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PubMed1987

Dose-response relations in urinary excretion of trimethylselenonium in the rat.

75Se-labeled selenite was administered to fasting rats by orogastric intubation (1.5-3000 micrograms/kg body wt). Urine was collected and characterized for total radioactivity as well as for radiolabeled trimethylselenonium (TMSe). At lower doses of selenite (up to 500 micrograms/kg body wt), 30% of the administered dose was excreted. At higher doses of selenite, fractional urine excretion decreased as a function of the dose. The observed decrease in fractional urine excretion was not caused by changes in the absorption of the administered radiolabel. There was a direct relationship between the amount of the administered dose of selenite (up to 1500 micrograms/kg body wt) and the proportion of urinary [75Se] excreted as TMSe. Pretreatment with seleno compounds (10 or 100 micrograms Se/kg body wt as selenite, or selenomethionine) for 35 d before a challenge dose of [75Se]selenite did not influence the excretion of total [75Se] or of [75Se]TMSe in urine. Ingestion of a choline-deficient diet, which should deplete the availability of methyl groups, did not have any effect on excretion of total [75Se] or of [75Se]TMSe in urine after a challenge dose of [75Se]selenite (500 micrograms/kg body wt). The data presented here permit the following conclusions: 1) Production of TMSe is dose dependent, 2) production of TMSe from a single acute dose does not depend on the history of selenium intake and 3) rats fed a methyl-deficient diet are able to eliminate Se via formation of TMSe.

Animals↗
PubMed1989

Uptake of 75Se-selenite by brush border membrane vesicles from chick duodenum stimulated by vitamin D.

Brush border membrane vesicles were isolated from mucosal homogenates of duodena from normal, rachitic and vitamin D-treated rachitic chicks using a discontinuous sucrose gradient, and further purified by glycerol gradient centrifugation. In vitro uptake of 75Se-selenite by purified brush border membrane vesicles was studied using a rapid filtration technique. The time course of 75Se uptake was non-linear; rapid initial binding was followed by a gradual decrease in the rate of uptake until an equilibrium value was reached at 60-120 min. The initial binding at 36 s was not affected by selenite concentration in the incubation buffer, while the fractional rate of uptake between the 36 s and 2 min time periods was clearly lower with 1 mM Se than with 4-100 microM Se. 75Se uptake did not show any dependency on the external Na-gradient, nor could it be inhibited by other anions (arsenate, phosphate). Treatment of rachitic chicks either with cholecalciferol (500 Iu, 72 h) or with 1,25(OH)2-cholecalciferol (0.5 microgram given 16 h prior to isolation of the vesicles) significantly enhanced 75Se uptake. A threefold excess of mannitol in the outside buffer reduced 75Se uptake by vesicles from vitamin D-deficient and D-treated chicks 60% and 35% respectively, but had no effect on vesicles from vitamin D-treated chicks preloaded with 75Se. Neither saponin treatment nor excess cold selenite could release the label from the vesicles preloaded with 75Se. These data are compatible with the hypothesis that selenite easily crosses the brush border membrane into the intravesicular space and, once inside, is tightly bound by the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Influence of dietary methionine on the metabolism of selenomethionine in rats.

To determine the influence of methionine on selenomethionine (SeMet) metabolism, weanling male rats were fed for 8 wk a basal diet marginally deficient in sulfur amino acids, containing 2.0 micrograms selenium (Se)/g as DL-SeMet and supplemented with 0, 0.3, 0.6 or 1.2% DL-methionine. Increased dietary methionine caused decreased selenium deposition in all tissues examined but increased glutathione peroxidase (GSHPx, EC 1.11.1.9) activity in testes, liver and lungs. A positive correlation was found between dietary methionine and the calculated percentage of selenium associated with GSHPx. In a second experiment, 75SeMet was injected into weanling male rats which had been fed the basal diet containing 2.0 micrograms selenium as DL-SeMet with or without the addition of 1.0% methionine. The selenoamino acid content of tissues and the distribution of 75Se in erythrocyte proteins were determined. In comparison to the rats fed the basal diet without added methionine, significantly more 75Se-selenocysteine was found in liver and muscle, more 75Se was found in erythrocyte GSHPx and less 75Se was found in erythrocyte hemoglobin of rats fed 1.0% methionine. These data suggest that methionine diverts SeMet from incorporation into general proteins and enhances its conversion to selenocysteine for specific selenium-requiring proteins, such as GSHPx.

Administration, Oral↗
PubMed1990

Relationship of membrane-bound sulfhydryl groups to vitamin D-stimulated uptake of [75Se]Selenite by the brush border membrane vesicles from chick duodenum.

The uptake of selenite by purified brush border membrane vesicles isolated from duodena of rachitic or vitamin D-treated chicks was studied by using radioactive selenite and a rapid filtration technique. Cholecalciferol treatment (500 IU at 72 h) significantly enhanced selenite uptake, a response that decreased when the vesicles were stored at room temperature for 2.5 h prior to the uptake measurement. Preincubation of the vesicles in 1.0 mmol/L H2O2 reduced [75Se]selenite uptake, indicating the involvement of oxidizable groups in the uptake reaction. Iodoacetic acid (IAA), a sulfhydryl-blocking reagent, at 1-2 mmol/L concentration eliminated the difference in selenite uptake due to cholecalciferol and had no effect on vesicles from rachitic animals. A higher concentration of IAA (10 mmol/L) enhanced selenite uptake manyfold and increased the absolute difference due to cholecalciferol treatment. Single intravenous doses of 100 IU cholecalciferol, 100 IU ergocalciferol, or 0.1 micrograms 1,25-dihydroxycholecalciferol also stimulated selenite uptake, suggesting a general response to vitamin D compounds. Normal animals given a single dose of 1,25-dihydroxycholecalciferol 12 h prior to killing also responded. Treatments that enhanced the uptake of [75Se]selenite also increased the amount of membrane-bound sulfhydryl groups, suggesting the involvement of membrane-bound sulfhydryl groups in the vitamin D response. A significant increase in selenite uptake by intravenous 1,25-dihydroxycholecalciferol occurred within 10 min. This rapid effect provides a new tool to probe early biochemical effects of vitamin D on intestinal epithelium.

Animals↗
PubMed1993

Synthesis of [75Se]selenoproteins is greater in selenium-deficient sheep.

Three Se-deficient and three Se-sufficient sheep with mean erythrocyte glutathione peroxidase activities of 30 and 249 mumol NADPH oxidized.min-1.g hemoglobin-1, respectively, were each labeled intraperitoneally with 555 MBq of sodium [75Se]selenite. All animals were killed and necropsied after 7 d. Peak plasma radioactivity occurred from 1 to 3 h post-labeling. Radioactivity in plasma associated with [75Se]selenoproteins was significantly higher in the Se-deficient sheep than in the Se-sufficient sheep 3 and 6 d after isotope administration. SDS-PAGE analysis of plasma followed by autoradiography indicated five selenoproteins, all of which were present in both groups. The molecular weights were 21.0, 23.0, 48.0, 55.5 and > 100 kDa. The protein with a mass of 55.5 kDa accounted for > 40% of the total radioactivity in both groups of sheep. Nine selenoproteins with molecular weights of 15.7, 18.8, 22.9, 26.8, 37.3, 42.4, 56.1, 62.7 and 71.3 kDa were detected in extracts from a range of tissues. Liver, kidney, heart and pituitary retained more radioactivity than the other tissues examined and the total amount of protein-associated 75Se in the liver, kidney and pituitary of Se-deficient sheep was significantly greater than that in Se-sufficient controls.

Animals↗
PubMed1994

The utilization of N-acetylcysteine and 2-oxothiazolidine-4-carboxylate by rat hepatocytes is limited by their rate of uptake and conversion to cysteine.

N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (OTC) are converted enzymatically to cysteine and have been used to stimulate hepatic glutathione synthesis. Using hepatocytes isolated from male Sprague-Dawley rats and 35S-labeled substrates, the uptake and metabolism of these cysteine precursors was measured and compared with those for cells provided with an equimolar amount of cysteine. Cysteine was utilized more rapidly than NAC or OTC for sulfate and taurine production and more rapidly than OTC for glutathione production. N-Acetyl-L-cysteine itself was taken up slowly by hepatocytes, but deacetylation of NAC to cysteine seemed to occur extracellularly. Utilization of OTC seemed to be limited by a low rate of uptake and slow intracellular conversion to cysteine. The rate of accumulation of [35S]glutathione from OTC was low compared to that from other substrates, but glutathione production accounted for 78% of the measured OTC metabolism. Although the rate of accumulation of [35S]glutathione was similar for hepatocytes incubated with [35S]cysteine or [35S]NAC, glutathione synthesis accounted for a higher percentage of NAC metabolism than of cysteine metabolism (62-81% vs. 46%). The apparent preferential distribution of OTC and NAC to glutathione vs. taurine and sulfate can be partly explained by a lower rate of substrate availability, but another unknown mechanism also appears to favor the conversion of NAC to glutathione.

Acetylcysteine↗
PubMed2004

Bioconcentration mechanism of selenium by a coccolithophorid, Emiliania huxleyi.

We investigated the uptake and bioconcentration of the essential element selenium by a coccolithophorid, Emiliania huxleyi, using [75Se]selenite. The time course of 75Se uptake showed a biphasic pattern, namely a primary phase and a subsequent secondary phase. The primary and secondary phases are due to a rapid selenite uptake process that attained a stationary level within 2 min and a slow Se-accumulation process that continued at a constant rate for 4 h or longer, respectively. Kinetic analysis revealed that the selenite uptake process consists of two components, one saturable and one linearly related to substrate concentration. The Km of the saturable component was 29.8 nM selenite; the uptake activity of this component was suppressed by inhibitors of ATP biogenesis, suggesting that selenite uptake is driven by a high-affinity, active transport system. During a 6-h incubation of cells with [75Se]selenite, 70% of the intracellular 75Se was incorporated into low-molecular-mass compounds (LMCs), and 17% was incorporated into proteins, but [75Se]selenite was barely detectable. A pulse-chase experiment demonstrated that the 75Se that had accumulated in LMCs was transferred into proteins. When the syntheses of amino acids and proteins were each separately inhibited, 75Se incorporation into LMCs and proteins was decreased. These results suggest that E. huxleyi rapidly absorbs selenite, filling a small intracellular pool. Then, Se-containing LMCs are immediately synthesized from the selenite, creating a pool of LMCs that are then metabolized to selenoproteins.

Adenosine Triphosphate↗
PubMed2000

Effects of arsenic-, platinum-, and gold-containing drugs on the disposition of exogenous selenium in rats.

Having found that the electrophilic model compound sulfobromophthalein markedly altered the fate of exogenous selenium in the body by reacting in vivo with nucleophilic selenium metabolites, the effects of metal-containing drugs with expected selenium reactivity were tested on biliary, urinary, and pulmonary excretion. Tissue distribution of selenium in selenite-injected rats was also examined. Coadministration with [(75)Se]selenite (10 micromol/kg, iv) of the trypanosomicid arsenicals (100 micromol/kg, iv) trimelarsan (TMA) or melarsoprol (MAP), the antitumor cisplatin (25 micromol/kg, iv), or the antirheumatic gold sodium thiomalate (25 or 50 micromol/kg, iv) significantly altered the disposition of (75)Se, whereas carboplatin (100 micromol/kg, iv) did not produce such an effect. The most dramatic alterations included the approximately 20-fold increase in the biliary excretion rate of selenium in response to TMA and MAP, the almost complete cessation of the exhalation of selenium as dimethyl selenide after administration of the arsenic- and gold-containing drugs, and the manifold accumulation of selenium in the blood plasma following gold injection. Direct chemical reaction of the drugs with nucleophilic selenite metabolites in the body may underlie these alterations. The tight coordination in time and extent observed between the biliary excretion of arsenic and selenium in rats receiving either of the arsenicals and selenite supports this hypothesis. However, attempts to detect selenium-containing biliary metabolites of TMA and MAP have failed, possibly owing to their instability. In summary, the arsenic-, platinum- and gold-containing drugs significantly influence the fate of exogenous selenium, whereby they may adversely affect the availability of this essential element for synthesis of selenoenzymes. Furthermore, the capability of TMA and MAP to enhance the biliary and total excretion of selenium renders these drugs significant candidates for antidotes in selenium intoxication.

Animals↗
PubMed1993

Postcholecystectomy diarrhea from villous atrophy of the terminal ileum.

We report a 60-year-old man with intermittent diarrhea for 15 years which was worsened by cholecystectomy. The results of routine laboratory tests, x-ray studies of the gut, and endoscopy were normal. Fecal fat excretion was normal, but total bile acid excretion was increased in the alkaline feces. The retention of 75SeHCAT was low. Jejunal mucosal biopsy showed normal mucosa. Ileal biopsy was performed at ileoscopy some 10 to 15 cm proximal to the ileocecal valve. Scanning-electron and light microscopy showed a transitional zone between villous atrophy in the distal and normal mucosa in the proximal part of the biopsy specimen. The response of diarrhea to cholestyramine treatment was unequivocal, suggesting bile acid malabsorption. The increased enterohepatic cycling of bile acids after cholecystectomy may be responsible for a decrease in their ileal uptake. Very often, as in our patient, the diarrhea precedes cholecystectomy and is considerably increased by it. Cholecystectomy may unmask a previously unrecognized bile acid transport defect. In our patient, this defect might have been caused by the villous atrophy of the terminal ileum.

Bile Acids and Salts↗
PubMed1994

Bile acid malabsorption associated with Graves' disease.

A 40-year-old man developed dyspepsia, watery diarrhea, and weight loss. A clinical diagnosis of hyperthyroidism due to Graves' disease was confirmed [free thyroxine, 87 pmol/L (normal range, 8.6-27 pmol/L)]. Bile acid malabsorption was demonstrated by a low 23-selena-25-homocholyltauric acid retention of 7.1% (normal, > 15%). Antithyroid treatment (carbimazole and propranolol) was instituted, and his diarrhea subsided with the control of hyperthyroidism (free thyroxine, 15 pmol/L) along with an improvement of bile acid absorption (Se-HCAT retention, 14.7%). This case very strongly suggests the existence of bile acid malabsorption in hyperthyroidism. The temporal association suggests that the diarrhea may have been due at least in part to bile acid malabsorption, raising the possibility that the latter may be an etiological factor in thyrotoxic diarrhea. We believe this is the first such report.

Adult↗
PubMed1998

Counting the cost of patients who do not attend nuclear medicine departments.

The mean rate of non-attendance at this hospital is 16%, with the Nuclear Medicine Department averaging 4%. Although only a small percentage, increasing demand for nuclear medicine studies has led to a need for greater efficiency to reduce financial losses. From April 1995 to March 1996, 104 patients did not attend over a range of 16 studies. We examined the types of study, patients and costs. The costs of wasted staff time, camera time and radiopharmaceutical ranged from pound sterling 24 (99Tc(m) thyroid) to pound sterling 470 (75Se cholesterol adrenal). This results in a loss equivalent to pound sterling 7258 over the year. There was no significant difference in non-attendance rates between different types of procedure, source and type of referral, or in the three age groups: children, working and retired population. Finally, we looked at cultural origins, segregating the groups into Asian and European origins based on surname. A significantly higher proportion of patients of Asian origin did not attend. This study has shown that it may be of benefit to target specific groups and tests. For example, at City Hospital, perhaps we should concentrate on our Asian community to ensure they understand fully what the study involves. It would also be worthwhile targeting the more expensive nuclear medicine studies.

Adolescent↗
PubMed2002

Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing's syndrome.

The aim of this study was to evaluate the sensitivity and accuracy of computed tomography (CT) scanning, 75Se-selenomethyl-norcholesterol scintigraphy (SNS) and magnetic resonance imaging (MRI) in patients with Cushing's syndrome (CS) undergoing adrenalectomy. A series of 67 patients with CS due to benign adrenal disease was reviewed. There were 11 (16.4%) men and 56 (83.6%) women, with an overall median age of 44 years (range 19-69 years). Prior to surgery all patients underwent both CT and SNS, and 58 (86.6%) underwent adrenal MRI. Thirty-five (52.2%) of the patients (group A) had histologically confirmed unilateral adrenal involvement (33 patients with a solitary adrenocortical adenoma, and two with unilateral nodular cortical hyperplasia), while 32 (47.8%) of the patients (group B) had CS caused by bilateral adrenal involvement, including two patients with multinodular adrenal hyperplasia. The sensitivity, specificity and accuracy of adrenal imaging in group A were 97.1%, 100% and 98.5% for SNS, 94.3%, 68.7% (P<0.05, chi2 test) and 82.1% for CT scan, and 92.3%, 60.0% (P<0.05) and 64.3% (P<0.05) for MRI, respectively. In group B the sensitivity, specificity and accuracy were 100%, 97.2% and 98.5% for SNS, 64.5% (P<0.05), 97.2% and 82.1% for CT scan, and 60.0% (P<0.05), 92.3% and 35.7% (P<0.05) for MRI, respectively. In conclusion, SNS represents the most sensitive and specific adrenal imaging study and should be used in all patients with confirmed biochemical diagnosis of CS undergoing adrenalectomy. The sensitivity and specificity of CT scan and MRI are similar, but the latter shows a lower accuracy, especially in patients with bilateral adrenal involvement.

Adrenal Cortex Neoplasms↗
PubMed1995

Direct assessment of the mechanism for a raised serum bile acid level in chronic liver disease.

BACKGROUND: Impaired hepatic uptake is the major cause of raised serum bile acid levels in liver disease, but confirmation in humans by direct measurement is lacking. The synthetic gamma-labelled bile acid 75Se-homocholic acid taurine (75SeHCAT) provides a tool for the direct measurement of hepatic bile acid handling. OBJECTIVE: To determine the interrelationships among hepatic handling of 75SeHCAT, the kinetics of its disappearance from plasma and serum bile acid levels in patients with chronic liver disease. DESIGN: We studied 12 patients with primary biliary cirrhosis and 14 with cirrhosis arising from other causes. Fasting serum bile acid levels were measured enzymatically. After intravenous administration of 75SeHCAT, we determined plasma disappearance rates (initial K1, late K2) from serial blood samples and hepatic uptake and excretory rates directly from dynamic abdominal gamma-camera scanning. Both scanning and sampling were carried out over a period of 90 min. RESULTS: Serum bile acid concentrations correlated with K1 and with hepatic uptake (Rs = -0.53, P < 0.01; Rs = -0.47, P < 0.02, respectively) but neither with K2 nor with the excretory rate. K1 and uptake were reduced (P < 0.05) in patients with high serum bile acid levels and in those with varices. Serum bile acid levels were higher in patients with varices (P < 0.05), which might suggest that portosystemic shunting occurred. However, this is unlikely because the varices were not independent of liver function. CONCLUSION: Hepatic bile acid uptake and excretion are independent processes. Hepatic uptake is related to initial, whereas hepatic excretion is related to late, plasma disappearance. Impaired hepatic uptake is a major determinant of the rise in serum bile acid levels in chronic liver disease.

Adult↗
PubMed1996

Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile acid induced diarrhoea.

OBJECTIVE: To assess the reliability of serum 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-3ox-C) in the differential diagnosis of bile acid induced diarrhoea by comparison with 75selenohomocholyltaurine whole body retention (SeHCAT WBR). DESIGN: One hundred and sixty-four patients with chronic diarrhoea were investigated prospectively in two centres (Edinburgh and Sweden) by two different tests which measure bile acid loss or synthesis: the SeHCAT test which measures the 7-day SeHCAT WBR and serum 7 alpha-3ox-C which reflects the rate of bile acid synthesis. RESULTS: Forty-six patients had SeHCAT WBR of less than 10% (19 with ileal disease or resection, nine with idiopathic bile acid induced diarrhoea and 18 with miscellaneous causes for bile acid induced diarrhoea). All patients with ileal or idiopathic disease showed a favorable response to treatment as did 13 of the miscellaneous group. Serum 7 alpha-3ox-C was raised in all subjects with ileal disease/resection, seven patients with idiopathic disease and all subjects in the miscellaneous group who responded to treatment. Sixteen out of 118 patients with SeHCAT WBR greater than or equal to 10% had raised serum 7 alpha-3ox-C. CONCLUSION: The positive predictive value of serum 7 alpha-3ox-C was 74%. The high negative predictive value (98%) of serum 7 alpha-3ox-C indicates the possible use of this test for excluding bile acid malabsorption in this population. All but two subjects who responded to treatment had raised serum 7 alpha-3ox-C concentrations. The possibility that the sensitivity of the test can be improved by repeat testing needs to be further investigated. There was a significant correlation between fractional catabolic rate (FCR) SeHCAT and serum 7 alpha-3ox-C (r = 0.63, P < 0.0001). Further data are required to validate the reference range in women over 70 years of age.

Adolescent↗
PubMed1998

Mechanisms of diarrhoea in myotonic dystrophy.

BACKGROUND: Gastrointestinal (GI) symptoms are common in myotonic dystrophy (MD). Diarrhoea is one of the more disabling of these GI complaints. The mechanisms behind diarrhoea in MD have not previously been investigated systematically. OBJECTIVE: To elucidate the mechanisms behind diarrhoea in MD. METHODS: Twenty patients with MD and suffering from diarrhoea were investigated in order to detect malabsorption (blood tests and faecal fat excretion) and bile acid malabsorption ([75Se]selenahomocholic acid-taurine (SeHCAT) retention) and to study intestinal morphology (duodenal and rectal biopsies). RESULTS: Two patients had deficiency of folic acid and four showed reduced levels of pancreatic isoamylase, but none of them had steatorrhoea. Two out of eight patients had abnormal bile acid breath tests with normal SeHCAT, indicating small bowel bacterial overgrowth and 12 displayed reduced SeHCAT retention. Duodenal biopsies were normal in eight patients and five out of nine rectal biopsies displayed slight inflammation. CONCLUSIONS: A possible mechanism of diarrhoea in MD could be identified in most of the patients. Bile acid malabsorption seems to be a frequent cause and can be treated successfully.

Adult↗