Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Much can be gained by reassessing the processes which determine the ability of lysosomes to take up or exclude, sequester and mobilize heavy metals. To achieve a better understanding of these events, the chemical forms, intracellular pathways and modes of delivery of metals to lysosomes, as well as the specific physiologic ligands and molecular targets susceptible to metal toxicity have to be identified. None of these can be derived from measurements of metal contents of whole lysosomal fractions because the metal's "effective concentration" at a specific target site may be affected by the binding properties of the lysosomal ligand as well as by those of cation carrier proteins present in the cytosol (e.g., metallothionein), and by interactions with and competitions by other cellular organelles. Therefore, the possibility of such events diminishing or enhancing a metal's direct effect observable in in vitro systems has to be considered before extrapolating to the in vivo situation. Another pitfall to be wary of is the equation of an organelle's relative affinity for a metal in vitro with its susceptibility to the metal's toxic effects. This is evident, albeit at a tissue level rather than at that of organelles, from the discordance between the low affinity of nervous tissue for lead and this metal's pronounced encephalopathic effect. The answers to some of the questions raised in this review may possibly lead to pharmacologic applications, particularly to the development of effective agents for the removal from or the inactivation of toxic metals deposited in lysosomes. At present, considerable uncertainty exists regarding the possible interaction of therapeutic chelating agents with lysosomes in vivo. We do not know, for example, whether the contrasts between the remarkable effectiveness of penicillamine in mobilizing copper from tissues and the limited effectiveness of desferioxamine in removing excess iron stores can be accounted for by differences in accessibility of these two chelators to lysosomes. Or, alternatively, can these differences in effectiveness be related to different ligands or macromolecules interacting with each metal? At least part of the lysosomal iron is bound to ferritin molecules which may not be susceptible to the action of chelating agents after incorporation. Such speculation is not without foundation since ferritin molecules are heterogeneous. However, whether this heterogeneity, which is reflected in different organ-specific patterns of distribution (Powell et al. 1973), is the result of differing affinities of the isoferritins for specific subcellular organelles has not been established. It is conceivable that ferritin molecules present in the cytoplasm may be subtly different from those taken up by lysosomes, implying that the latter are endowed with capabilities for selection of specific macromolecules...
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PMID:Heavy metals and lysosomes. 78 27

The effect of long-term dietary cadmium treatment upon the distribution of the metals copper, iron and zinc has been compared in various organs of male and female rats. The renal accumulation of cadmium was similar in both sexes without a plateau being reached. In contrast, the hepatic accumulation of cadmium was higher in the female than in the male rat and a plateau was observed after 30-35 weeks of dietary cadmium treatment. Most of the cadmium which accumulated in these organs was recovered in the metallothionein fraction andthe concentration of hepatic cadmiumthionein in the female rat was correspondingly higher than in the male rat. Accumulation of cadmium was associated with an increased zinc concentration in the liver and an increased copper concentration in the kidney; these increases were correlated with increases in liver and kidney metallothioneins induced by cadmium. Uptake of cadmium into organs other than liver and kidney occurred to a small extent but was not associated with changes in the concentration of copper and zinc. Cadmium also accumulated in the intestinal mucosa where it could be recovered in a fraction corresponding to metallothionien. A loss of iron from the liver and kidney was also observed following dietary cadmium treatment and involved mainly a loss of iron from ferritin.
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PMID:Influence of dietary cadmium on the distribution of the essential metals copper, zinc and iron in tissues of the rat. 100 32

The combination of transcriptional and translational control elements in an inducible expression vector suitable for use in stably transformed cell lines was explored. To this end, ferritin translational control elements have been inserted downstream from a mouse metallothionein (mMT-I) transcriptional promoter (PmMT-I), and upstream from various reporter protein-encoding open reading frames (ORFs), all carried on a bovine papillomavirus shuttle vector. Protocols which stimulate transcription (with zinc) and translation (with iron) were developed to optimize the induction of reporter protein synthesis. It was found that insertion of an iron regulatory element between the PmMT-I and a reporter ORF bestowed a sixfold inducibility of reporter protein synthesis with iron and a 90-fold inducibility with iron plus zinc in a classical superinduction protocol. Surprisingly, inclusion of other rabbit ferritin light chain sequences (rFL), including the ORF, enhanced reporter inducibilities to over 15- and 500-fold, respectively. These additional rFL sequences not only increased inducibility but also (i) increased the half-life of the mRNA and (ii) strongly inhibited translation of an ORF located downstream from the 5' proximal ORF. The maximum levels of reporter proteins attained in transformed cells after prolonged induction represented from 1% to 7% of total cellular protein. These inducible expression vectors should prove useful for the production and study of cytotoxic proteins.
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PMID:Inducible expression bovine papillomavirus shuttle vectors containing ferritin translational regulatory elements. 133 55

Stimulation of the immune system results in a series of metabolic changes that are antagonistic toward growth. Monokines, including interleukin-1, tumor necrosis factor, and interleukin-6, are released from cells of the monocyte-macrophage lineage after recognition of immunogens. They appear to mediate homeorhetic response, which alters the partitioning of dietary nutrients away from growth and skeletal muscle accretion in favor of metabolic processes which support the immune response and disease resistance. These alterations include 1) decreased skeletal muscle accretion due to increased rates of protein degradation and decreased protein synthesis; 2) increased basal metabolic rate resulting in increased energy utilization; 3) use of dietary amino acids for gluconeogenesis and as an energy source instead of for muscle protein accretion; 4) synthesis by the liver of acute phase proteins; 5) redistribution of iron, zinc, and copper within the body due to the hepatic synthesis of metallothionein, ferritin, and ceruloplasmin; (6) impaired accretion of cartilage and bone; and 7) release of hormones such as insulin, glucagon, and corticosterone. These monokines also influence the differentiation of cells. Tumor necrosis factor suppresses the differentiation of myoblasts and adipocytes whereas the chicken monokine myelomonocytic growth factor induces the differentiation of granulocytes.
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PMID:Monokines in growth and development. 171 68

Beryllium (Be+2), a divalent metal ion, is toxic to both man and animal. Although the molecular basis for its toxicity is unknown, it is well established that micromolar concentrations of beryllium specifically inhibit certain enzymes. Previous in vitro studies have shown that the presence of ferritin, an iron-storage protein, reactivated these enzymes by sequestering beryllium (Price and Joshi, 1984). In the present study we demonstrate in vivo that beryllium and zinc are bound by ferritin in greater amounts than Pb+2, Cu+2, and Cd+2. Beryllium did not induce the synthesis of metallothionein. In animals pretreated with an iron salt (ferric ammonium citrate, 40 mg/kg body wt), liver ferritin was elevated approximately five times and the toxicity of intravenously injected beryllium was significantly attenuated. Excretion and deposition studies suggested that iron salt treatment resulted in a reduction of liver beryllium. Thus the protection against beryllium toxicity by ferric ammonium citrate may be due to increased production of ferritin which binds beryllium and its subsequent elimination in the feces.
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PMID:Ferritin and in vivo beryllium toxicity. 394 60

Rats were injected with 1 mg of Zn2+ as zinc sulfate or 2 mg of Cd2+ as cadmium sulfate per kg of body weight on a daily basis. After seven injections, ferritin and metallothionein were isolated from the livers of the rats. Significant amounts of zinc were associated with ferritin. Incubation of such ferritin with apoenzymes of calf intestinal alkaline phosphatase, yeast phosphoglucomutase, and yeast aldolase restored their enzymic activity. The amount of zinc injected was insufficient to stimulate significant synthesis of metallothionein, but similar experiments with injection of cadmium did stimulate the synthesis of metallothionein. The amount of Zn2+ in ferritin of Cd-injected rats was greater than that in ferritin in Zn-injected rats, which was greater than that in ferritin of normal rats. Thus at comparable protein concentration ferritin from Cd-injected rats was a better Zn2+ donor than was ferritin from Zn-injected or normal animals. Ferritin is a normal constituent of several tissues, whereas metallothionein is synthesized under metabolic stress. Thus ferritin may function as a "metal storage and transferring agent" for iron and for zinc. It is suggested that ferritin probably serves as the initial chelator for Zn2+ and perhaps other metal ions as well and that under very high toxic levels of metal ions the synthesis of metallothionein is initiated as the second line of defense.
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PMID:Ferritin: a zinc detoxicant and a zinc ion donor. 621 27

This study systematically examined the characteristics of specific binding of adult diferric transferrin to its receptor using a Triton X-100 solubilized preparation from human placentas as the receptor source. The following information was obtained. The ionic strength for maximal binding is in the range of 0.1-0.3 M NaCl. The pH optimum for specific binding extends over the range, from pH 6.0-10.0. Specific binding of diferric transferrin is not affected by 2.5 approximately 50 mM CaCl2 or by 10 mM EDTA. Triton X-100 in the concentration range of 0.02-3.0% does not affect specific binding. Specific binding is saturated within 10 min at 25 or 37 degrees C in the presence of excess amounts of diferric transferrin. The binding is reversible and the dissociation of diferric transferrin from the transferrin receptor is complete within 40 min at 25 degrees C. Apotransferrin, both adult and fetal, showed less binding than the holotransferrin species by competitive binding assay in the presence of 10 mM EDTA independent of up to 20 mM CaCl2. A 1500-fold molar excess of adult and fetal apotransferrin is required to give 40% inhibition for 125I-labeled diferric transferrin binding. Since calcium ion is not a factor, and since apotransferrin has such high binding affinity for iron (Ka = 1 X 10(24], this experiment suggests that the EDTA was necessary to prevent conversion of apotransferrin to holotransferrin from available iron in the reaction system. The specificity of the transferrin receptor for transferrin was examined by competitive binding studies in which 125I-diferric transferrin binding was measured in the presence of a series of other proteins. The proteins tested in the competitive binding studies were classified into three groups; in the first group were human serum albumin and ovalbumin; in the second group were proteins containing iron ions, such as hemoglobin, hemoglobin-haptoglobin complex, heme-hemopexin complex, ferritin, and diferric lactoferrin; in the third group were the metal-binding serum proteins, ceruloplasmin and metallothionein. None of these proteins except ferritin showed inhibition of diferric transferrin binding to the receptor. The effect of ferritin was small since a 700- to 1500-fold molar excess of ferritin is required for 50% inhibition of binding of diferric transferrin to the receptor.
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PMID:Characterization of transferrin binding and specificity of the placental transferrin receptor. 631 Nov 10

An analysis of 239Pu-labelled protein complexes in serum and liver cytosol fractions prepared from rats injected intravenously with 239Pu-citrate indicated that among the possible metal-binding proteins, ferritin, transferrin and metallothionein, 239Pu was bound almost exclusively to transferrin. The method employed for the quantitative determination of 239Pu-transferrin was chromatography on immobilized rabbit anti-rat apo-transferrin. There was no evidence that transferrins from serum and liver cytosol are serologically different. The residual blood content of perfused and non-perfused liver was measured using 51Cr-labelled red blood cells and the amounts of blood-derived 239Pu and 239Pu-transferrin in the liver cytosol were calculated. The results are discussed with respect to the possible role of transferrin in the uptake of Pu into cells.
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PMID:Identification of transferrin as the principal plutonium-binding protein in the blood serum and liver cytosol of rats: immunological and chromatographic studies. 660 89

Arsenite is extremely toxic and, though non-mutagenic, is a carcinogen. To determine the effects of arsenite on changes in cell physiology, we searched for genes in HeLa cells whose mRNAs are more abundant after cellular exposure to arsenite. A cDNA subtraction was performed between cDNA synthesized from HeLa cells grown in the absence and presence of 5 microM sodium arsenite. Isolation and sequencing of three clones that showed a higher hybridization signal to RNA from arsenite-exposed cells, versus unexposed cells, revealed that two of the cDNAs coded for human ferritin H chain and the other coded for metallothionein-II. These results suggest the possibility that arsenite exposure may lead to increased levels of oxygen radicals, which augmented metallothionein and ferritin can act to detoxify.
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PMID:Metallothionein-II and ferritin H mRNA levels are increased in arsenite-exposed HeLa cells. 799 84

Iron is an essential element in all living cells because it serves machineries for biological oxidation including hemoglobin, cytochrome c oxidase, etc. Copper is also essential for mammalian life since copper is the prosthetic element of several life-essential enzymes. Although intracellular excessive iron and copper were usually sequestrated in ferritin and metallothionein molecules, accumulation of excess iron and copper may also cause severe tissue injury by including oxyradicals and lipid peroxidation and eventually bring about tissue fibrosis such as liver cirrhosis. Hemochromatosis and Wilson's disease are known as iron and copper accumulation disorders, respectively. In this chapter, we review the cirrhosis in hemochromatosis and Wilson's disease.
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PMID:[Liver cirrhosis in primary hemochromatosis and Wilson's disease]. 811 95


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