D. & Lyons, P. R. (1995) Liver and kidney necrosis in selenium-deficient rats depleted of glutathione. Lab. Investig. 72:723-730.[Medline]
8.
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.
9.
Davis, C. D. & Uthus, E. O. (2002) Dietary selenium and azadeoxycytidine treatment affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells. J. Nutr. 132:292-297.
10. Boushey, C. J., Beresford, S. A., Omenn, G. S. & Motulsky, A. G. (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 274:1049-1057.[Abstract]
11. Kang, S.-S., Wong, P.W.K. & Malinow, M. R. (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu. Rev. Nutr. 12:279-298.[Medline]
12. Ueland, P. M., Refsum, H. & Brattström, L. (1992) Plasma homocysteine and cardiovascular disease. Francis, R. B., Jr eds. Atherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function 1992:183-236 Marcel Dekker New York, NY. .
13. Ueland, P. M., Refsum, H., Stabler, S. P., Malinow, M. R., Andersson, A. & Allen, R. H. (1993) Total homocysteine in plasma or serum. Methods and clinical applications. Clin. Chem. 39:1764-1779.[Abstract]
14. Allen, R. H., Stabler, S. P., Savage, D. G. & Lindenbaum, J. (1994) Metabolic abnormalities in cobalamin (vitamin-B12) and folate deficiency. FASEB J 7:1344-1353.[Abstract]
15. Stabler, S. P., Lindenbaum, J. & Allen, R. H. (1996) The use of homocysteine and other metabolites in the specific diagnosis of vitamin B-12 deficiency. J. Nutr. 126:1266S-1272S.
16. Finley, J., Matthys, L., Shuler, T. & Korynta, E. (1996) Selenium content of foods purchased in North Dakota. Nutr. Res. 16:723-728.
17. Paglia, D. & Valentine, W. (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 70:158-169.[Medline]
18. Durand, P., Fortin, L. J., Lussier-Cacan, S., Davignon, J. & Blache, D. (1996) Hyperhomocysteinemia induced by folic acid deficiency and methionine load-applications of a modified HPLC method. Clin. Chim. Acta 252:83-93.[Medline]
19. Georgi, G., Pietsch, C. & Sawatzki, G. (1993) High-performance liquid chromatographic determination of amino acids in protein hydrolysates and in plasma using automated pre-column derivitization with o-phthaldialdehyde/2-mercaptoethanol. J. Chromatogr. Biomed. Appl. 613:35-42.
20. Bottiglieri, T. (1990) Isocratic high performance liquid chromatographic analysis of S-adenosylmethionine and S-adenosylhomocysteine in animal tissues: the effect of exposure to nitrous oxide. Biomed. Chromatogr. 4:239-244.[Medline]
21.
Finkelstein, J. D. & Mudd, S. H. (1967) Transsulfuration in mammals. The methionine-sparing action of cysteine. J. Biol. Chem. 242:873-880.
22. Xue, G.-P. & Snoswell, A. M. (1985) Comparative studies on the methionine synthesis in sheep and rat tissues. Comp. Biochem. Physiol. B 80:489-494.[Medline]
23. Sauer, H. (1983) Methionine synthase. Bergmeyer, H. U. eds. Methods of Enzymatic Analysis 3rd ed. 1983:304-311 Verlag Chemie Deerfield Beach, FL. .
24. Suda, M., Nakagawa, H. & Kimura, H. (1971) Cystathionine synthase (rat liver). Tabor, H. Tabor, C. W. eds. Methods in Enzymology 1971:454-458 Academic Press New York, NY. .
25.
Mudd, S. H., Finkelstein, J. D., Irreverre, F. & Laster, L. (1965) Transsulfuration in mammals. Microassays and tissue distribution of three enzymes of the pathway. J. Biol. Chem. 240:4382-4392.
26. Cantoni, G. L. (1955) Methionine-activating enzyme, liver. Colowick, S. P. Kaplan, N. O. eds. Methods in Enzymology 1955:254-256 Academic Press New York, NY. .
27. Stipanuk, M. H. (1979) Effect of excess dietary methionine on the catabolism of cysteine in rats. J. Nutr. 109:2126-2139.
28. Smolin, L. A. & Benevenga, N. J. (1982) Accumulation of homocyst(e)ine in vitamin B-6 deficiency: a model for the study of cystathionine ß-synthase deficiency. J. Nutr. 112:1264-1272.
29. Smolin, L. A. & Benevenga, N. J. (1984) Factors affecting the accumulation of homocyst(e)ine in rats deficient in vitamin B-6. J. Nutr. 114:103-111.
30. House, J. D., Brosnan, M. E. & Brosnan, J. T. (1998) Renal uptake and excretion of homocysteine in rats with acute hyperhomocysteinemia. Kidney Int 54:1601-1607.[Medline]
31.
Svardal, A., Refsum, H. & Ueland, P. M. (1986) Determination of in vivo protein binding of homocysteine and its relation to free homocysteine in the liver and other tissues of the rat. J. Biol. Chem. 261:3156-3163.
32.
Jacobs, R. L., Stead, L. M., Brosnan, M. E. & Brosnan, J. T. (2001) Hyperglucagonemia in rats results in decreased plasma homocysteine and increased flux through the transsulfuration pathway in liver. J. Biol. Chem. 276:43740-43747.
33. Mosharov, E., Cranford, M. R. & Banerjee, R. (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39:13005-13011.[Medline]
34. Iwata-Ichikawa, E., Kondo, Y., Miyazaki, I., Asanuma, M. & Ogawa, N. (1999) Glial cells protect neurons against oxidative stress via transcriptional up-regulation of the glutathione synthesis. J. Neurochem. 72:2334-2344.[Medline]
35. Finkelstein, J. D. (1990) Methionine metabolism in mammals. J. Nutr. Biochem. 1:228-237.[Medline]
36. Bunk, M. J. (1980) Relationship of Appetite, Glutathione Peroxidase Activity, and Dietary Sulfur-Containing Amino Acids to the Onset of Nutritional Pancreatic Atrophy in the Selenium Deficient Chick and Rat 1980 Doctoral thesis Cornell University, Ithaca, NY. .
37. Bostom, A., Brosnan, J. T., Hall, B., Nadeau, M. R. & Selhub, J. (1995) Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 116:59-62.[Medline]
38. House, J. D., Brosnan, M. E. & Brosnan, J. T. (1997) Characterization of homocysteine metabolism in the rat kidney. Biochem. J. 328:287-292.
39. Refsum, H., Guttormsen, A. B., Fiskerstrand, T. & Ueland, P. M. (1998) Hyperhomocysteinemia in terms of steady-state kinetics. Eur. J. Pediatr. 157(suppl. 2):S45-S49.
40. Behne, D. & Kyriakopoulos, A. (2001) Mammalian selenium-containing proteins. Annu. Rev. Nutr. 21:453-473.[Medline]
41. Brown, K. M. & Arthur, J. R. (2001) Selenium, selenoproteins and human health: a review. Public Health Nutr 4:593-599.[Medline]
42. Feng, Y., Finley, J., Davis, C. D., Becker, W. K., Fretland, A. J. & Hein, D. W. (1999) Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2'-dimethyl-4-aminobiphenyl. Toxicol. Appl. Pharmacol. 157:36-42.[Medline]
43. Ueland, P. M., Mansoor, M. A., Guttormsen, A. B., Muller, F., Aukrust, P., Refsum, H. & Svardal, A. M. (1996) Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status-a possible element of the extracellular antioxidant defense system. J. Nutr. 126:1281S-1284S.
44. Millian, N. S. & Garrow, T. A. (1998) Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arch. Biochem. Biophys. 356:93-98.[Medline]
45. Garrow, T. A., Millan, N. S. & Castro, C. (2001) Redox regulation of betaine-homocysteine methyltransferase (BHMT) activity. FASEB. J. 51:A403.
46.
Ueland, P. M. (1995) Homocysteine species as components of plasma redox thiol status. Clin. Chem. 41:340-342.
47.
Stamm, E. B. & Reynolds, R. D. (1999) Plasma total homocyst(e)ine may not be the most appropriate index for cardiovascular disease risk. J. Nutr. 129:1927-1930.
48. Dudman, N. P., Guo, X. W., Gordon, R. B., Dawson, P. A. & Wilcken, D. E. (1996) Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. J. Nutr. 126:1295S-1300S.
49.
Selhub, J. & Miller, J. W. (1992) The pathogenesis of homocysteinemia: interpretation of the coordinate regulation by S-adenosylmethionine of remethylation and transsulfuration of homocysteine. Am. J. Clin. Nutr. 55:131-138.
50. Arnadottir, M., Hultberg, B., Nilsson-Ehle, P. & Thysell, H. (1996) The effect of reduced glomerular filtration rate on plasma total homocysteine concentrations. Scand. J. Clin. Lab. Investig. 56:41-46.[Medline]
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