Disease relevance of Mt1a

• These findings suggest that disruption of the SCKKSCC motif can inhibit proximal tubular MT uptake and thereby eliminate much of the renal accumulation and toxicity of heavy metals such as cadmium, gold, copper, and cisplatinum [1].
• MT and Mn-SOD induced by cytokines in the liver exert an antioxidative role during acute phase response, therefore preventing tissues from injury by oxidative stress [2].
• The refined metallothionein structure has a root-mean-square deviation of 0.016 A from ideality of bonds and normal stereochemistry of phi, phi and chi torsion angles [3].
• Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes [4].
• Protective role of metallothionein in stress-induced gastric ulcer in rats [5].

Psychiatry related information on Mt1a

• The growth inhibitory factor (GIF) is a new metallothionein (MT)-like protein that is downregulated in Alzheimer's disease (AD) brain [6].
• The results from a second experiment demonstrate that the attenuation of the MTII-induced anorexia was due to learned schedules of food intake rather than food deprivation per se [7].
• In the present experiment, the effects of food and water deprivation alone or of immobilization stress plus food and water deprivation on liver, brain, and heart MT have been studied in adult male rats [8].
• Our results indicate that MT-II has a very limited brain penetration capability, and its effect on feeding behavior following systemic administration may be mediated by either the brain regions in close proximity to the CVOs or sites outside of the BBB, including CVOs or other peripheral systems [9].
• Unlike satiation, rats that received exposure after MTII exhibited continued high levels of responding to the tone [10].

High impact information on Mt1a

• Activation of a heterologous promoter in response to dexamethasone and cadmium by metallothionein gene 5'-flanking DNA [11].
• Here we demonstrate that although the rat and human GH genes alone do not restore growth in transgenic mutants, a metallothionein-rat growth hormone fusion gene (MT-rGH) does [12].
• However, those studies were done before anything was known of the specific binding of cadmium to metallothionein, an intracellular low molecular weight protein [13].
• The induced synthesis of metallothionein has a marked effect on the pharmacokinetics of cadmium and other divalent metals [13].
• Circulating metallothionein was measured by radioimmunoassay over a 13-day period in male Sprague-Dawley rats that received a sequence of three intraperitoneal injections (at 3-day intervals) of either 5 milligrams of zinc or 0.8 milligrams of cadmium per kilogram of body weight [14].

Chemical compound and disease context of Mt1a

• In contrast, induction of the metallothionein I gene by dexamethasone did not alter the basal pattern of hypersensitivity [15].
• Treatment of the hepatoma bearing rats with 5-azacytidine, a demethylating agent, induced basal as well as heavy metal-activated MT-I gene expression in the hepatoma, implying that methylation was indeed responsible for silencing the gene [16].
• Dimethylsulfoxide, a chemical scavenger for reactive oxygen species, was used to confirm the antioxidant effect of MT and found to suppress myocardial infarction and lipid peroxidation just as MT did [17].
• The hypermethylation of MT-I promoter was probably caused by significantly higher (as much as 7-fold) level of DNA methyl transferase activity as well as enhanced expression of its gene in the hepatoma relative to the host liver [16].
• Bisulfite genomic sequencing showed significant (>90%) demethylation of CpG dinucleotides spanning MT-I promoter in the hepatoma following treatment with 5-AzaC [16].

Biological context of Mt1a

• The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses [18].
• Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures [19].
• Concomitant with the up-regulation of metallothionein gene expression, IL-6 also increased cellular zinc [19].
• Thus, IL-6 is a major cytokine mediator of metallothionein gene expression and zinc metabolism in hepatocytes and provides cytoprotection from CCl4-induced hepatotoxicity via a mode consistent with dependence upon increased cellular metallothionein synthesis and zinc accumulation [19].
• Pretreatment with TNF, however, did not affect the increased levels of plasma fibrinogen and liver MT induced by the following paraquat treatment, although it did prevent lipid peroxidation in the liver [2].

Anatomical context of Mt1a

• Anti-megalin antisera, but not control sera, displace >90% bound MT from rat renal brush-border membranes [1].
• Megalin ligands including beta(2)-microglobulin and also recombinant MT fragments compete for uptake by megalin-expressing rat yolk sac BN-16 cells [1].
• MT-I and MT-II are expressed in many tissues, whereas MT-III is expressed exclusively in the central nervous system (CNS) [20].
• MT-I and MT-II are widely expressed isoforms, whereas MT-III is mainly expressed in the central nervous system and is the only isoform that inhibits survival and neurite formation of rat cortical neurons in vitro [21].
• Effect of zinc, copper and glucocorticoids on metallothionein levels of cultured neurons and astrocytes from rat brain [22].

Associations of Mt1a with chemical compounds

• Dexamethasone increased MT-I levels in both neurons and astrocytes in vitro in a concentration-dependent manner [22].
• We studied the effect of metallothionein (MT), glutathione and metal (Fe and Zn) accumulation [23].
• Bosentan treatment partially prevented the increase in MT levels in both liver and kidney, along with reduced serum creatinine and increased urinary creatinine levels [24].
• Moreover, GIF at 40-80 microm inhibited tyrosine nitration by peroxynitrite as efficiently as metallothionein I+II at the same concentration [25].
• ESR spin-trapping studies demonstrated that GIF at 2-6 microm scavenged hydroxyl radicals generated by a Fenton-type reaction or the photolysis of hydrogen peroxide much more effectively than the same concentration of metallothionein I+II [25].

Physical interactions of Mt1a

• First, MT binds megalin, but not cubilin, in direct surface plasmon resonance studies [1].
• Metallothionein-like cadmium binding protein in rat testes administered with cadmium and selenium [26].

Regulatory relationships of Mt1a

• Endotoxin and intracerebroventricular injection of IL-1 and IL-6 induce rat brain metallothionein-I and -II [20].
• Interestingly, most MT in control rat cerebrum and cerebellum was accounted for by MT-III, with MT-I/II being less than 10% [27].
• The interaction between pp60c-src and MT appears to influence the formation of both MT2 and MT3 [28].
• The kainate-selective glutamate receptor GluR6 was constitutively expressed under the control of a metallothionein promoter [29].
• We have shown previously that the heavy metal-induced metallothionein-I (MT-I) gene expression is specifically repressed in a rat fibroblast cell line (Ku-80) overexpressing the 80-kDa subunit of Ku autoantigen but not in cell lines overexpressing the 70-kDa subunit or Ku heterodimer [30].

Other interactions of Mt1a

• Third, megalin and fluorescently labeled MT colocalize in BN-16 cells, as shown by fluorescent microscopic techniques [1].
• When recombinant MTs were added to cultures grown in the presence of brain extract, MT-III but not MT-I had an inhibitory effect on neuron survival, confirming that MT-III is a specific inhibitory factor in this assay [31].
• Synergistic induction of metallothionein synthesis by interleukin-6, dexamethasone and zinc in the rat [32].
• Endothelin-1-mediated alteration of metallothionein and trace metals in the liver and kidneys of chronically diabetic rats [24].
• IL-11 and to a lesser extent LIF, are also potential mediators of MT synthesis in inflammation [33].

Analytical, diagnostic and therapeutic context of Mt1a

• In the present study, high expression of MT-III and MT-I + II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats [18].
• MT synthesis in the lung and heart was evaluated by immunoassay using a specific antibody to MT-1, because of its low concentration in these tissues [32].
• Compared with the control group, the stress groups had higher inductions of MTs and MT-1 and MT-3 mRNA in hippocampus [34].
• Time-course studies of MT mRNA expression after single Cd injection were observed by Northern-blot analysis [35].
• The accumulation of MT in hepatocytes in the presence of Zn (10 mumol/L)+Dex (1 mumol/L) was enhanced 29% and 49% by media from lipopolysaccharide (LPS)-stimulated peritoneal macrophage (PMM) and Kupffer cell cultures (KCM), respectively [33].

References