Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intracellular copper content of mouse hepatocytes has been altered by incubating with either increasing amounts of extracellular copper or increasing amounts of diamsar, a copper chelator. Metallothionein 1 (MT1) and MT2 mRNA levels in the cells increased in proportion to the intracellular copper concentration. The degree of stimulation was similar for both MT1 and MT2, with mRNA levels increasing approximately fourfold for a six- to eightfold increase in intracellular copper levels. In contrast, neither copper uptake nor ceruloplasmin mRNA showed any response to intracellular copper levels. Unlike the situation in the rat, there was no clear evidence for saturation of copper uptake. Incubating cells with increasing amounts of 64Cu resulted in a linear increase in the amount taken up over 2 h. The amount of 64Cu accumulated was the same in control and copper-depleted cells, which suggests that neither ceruloplasmin production nor copper uptake is regulated by intracellular copper levels. However, other possibilities, such as the chelators not being able to deplete the pool(s) responsible for the control of ceruloplasmin production or copper uptake, must also be considered.
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PMID:Effects of cellular copper content on copper uptake and metallothionein and ceruloplasmin mRNA levels in mouse hepatocytes. 223 Oct 26

Interleukin 1 (IL 1) production is stimulated by infection, cellular injury, and inflammation. This cytokine directs a wide spectrum of host responses. Human interleukin 1 alpha (IL 1 alpha) was used to examine the time course of effects on zinc metabolism as part of the acute phase response. IL 1 produced a transient depression in the serum zinc concentration and increased serum ceruloplasmin. Metallothionein levels were increased in liver 14-fold after IL 1. Increased expression of metallothionein-1 and -2 genes following IL 1 were observed in liver, bone marrow, and thymus. Pulse-labeling experiments with i.v.-administered 65Zn showed that IL 1 drastically altered zinc distribution kinetics among tissues. More 65Zn was taken up (and/or retained) by the liver, bone marrow, and thymus 6 h after IL 1, whereas correspondingly less 65Zn was found in bone, skin, and intestine. Uptake by other tissues was not affected by IL 1. Chromatography of cytosol from tissues with increased 65Zn uptake suggests the IL 1-induced redistribution may be driven by enhanced metallothionein synthesis. Collectively, the results show that IL 1 regulates zinc metabolism and may direct its preferential, tissue-specific distribution via elevated metallothionein-1 and -2 gene expression.
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PMID:Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. 245 83

Two-wk-old broiler chicks were inoculated via crop intubation with Eimeria acervulina at two doses: 10(5) or 10(6) sporulated oocysts/bird or with Eimeria tenella at a dose of 10(5) sporulated oocysts/bird. Serum and liver samples were collected on days 3 and 6 post-inoculation (PI). There were no significant changes in serum or liver zinc, copper, and iron concentrations in any of the infected groups by 3 d PI. However, on d 6, PI serum protein was significantly reduced in all of the infected groups compared to their pair-fed controls. The chicks infected with E. tenella had significantly reduced serum zinc (1.20 vs 1.77 micrograms/mL) and iron (0.44 vs 1.28 micrograms/mL) concentrations and significantly elevated serum copper (0.28 vs 0.17 micrograms/mL) and ceruloplasmin levels (20.33 vs 11.11 micrograms/mL) compared to their pair-fed counterparts. Those chicks infected with E. acervulina (10(6) oocysts/bird) exhibited significantly reduced serum iron concentration by 6 days PI (0.90 vs 1.14 micrograms/mL). Liver zinc was significantly increased in the chicks infected with E. tenella (349 vs 113 micrograms/g dry liver wt), as was copper (24 vs 19 micrograms/g), whereas liver iron concentration was significantly reduced (172 vs 243 micrograms/g) compared to pair-fed controls. At both dose levels, the chicks infected with E. acervulina exhibited a significant reduction in liver iron by 6 d PI. Hepatic cytosol metals generally reflected whole tissue levels. Metallothionein (MT)-bound zinc was significantly elevated in the chicks infected with E. tenella. Iron bound to a high molecular weight, heat-stable protein fraction (presumably cytoplasmic ferritin) was significantly reduced in chicks infected with E. acervulina, as well as those infected with E. tenella. Collectively, the changes in serum zinc, copper, and iron concentrations, as well as the changes in hepatic zinc and MT-zinc concentrations in the chicks infected with E. tenella were similar to changes evoked during an acute phase response to infection. It is possible that a secondary bacterial infection or inflammation stemming from erosion of the lining of the cecum may play a role in the response of trace element metabolism to the E. tenella infection.
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PMID:Serum and liver zinc, copper, and iron in chicks infected with Eimeria acervulina or Eimeria tenella. 248 59

Metallothionein (MT) levels were measured by radioimmunoassay in lungs of animals exposed 0, 3, and 6 days to 85% oxygen. MT levels increased with duration of exposure from 112.0 ng/lung in sham air control animals to 872.6 ng/lung in animals exposed for 6 days to oxygen. Gel chromatographic analysis of lung homogenates from oxygen-exposed animals revealed the presence of a copper- and zinc-binding component with an approximate molecular weight of 12,000 Da. It was heat stable and cross-reacted with anti-MT. The induction of pulmonary Cu/Zn-thionein was accompanied by an acute phase response, characterized by elevated serum Cu and ceruloplasmin levels and depressed serum Zn. Total lung Cu and Zn also increased, perhaps as a consequence of normal repairative processes necessitated by the oxidant injury. Increased adrenal weight and coincident thymic atrophy in oxygen-exposed animals suggested the participation of adrenocorticosteroids in the induction process.
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PMID:Induction of pulmonary metallothionein following oxygen exposure. 258 73

A monkey model has been set up for protein calorie malnutrition and calcium deficiency. Oral exposure of 5ppm Cd/kg body wt./day for 24 weeks led to increased excretion of Cd, metallothionein (MT) and zinc. Rehabilitation of PCM monkeys for one year resulted in gradual reduction and finally complete disappearance of urinary metallothionein. During Cd exposure, the accumulation of Cd and induction of MT was significantly higher in liver, kidney and intestine. MT was also induced in heart, lung and testis of Cd exposed PCM and calcium deficient monkeys. Metallothionein from liver has been resolved into three isoforms, viz MTa, MTb and MTc on DEAE-Sephadex A 25 ion exchange column. MTc is the major isoform in Cd-treated, normal and protein calorie malnourished monkeys whereas MTb is the major isoprotein in the cadmium treated calcium deficient monkeys. The iso-metallothioneins varied in their metal composition in the nutritional stress conditions and showed different capacities to reactivate apo-enzymes viz. alkaline phosphatase, ceruloplasmin, superoxide dismutase and glutathione peroxidase. Thus, metallothionein plays a key role in metal metabolism during cadmium toxicity under nutritional stress conditions.
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PMID:Role of metallothionein in metal detoxification and metal tolerance in protein calorie malnutrition and calcium deficient monkeys (Macaca mulatta). 295 56

The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth. Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.
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PMID:The ontogeny of liver copper metabolism in the guinea pig: clues to the etiology of Wilson's disease. 371 Apr 31

Cd, Cu, and Zn were determined in plasma and blood cells of rats given daily sc injections of 0.5 mg Cd per kilogram of body weight for 4, 8, and 15 wk. The distribution of these metals in the plasma was also examined by Sephadex G-75 chromatography. In the whole blood Cd increased continuously and reached 1.5 micrograms/ml at 15 wk. Plasma Cd was less than 2% of the total Cd in blood at first and increased to 7.8% in the last week. A significant portion of plasma Cd was found in the metallothionein fraction at 4 wk. The Cd in this fraction increased to more than 50% of the plasma Cd after the 15-wk exposure. The rest of the plasma Cd was distributed in high-molecular-weight protein fractions. Blood Cu was up to 1.3-1.4 micrograms/ml (about twice the value for controls) from 4 to 8 wk, but diminished to about a half the control value at 15 wk. These changes were greater in the plasma and parallel to the Cu contents of the ceruloplasmin fraction. A small amount of plasma Cu was found in the metallothionein fraction at 4 wk. In this fraction Cu increased to about 8% of the plasma Cu at the last week. Blood Zn remained almost unchanged at first but decreased in the last week. Most of the plasma Zn was recovered from high-molecular-weight protein fractions, but not from the metallothionein fraction. Metallothionein in the plasma contained more Cu than Cd. Plasma concentrations of Cd bound to this protein were 0.008, 0.029, and 0.104 micrograms/ml, and the Cu/Cd molar ratios were 9.9, 3.4, and 1.1 at 4, 8, and 15 wk, respectively.
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PMID:Cadmium, copper, and zinc distribution in blood of rats after long-term cadmium administration. 723 Feb 73

Metallothionein (MT) synthesis induced by the inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF), was studied in vivo. Administration of recombinant human IL-6 or TNF to rats caused the acute phase responses including rapid decreases in plasma zinc (Zn), and increases in plasma copper (Cu) and ceruloplasmin. Hepatic concentration of MT-I, one of MT isoforms, began to increase within 3 h after the injection of IL-6 or TNF. In IL-6-treated rats, MT-I concentration in liver reached a maximum level at 12 h and decreased with a transient rebound, whereas, in TNF-treated rats, a high level of MT-I lasted for about 48 h. MT-II, the other MT isoform, was induced more than MT-I in liver by both cytokines. MT-I was also induced in lung and heart by TNF, but little by IL-6. The data suggest that IL-6 may be responsible for MT synthesis in liver, whereas TNF may be responsible not only in liver but also in lung and heart. Furthermore plasma concentration of MT did not always reflect the enhanced concentration of MT by TNF and IL-6 in liver, suggesting involvement of many factors influencing plasma MT levels. The interrelation between IL-6 and TNF for MT synthesis has also been discussed.
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PMID:Differential induction of metallothionein synthesis by interleukin-6 and tumor necrosis factor-alpha in rat tissues. 818 7

We previously demonstrated that rats exposed to the peroxisome proliferator (PP) diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxidase activity, which suggests tissue copper deposition. Copper is highly toxic in excess, and results in cellular damage and hepatocellular carcinomas (HCC). This study addresses changes in expression of copper-related genes and metal accumulation in hyperplastic liver and tumors induced by PP. Male rats were fed diets containing DEHP or clofibrate (CLF) for 3-60 days (hyperplasia) and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-beta-hydroxyethyl) acetamide for 10 months (HCC). During hyperplasia, an immediate and progressive decrease in serum CP activity was observed (P < 0.05), as were reductions in mRNA levels for both CP and Wilson's disease gene (WD gene, a P-type ATPase) (P < 0.05). Tumor-bearing rats had lower serum CP activity (P < 0.05), and CP and WD gene mRNA levels were reduced in tumors (P < 0.05), and in liver surrounding tumors (SL) (P < 0.05). Metallothionein mRNA showed no consistent changes during hyperplasia. Tumors showed a 2.5-fold induction of metallothionein mRNA (P < 0.05), and a 1.2-fold increase in SL. Temporal increases in liver copper content occurred during hyperplasia, with increases of 2-fold (DEHP) and 3.3-fold (CLF) at 60 days (P < 0.05). Copper content was 2.2-fold higher in tumors (P < 0.05) and 1.7-fold higher in SL; iron did not increase and zinc decreased temporally. Thus, copper accumulation and changes in copper-related gene expression may be contributing factors in liver neoplasia in PP-treated rats. Loss of CP results in decreased free radical scavenger capacity and thus may enhance oxidative damage induced by PPs.
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PMID:Hepatic hyperplasia and cancer in rats: alterations in copper metabolism. 1035 93

Metallothionein (MT) protects the body from both harmful non-essential and excessive essential metals. Copper (Cu) is an essential metal, and its concentration in the body is regulated at a constant level between excess and deficient ones. Cu accumulating in the livers of Wilson disease patients and its animal model, Long-Evans rats with a cinnamon-like coat color (LEC) rats, is in the form of Cu,Zn-MT, MT being an antioxidant. Contrary to the efficient production of MT in response to excessive accumulation of Cu in LEC rats, Cu-binding to MT only occurs marginally under normal conditions. However, the present study revealed that Cu binds to MT more with a severe Cu-deficiency. Namely, male C57BL/6J mice were fed a Cu-deficient diet (0.037 mg Cu/g) and deionized water containing trientine, and then the concentration and distribution of Cu were determined. It was suggested that the cessation of biliary excretion and limitation of the Cu supply to ceruloplasmin are the first responses on feeding of a Cu-deficient diet, followed by an increase in Cu-MT with maintenance of the Cu concentration in the liver. These results suggest that MT causes the recruitment of Cu in a Cu-deficient environment by sequestering Cu from degraded Cu-enzymes and delivering it to Cu chaperones.
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PMID:Roles of metallothionein in copper homeostasis: responses to Cu-deficient diets in mice. 1180 37


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