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The present study was undertaken to investigate the association between MT gene polymorphism and type 2 diabetes mellitus. Using the PCR-based restriction fragment length polymorphism method, seven single nucleotide polymorphisms (SNPs) in MT genes (rs8052394 and rsl 1076161 in MT]A gene, rs8052334, rs964372, and rs7191779 in MTIB gene, rs708274 in MTIE gene, and rsl0636 in MT2A gene) were detected in 851 Chinese people of Han descent (397 diabetes and 454 controls). Several serum measurements were also examined randomly for 43 diabetic patients and 41 controls. The frequency distributions of the U allele in SNP rs8052394 of MT]A gene were significantly associated with the incidence of type 2 diabetes. There was no difference between patients and controls for the rest of six SNPs. Serum levels of interleukin-6 and tumor necrosis factor-a were higher, and serum superoxide dismutase activity was significantly lower in the diabetic group than those in the control group. For diabetic patients, serum superoxide dismutase activity was significantly lower in GO or GA carriers than those of AA carriers of rs8052394 SNP. Increased serum levels in diabetic patients were positively associated with rs964372 SNP, and type 2 diabetes with neuropathy was positively associated with rsl0636 and rsl 1076161. These results suggest that multiple SNPs in MT genes are associated with diabetes and its clinical symptoms. Furthermore, MTJA gene in rs8052394 SNP is most likely the predisposition gene locus for diabetes or changes of serum superoxide dismutase activity. [ABSTRACT FROM AUTHOR]

Abstract: Previous reports have shown that metallothionein (MT) may modulate p53 activity through zinc exchange. However, little is known on a direct interaction between MT and p53 in cells. The results demonstrate an interaction between MT and p53 can occur in vitro. The complex between MT and p53 was observed in breast cancer epithelial cells with both wild and inactive type of p53. Furthermore, it was shown that wt-p53 was preferentially associated with Apo-MT. Our data suggest that co-expression of MT and p53 and their complex formation in tumor cells may be involved in regulation of apoptosis in these cells. [Copyright &y& Elsevier]

Rats fed diets with cadmium (Cd) concentrations similar to that found in human diets, and nutritionally marginal with respect to iron (Fe), zinc (Zn), and calcium (Ca) retained 10 times more Cd in the duodenum than rats fed adequate mineral diets. In the current study, 2 experiments were performed to determine the role of intestinal metallothionein (MT) in the accumulation of duodenal Cd, and to determine whether endogenous rice grain Cd is as available as Cd exogenously incorporated into the grain. In Expt. 1, wild-type and MT-null mice were fed 40% rice diets containing marginal or adequate amounts of Fe, Zn, and Ca, and 240 mug Cd/kg. Duodenal Cd was 10 times higher in both wild-type and MT-null mice regardless of their mineral status. In Expt. 2, one group of rats was fed 40% rice diets in which Cd was incorporated into the rice during growth and maturation, and another group was fed 40% rice diets in which Cd was incorporated into the rice during cooking. Each group also was fed either marginal or adequate amounts of Zn, Fe, and Ca. After 5 wk, rats were given a single meal labeled with (109)Cd, and the amount of label retained after 7 d was determined by whole-body counting. Rats with marginal mineral status retained 10 times more (109)Cd than those with adequate status; however, there was no difference between rats fed endogenous or exogenous Cd rice. Although duodenal Cd concentration was 8 times higher in the marginally fed rats, MT concentration was unchanged. These 2 experiments indicate that MT induction is not involved in duodenal Cd accumulation in animals with marginal dietary status of Fe, Zn, and Ca. In addition, they support the hypothesis that marginal deficiencies of Fe, Zn, and Ca, commonly found in certain human populations subsisting on rice-based diets, play an important role in increasing the risk of dietary Cd exposure. [ABSTRACT FROM AUTHOR]

In the present study, the role of endothelin-1 (ET-1) on alterations of hepatic and renal metallothionein (MT) and trace metals (Zn, Cu, and Fe) were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetic rats, age- and sex-matched controls, as well as control and diabetic animals on a dual ET A /ET B receptor blocker, bosentan, were investigated after 6 months of follow-up. MT was measured by cadmium-heme assay. Metals were measured by atomic absorption spectrometer. ET-1 mRNA was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Hepatic and renal ET-1 mRNA was increased in diabetic rats as compared to control rats, along with an increase in both hepatic and renal MT proteins. The increased hepatic MT protein level was associated with decreases in hepatic Cu and Fe, whereas increased renal MT was associated with increases in renal Cu and Fe accumulation. Zn levels were unaltered in both organs in diabetic rats. Bosentan treatment partially prevented the increase in MT levels in both liver and kidney, along with reduced serum creatinine and increased urinary creatinine levels. Further bosentan treatment corrected the increased Cu and Fe levels in the kidney in diabetic rats, but reduced hepatic Cu and Fe levels. No significant effects of bosentan treatment on nondiabetic rats were observed. The data suggest that the possible effects of ET antagonism in diabetes may be mediated via changes in MT and trace metals. [ABSTRACT FROM AUTHOR]

Studies high-glucose-induced metallothionein (MT) expression in endothelial cells. Cell viability and proliferation; Effect of high glucose concentrations on endothelin-1 mRNA level; Role of endothelin-1 in MT expression.

Prior studies show that a single subcutaneous (sc) exposure to cadmium (Cd) will induce injection site sarcomas (ISS) in rats. These tumors, thought clearly malignant, do not often metastasize or invade subdermal muscle layers because of their location. Recent evidence indicates that when tumorigenic cells chronically exposed to Cd in vitro are inoculated into mice, tumor progression and invasiveness in the mice are enhanced. Thus, we studied the effects of repeated Cd exposures on tumor incidence, progression, and metastatic potential in rats. Wistar (WF) and Fischer (F344) rats (30 per group) were injected sc in the dorsal thoracic midline with CdCl2 once weekly for 18 weeks with doses of 0, 10, 20, or 30 μmol Cd/kg. This resulted in total doses of 0, 180, 360, or 540 μmol/kg. One other group of each strain received a low, loading dose of Cd (3 μmol/kg) prior to 17 weekly injections of 30 μmol/kg (total dose 513 μmol/kg). Rats were observed for 2 years. Many F344 rats (57%) died within one week after the first injection of the highest dose, but WF rats were not affected. The low loading dose prevented acute lethality of the high dose in F344 rats. Surprisingly, latency (time to death by tumor) of ISS was the shortest in the groups given the low loading dose in both strains. ISS in these groups also showed the highest rate of metastasis and subdermal muscle layer invasion. Based on ISS incidence in the groups given the lowest total dose of Cd (180 μmoles/kg), F344 rats were more sensitive to tumor induction, showing an incidence of 37% compared to 3% in WF rats. On the other hand, Cd-induced ISS showed a higher overall metastatic rate in WF rats (18 metastatic ISS/68 total tumors in all treated groups; 27%) compared to F344 rats (6%). Immunohistochemically, the primary ISS showed high levels of metallothionein (MT), a cadmium-binding protein, while metastases were essentially devoid of MT. These results indicate that repeated Cd exposures more rapidly induce ISS. An initial low exposure to Cd further accelerates the appearance and enhances the metastatic potential and invasiveness of these tumors. The primary and metastatic ISS appear to have a differing phenotype, at least with regard to MT production. The association between multiple Cd exposures and enhanced metastatic potential of the ensuing tumors may have important implications in chronic exposures to Cd, or in cases of co-exposure of Cd with organic carcinogens, as in tobacco smoking. [ABSTRACT FROM PUBLISHER]

Background: Three isoforms of metallothionein (MT-I, -II, and -III) have been detected in mice brain but little is known on their inducibility. Therefore, changes in MT levels in brain were investigated in MT-I overexpressing transgenic mice (MT-I*) and wild type mice of the same strain (C57BL/6J) after oral administration of ethanol. Methods: All experimental mice were given 4 g/kg of ethanol by gastric intubation. In addition, to account for the stress of animal handling, both groups of mice (MT-I* and C57) were given distilled water by gastric intubation and used as controls. At different times after ethanol/water treatment, the mice were killed and the brains were dissected into six regions. The total amount of MT in the brain and different regions were measured by a cadmium-binding assay. Zinc and copper were measured by atomic absorption spectrometry. The results were compared with untreated mice and corresponding control mice. Results: In C57BL/6J mice, the whole brain MT was increased by ∼1.29-fold at 12 hr and ∼1.27-fold at 18 hr after ethanol administration compared with basal levels. In MT-I* male mice, the whole brain MT was increased by ∼1.64-fold at 12 hr and ∼1.62-fold at 18 hr after ethanol administration, whereas in MT-I* female mice, it was increased by ∼1.57-fold at 12 hr and ∼1.57-fold at 12 hr and ∼61-fold at 18 hr after ethanol administration. Although the zinc and copper levels in the whole brain were not altered, the zinc level in the cerebellum at 12 and 18 hr in male and female MT-I* mice were increased, and zinc levels in the hippocampus of male MT-I* mice were increased at 12 and 18 hr after ethanol treatment. Conclusions: Acute or chronic ethanol administration can cause generation of oxygen free radical and oxidative stress to the brain. The generation of free radicals is thought to be one of the causes of cell injury after ethanol administration. The mechanism of induction of MT in brain after oral ethanol administration may be associated with oxidative stress caused by ethanol or its metabolites, and can be considered as a protective mechanism against ethanol toxicity. [ABSTRACT FROM AUTHOR]

Body retention and tissue distribution of Cd from oral 109 CdCl 2 and 109 Cd‐metallothionein were studied in C57BL/6J mice given identical doses (60 μg Cd and 2 μCi 109 Cd). Measurement of 109 Cd radioactivity in mice showed identical absorption but differences in tissue distribution of Cd from the two forms. A significantly greater deposition of Cd was observed in the kidney of mice fed Cd‐metallothionein than in the CdCl 2 group where a major portion of Cd was deposited in the liver. Most of the radioactive Cd in the renal and hepatic tissues and in the duodenum was bound to metaltothionein 24 h after oral Cd‐metallothionein, whereas only 30 and 38% of the cadmium in liver and kidney supernatants, respectively, were bound to metallothionein after oral CdCI 2 . These results suggest that the dietary form of Cd may influence the renal deposition of Cd. [ABSTRACT FROM PUBLISHER]

Intravenous injection of 109Cd‐labeled CdCI2 (I mg/kg) to control rats and rats that had been injected with CdCI2 (0.25 mg/kg) 24 hr earlier showed that there was a decrease in the biliary excretion of 109Cd in the latter group. The 24 hr pretreatment with CdCI2 resulted in induced synthesis of metallothionein in rat liver and kidney. The binding of cadmium to liver tissue was increased and the renal accumulation of cadmium was unaltered on cadmium pretreatment. Rat liver metallothionein was isolated from rats injected repeatedly with CdCl2 Intravenous injection of cadmium‐bound metallothionein gave a different distribution of cadmium in the tissues and biological fluids as compared to injection of CdCl2. A major percentage of cadmium was deposited in the kidney with urinary excretion after injection of rat cadmium‐metallothionein to control rats. The biliary excretion of cadmium after cadmium‐metallothionein injection was minimal. About 90% of cadmium in the kidney cortex and urine could be recovered as cadmium‐thionein in sephadex gel filtration, 3 hr after cadmium‐thionein injection. [ABSTRACT FROM PUBLISHER]

In protecting the body against the noxious effects of dietary cadmium ions, cadmium is bound to metallothionein in the proximal intestine, and subsequently excreted into the lumen with desquamation of the epithelium. The purpose of this study was to determine the extent to which cadmium in the form of intestinal cadmium‐thionein is absorbed from the intestinal lumen and to appraise the toxicity of cadmium‐thionein on the intestinal mucosa. With open‐ended duodenal perfusion, equivalent amounts of cadmium administered as CdCl2 or cadmium‐thionein entered the mucosa, but significantly less cadmium from the perfusate of cadmium‐thionein passed into the body. Exposure of the mucosa to CdCl2 for 1 hr led to minor abnormalities in the form of broadening of villi with pseudostratification of epithelium, and swelling of mitochondria, whereas cadmium‐thionein produced extensive necrosis of absorptive cells. The results suggest that cadmium‐thionein may play a paradoxical role, providing protection against the cadmium ion in the intracellular milieu, but promoting cadmium toxicity when it is present in sufficient amounts in the lumen of the intestine. [ABSTRACT FROM PUBLISHER]

Biliary excretion of cadmium was studied in rats after intravenous injection of different doses of cadmium chloride (0.1–2 mg Cd/kg). The rate of bile flow was not affected by cadmium injection and cadmium was excreted into bile during the first 2 hr after injection. The biliary excretion of cadmium increased with increasing dose of CdCl1. Cumulative biliary excretion of cadmium for 5 hr was 0.065% of the administered dose for groups injected with 0.1 mg Cd/kg as compared to 16.9% of the administered dose for 2 mg Cd/kg. During the 5 hr experimental period, most of the cadmium in liver cytosol was bound to high‐molecular‐weight proteins and less than 10% was bound to the metallothionein fraction. The biliary cadmium was recovered as a low‐molecular‐weight compound (less than 4,000) in experiments with various doses of cadmium and no cadmium was attached to high‐molecular‐weight proteins or metallothionein in the bile. The low‐molecular‐weight cadmium complex in bile was partially characterized as Cd‐glutathione by thin‐layer chromatography and amino acid analysis. [ABSTRACT FROM PUBLISHER]

To investigate the role of metals in the regulation of the ontogenic expression of rat liver metallothionein (MT) mRNA, the concentrations of zinc, MT and MT mRNA were determined in livers of fetal and newborn rats from dams which were fed with a control or zinc-deficient or copper-deficient or iron-deficient diet from day 12 of gestation. The liver samples were analyzed for MT-mRNA levels using a mouse MT-I cRNA probe. Although the newborn hepatic levels of each metal (zinc or copper or iron) was specifically reduced corresponding to the respective mineral deficiencies, the hepatic concentrations of total MT and MT-I mRNA were significantly decreased only in pups born from zinc-deficient dams. Injection of the zinc-deficient newborn pups with 20 mg Zn as ZnSO4/kg restored with MT-I mRNA levels to slightly above control values within 5 h of injection. The hepatic zinc, MT and MT-I mRNA levels were observed to increase significantly in control fetal rat liver on days 17-21 of gestation but there were little changes in either zinc or MT in fetal livers from zinc-deficient dams during the late gestational period. The MT-I mRNA level also did not show an increase on days 18 and 20 of gestation in zinc-deficient fetal liver as compared to controls. These results demonstrate a direct role of zinc in hepatic MT gene expression in rat liver during late gestation. Immunohistochemical localization of MT using a specific antibody to rat liver MT showed that the staining for MT in zinc-deficient pup liver was mainly in the cytosol in contrast to the significant nuclear MT staining observed in control newborn rat liver. The results suggest that maternal zinc deficiency has a marked effect not only in decreasing the levels of hepatic MT and MT-I mRNA but also in the localization of MT in newborn rat liver. [ABSTRACT FROM AUTHOR]

Examines the effect of mixture of stable and radioactive mercury vapor on human subjects. Analysis on the distribution of inhaled mercury to the different organs; Impact of mercury vapor on the lungs; Measurement of the body parts for mercury clearance through external gamma counting.

Examines the metallothionein (MT) levels in liver and kidney of Canadians as a potential indicator of environmental exposure to cadmium (Cd). Hypothesis of MT as a regulatory and detoxifying intracellular metalloprotein; Correlation between MT and Cd and zinc (Zn) levels in kidney; Linear relationship between MT and Zn in the liver.

Describes the distribution of mercury in red blood cells and plasma. Excretion of mercury in human subjects after inhalation of vapor; Correlation between urinary excretion and plasma radioactivity of mercury; Use of blood mercury levels as an index of mercury exposure; Absence of reliable index for mercury concentration in the brain.