Metallothionein and copper metabolism in liver.
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Animals↗
Biomedical subjects
I Bremner
Publications and source records attributed to I Bremner.
Plasma 65Zn kinetics in the rat.
The amount of 65Zn in the plasma of rats after intravenous injection was found to decline following closely two-compartment kinetics over a period of 90 min. Comparative analysis of the amount of 65Zn present in the two kinetic pools at various time-intervals post-injection with the actual physiological location of the 65Zn, revealed that the initial pool (Qa) is primarily the blood plasma, while the second pool (Qb) is primarily within the liver. The plasma Zn concentration and Qa were both found to fall reproducibly during Zn depletion, whereas Qa and Qb increased following injection of Escherichia coli endotoxin in contrast to the decline in plasma Zn concentration. Further investigation of the nature of Qb indicates that it represents in part a metabolic pool within the liver which varies substantially in response to Zn status in a manner similar to metallothionein.
Animals↗
Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men.
The mechanisms involved in the homeostatic regulation of zinc were studied in five male subjects by using stable 70Zn as a marker. When dietary zinc was reduced from 85 to 12 mumol/d, adaptation was achieved by a mean (+/- SEM) reduction in urine zinc of 48 +/- 7% and in fecal zinc of 46 +/- 12% over 25 d in four subjects. The latter was caused by an increase in the efficiency of zinc absorption from 38 +/- 3% to 93 +/- 1% after 15 d of zinic deprivation and by a reduction in intestinal endogenous losses of zinc. In a fifth subject, who had some evidence of a resolving alcohol-induced hepatitis, urine and fecal zinc were reduced by 64% and 41%, respectively, in 15 d and zinc absorption increased from 46% to 93%. More information on adaptive responses is needed to enable current dietary recommendations to be reconsidered.
Absorption↗
Intestinal absorption and losses of copper measured using 65Cu in zinc-deprived men.
The absorption and intestinal losses of endogenous Cu in response to a low Zn diet were studied in five young male subjects using stable 65Cu as an oral tracer. The subjects received a semi-purified formula diet providing 85 mumol (5.6 mg) Zn/d during 15-day baseline and repletion phases and 12 mumol (0.8 mg) Zn/d during an intervening period of 25 days. Thirty-eight mumol (2.4 mg) Cu/d was provided throughout the study. In four of the subjects, the mean +/- SEM luminal disappearance of 65Cu was 37 +/- 4 per cent during the baseline phase and was unaffected by Zn deprivation (32 +/- 7 per cent) or repletion (30 +/- 7 per cent) as were intestinal losses of endogenous Cu [7 +/- 4, 8 +/- 3, 8 +/- 3 mumol/d (0.4 +/- 0.1, 0.5 +/- 0.1, 0.5 +/- 0.1 mg/d) during baseline, Zn deprivation and Zn repletion phases, respectively]. In a fifth subject, who had some evidence of a resolving alcohol-induced hepatitis, the luminal disappearance of 65Cu was 31, 44 and 42 per cent and the intestinal losses of endogenous Cu 11, 2 and 6 mumol/d (0.7, 0.1 and 0.4 mg/d) during the baseline, Zn deprivation and Zn repletion phases respectively. Plasma Cu concentrations, however, fell throughout the study in all the subjects, despite consistently positive Cu balances. There may be subtle effects of a low dietary intake of Zn on Cu metabolism which were not revealed by the methods used in this study.
Adult↗
Metallothionein and the trace minerals.
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Free Radicals↗
Urinary excretion of metallothionein-I and its degradation product in rats treated with cadmium, copper, zinc or mercury.
The metallothionein-I (MT-I) content of urine following administration of cadmium (Cd), copper (Cu), mercury (Hg) or zinc (Zn) to rats was determined by radioimmunoassay. Urinary excretion of MT-I was increased significantly after injection of each of these metals. Fractionation of urine from Cd-treated rats on Sephadex G-50 showed a single immunoreactive component corresponding to native MT-I, whereas in urine from Cu, Zn or Hg-treated rats 2 immunoreactive components corresponding to MT-I and a possible degradation production were observed. Since a comparable low molecular weight component corresponding to this degradation product was not detected to the same extent on fractionation of plasma from Cu-exposed rat, it seemed to be derived from degradation of MT in the kidney.
Animals↗
Metallothionein immunoreactivity in the liver and kidney of copper injected rats.
Adult male rats were injected intraperitoneally with copper sulphate in physiological saline (3 mg copper/kg body wt). Metallothionein-I (MT-I) levels in liver, kidney, plasma and red blood cells were measured by radioimmunoassay (RIA), prior to the injection and after 7, 16 and 24 h. Copper and zinc levels in liver and kidneys were also monitored. Concentrations of MT-I in liver and kidneys showed a rapid increase and remained elevated for 24 h. Copper concentrations also increased in both tissues but zinc levels remained constant in the kidney and rose only slightly in the liver. MT-I levels increased gradually in plasma but decreased in the red blood cells. Immunochemistry of liver and kidney, using the direct peroxidase technique with antiserum to rat MT-I, revealed an increase in staining in both tissues after copper administration, consistent with the RIA results. The change in distribution of immunoreactive material with time after copper injection indicates a role for MT in the sequestration and excretion of copper in acutely loaded animals.
Animals↗
Determination of molybdenum in plasma using graphite furnace atomic absorption spectrometry.
A sensitive method is described for the determination of Mo in plasma or serum by graphite furnace atomic absorption spectrometry. The method involves extraction of the metal as the 8-hydroxyquinoline complex and is free of the interference effects that prevent the direct analysis of plasma for Mo. Recoveries of internal standards were excellent and results from the analysis of a National Institute of Standards and Technology Standard Reference Material were in good agreement with certified values. The sensitivity of the method, based on the analysis of 1 ml of plasma, is ca. 3 ng ml-1.
Animals↗
Effects of iron deficiency on metallothionein-I concentrations in blood and tissues of rats.
The effects of iron deficiency and of restriction of food intake on blood and tissue metallothionein-I (MT-I) concentrations in rats were investigated. Compared to ad libitum fed controls, MT-I concentrations in the blood cells of the iron-deficient rats were higher, whereas concentrations in pair-fed control rats were lower. Iron deficiency also increased MT-I concentrations in the bone marrow but concentrations in the liver were unchanged and those in the kidneys were reduced. The MT-I in the blood cells was associated mainly with the lighter cell fractions which were rich in reticulocytes. It is suggested that concentrations of MT-I in blood cells reflect erythropoietic activity.
Anemia, Hypochromic↗
Control of selenium and cobalt deficiency in lambs by supplementation of oral anthelmintics.
The benefits of the inclusion of cobalt and selenium supplements in anthelmintic preparations were demonstrated in a 10 week trial with cobalt- and selenium-deficient blackface wethers. The anthelmintics were based on oxfendazole and on levamisole plus oxyclozanide; three doses provided, in total, 38 mg cobalt and 7.2 or 11.3 mg selenium. Administration of the supplements prevented the weight loss and reduction in food intake observed in unsupplemented animals. Blood glutathione peroxidase activities were restored to normal and increases in serum vitamin B12 levels were observed which were consistent with the prevention of both cobalt and selenium deficiencies.
Animals↗
A convenient method for the treatment of chronic copper poisoning in sheep using subcutaneous ammonium tetrathiomolybdate.
Effective control of copper poisoning in sheep was obtained by the subcutaneous injection of ammonium tetrathiomolybdate. Three doses, each of 3.4 mg/kg bodyweight, were given on alternate days. This treatment caused a substantial reduction in liver copper content and in liver damage. It also decreased the mortality rate in animals that had developed the haemolytic crisis. The subcutaneous route is as effective as the intravenous route and is more convenient. No adverse side-effects of the treatment were observed.
Animals↗
EXAFS studies of metallothionein.
Extended x-ray absorption fine structure (EXAFS) has been used to investigate the metal environment in a number of metallothioneins (MT). In all cases, the primary coordination sphere consists of sulphur atoms. In some cases, evidence for cluster formation is obtained.
Animals↗
Nutritional and physiological significance of metallothionein.
The biological function of metallothionein (MT) is still a matter of considerable conjecture. Convincing evidence has accrued that the protein can play an important role in the detoxification of certain heavy metals but a more fundamental role may be concerned with the metabolism of the essential elements zinc and copper. In addition the effects of physical and inflammatory stress and of infection on MT production imply an involvement in defence mechanisms against these conditions. MT may also act as a general detoxifying agent against certain xenobiotics.
Animals↗
Metallothionein in blood, bile and urine.
The development of radioimmunoassays for rat metallothionein-I (MT-I) has revealed that this protein is present in many extracellular fluids. Plasma concentrations are low in normal animals but may be substantially increased in animals with elevated tissue MT levels. MT-I is also excreted in varying amounts into urine and bile, and there is evidence for the presence of degradation products of MT-I, detectable by radioimmunoassay, in these fluids. Investigation of the secretion of MT can provide valuable information on the turnover of the protein in tissues and lead to the development of novel diagnostic tests for the assessment of trace metal status.
Animals↗
Induction of synthesis and degradation of metallothionein-I in the tissues of rats injected with zinc.
A radioimmunoassay specific for metallothionein-I (MT-I) has been used for the estimation of this protein in various tissues of the rat following a single intraperitoneal injection of ZnSO4 (2 mg Zn/kg body weight). Quantitative information has also been obtained about the rates of clearance of MT-I from selected tissues following Zn injection. Wide variations were observed in the basal levels of the protein in different tissues of the rat. The levels of MT-I (micrograms/g fresh weight) were high in kidneys (16.9) and testes (14.3), whereas liver (2.4), pancreas (2.2), intestinal mucosa (2.6) and spleen (0.53) contained only small amounts of the protein. MT-I levels in the liver and pancreas increased several fold following Zn injection. The liver had the highest MT-I levels (23.1) at 12 h post-injection, whereas pancreas recorded the highest level (21.6) at 4 h post-injection. The intestinal mucosa registered only a small increase in MT-I; kidneys, spleen and testes were almost unaffected. Concentrations of MT-I returned to the basal levels at 72 h post-injection in all the tissues studied. The biological half-lives of MT-I in the liver, pancreas and mucosa were estimated to be 13.7, 9.8 and 15.0 h respectively.
Animals↗
Involvement of metallothionein in the hepatic metabolism of copper.
Metallothionein (MT) is often a major copper-binding protein in the liver, particularly of copper-loaded animals. This review describes the isolation of hepatic copper-MT, its physicochemical properties, biosynthesis and intracellular distribution, and possible routes for its degradation and secretion. There is increasing evidence that MT plays an important role in the cellular detoxification of copper, although an involvement in the uptake, storage and transfer of copper has also been proposed. These roles are discussed.
Animals↗
Effect of maternal zinc supply on blood and tissue metallothionein I concentrations in suckling rats.
Changes in metallothionein I (MT-I) levels were measured in blood and tissues of rat pups from dams given diets containing 6, 9 or 40 mg zinc/kg from wk 1 or gestation and throughout lactation. After 1, 2 and 3 wk of lactation, litters from each group were killed and tissues analyzed for MT-I. The relatively mild degree of zinc deficiency, which had no effect on fetal viability or litter size and caused only slightly lower pup weight, caused significantly lower MT-I concentrations in pup liver, thymus, plasma and red cells, particularly in pups from dams receiving 6 mg zinc/kg. Maternal zinc supply is therefore a major determinant of MT-I concentrations in neonatal tissues, and assay of this protein in blood plasma and red cells may give a useful indication of zinc status.
Animals↗
Effects of changes in dietary zinc, copper and selenium supply and of endotoxin administration on metallothionein I concentrations in blood cells and urine in the rat.
These studies were designed to investigate the effects of low dietary zinc, copper or selenium intake of certain types of stress and of injection of zinc, copper or cadmium on metallothionein I (MT-I) concentrations in the blood and urine of rats. The aim was to establish whether such measurements could be of value in the diagnosis of zinc deficiency. Marginal zinc deficiency rapidly caused a major decrease in MT-I levels in the blood cells and to a lesser extent in urine. Injection of zinc and also of cadmium and copper had the opposite effect and increased MT-I concentrations in both samples, although the effects of zinc on blood cells and urine were relatively transient. The MT-I in the blood cells was associated mainly with the erythrocytes. No changes in blood or urine MT-I levels were found in copper- and selenium-deficient rats. Neither cold stress nor restriction of food intake for 24 h had any significant effect on MT-I levels in the blood cells or urine. Endotoxin injection increased urinary MT-I excretion in both zinc-adequate and zinc-deficient rats but did not affect blood cell MT-I levels in either group of animals. It appears therefore that assay of erythrocyte MT levels could be of particular value in the diagnosis of zinc deficiency, especially when it is accompanied by stress or infection.
Animals↗