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Metallothioneins (MT) are a group of low-molecular weight, cysteine rich intracellular proteins, which are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins have been associated with protection against DNA damage, oxidative stress and apoptosis. Moreover, MT may potentially activate certain transcriptional factors by donating zinc. Although MT is a cytosolic protein in resting cells, it can be translocated transiently to the cell nucleus during cell proliferation and differentiation. A number of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder. However, MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. In certain tumors such as germ cell carcinoma, the expression of MT is closely related to the tumor grade and proliferative activity. Increased expression of MT has also been observed in less differentiated tumors. Thus, expression of MT may be a potential prognostic marker for certain tumors. There are few reports on the expression of the different isoforms of MT which have been analyzed by specific gene probes. They reveal that certain isoforms are expressed in specific cell types. The factors which can influence MT induction in human tumors are not yet understood. Down-regulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes such as the p53 tumor suppressor gene. In vitro studies using human cancer cells suggest a possible role for p53 and the estrogen-receptor on the expression and induction of MT in epithelial neoplastic cells. Some of the evidence supporting a role for MT in both intrinsic and acquired drug resistance is critically evaluated in this review. Since chemoresistance in human tumors is a multifactorial phenomenon, it is difficult to conclude that MT is a more crucial factor than others. Therefore, additional experimental data on MT and its isoforms in human tumors, are needed to elucidate the biological functions of MT during tumor progression, along with other tumor markers. [Copyright &y& Elsevier]

Protection of radiation-induced DNA damage by metallothionein (MT) has been documented, but there is no detailed information about its efficiency compared to other antioxidants or the effect of metals which bind to MT on the protective effect of MT in radiation-induced DNA damage. In this study, we used a cell-free system to investigate the effect of MT with other antioxidants, such as albumin and glutathione and we compared the efficiency of MT bound to different metals on radiation-induced DNA damage. DNA damage was measured by loss in ethidium bromide/DNA fluorescence and increased mobility of DNA on gel electrophoresis. Gamma rays at 30 Gy induced significant DNA damage and zinc-MT showed a significant higher protection from radiation-induced DNA damage than both glutathione and albumin. Metallothionein bound to other metals, such as copper and cadmium, also showed protection of radiation-induced DNA damage, but the protective effect by zinc-MT was the highest. These results suggest that MT, in particular bound to zinc, is a high-capacity antioxidant to protect radiation-induced DNA damage. [Copyright &y& Elsevier]

Copper is both essential for life and toxic. Aberrant regulation of copper at the level of intracellular transport has been associated with inherited diseases, including Wilson’s disease (WND) in humans. WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues, liver degeneration, and neurological dysfunction. The toxic milk (TX) mutation in mice results in a phenotype that mimics human WND, and TX has been proposed to be a model of the disease. We characterized TX mice as a model of altered metal ion and MT levels during development, and after treatment with the metal ion chelators tetrathiomolybdate (TTM) and deferiprone (L1). We report that hepatic, renal and brain copper and MT are elevated in TX mice at 3 and 12 months of age. Zinc was significantly higher in TX mouse liver, but not brain and kidney, at both time points. Nodules appeared spontaneously in TX mouse livers at 8–12 months that maintained high copper levels, but with more normal morphology and decreased MT levels. Treatment of TX mice with TTM significantly reduced elevated hepatic copper and MT. Transient increases in blood and kidney copper accompanied TTM treatment and indicated that renal excretion was a significant route of removal. Treatment with L1, on the other hand, had no effect on liver or kidney copper and MT, but resulted in increased brain copper and MT levels. These data indicate that TTM, but not L1, may be useful in treating diseases of copper overload including WND. [ABSTRACT FROM AUTHOR]

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]

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]

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.

Abstract: A previous study (Oliver, J.R., Mara, T.W., Cherian, M.G. 2005. Impaired hepatic regeneration in metallothionein-I/II knockout mice after partial hepatectomy. Exp. Biol. Med. 230, 61–67) has shown an impairment of liver regeneration following partial hepatectomy (PH) in metallothionein (MT)-I and MT-II gene knockout (MT-null) mice, thus suggesting a requirement for MT in cellular growth. The present study was undertaken to investigate whether MT may play a similar role in hepatic injury and regeneration after acute treatment with thioacetamide (TAA). Hepatotoxicity of TAA is caused by the generation of oxidative stress. TAA was injected ip to both wild-type (WT) and MT-null mice. Mice were killed at 6, 12, 24, 48, 60, and 72 h after injection of TAA (125 mg/kg) or 48 h after injection of saline (vehicle control), and different parameters of hepatic injury were measured. The levels of hepatic lipid peroxidation were increased at 12 h in both types of mice; however, lipid peroxidation was significantly less in WT mice than MT-null mice at 48 h after injection of TAA. Analysis of hepatic glutathione (GSH) levels after TAA injection showed depletion of GSH at 12 h in WT mice and at 6 h in MT-null mice; however, significantly more GSH was depleted early (6–24 h) in MT-null mice than WT mice. An increase in hepatic iron (Fe) levels was observed in both types of mice after injection of TAA, but Fe levels were significantly higher in MT-null mice than WT mice at 6–60 h. The levels of hepatic copper (Cu) and zinc (Zn) were significantly higher in WT mice than MT-null mice at 6–60 h for Cu, and at 24 h and 60 h for Zn, respectively. Histopathological examination showed hemorrhagic necrosis in the liver of both types of mice at 12–72 h, with hepatic injury being more prominent in MT-null mice than WT mice. The hepatic MT levels were increased in WT mice after injection of TAA, and were highest at 24–72 h. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24–72 h after TAA injection. Cell proliferation, as assessed by immunohistochemical staining for proliferating cell nuclear antigen, was detected mainly in the livers of WT mice at 48–72 h after TAA treatment. Hepatic proliferation index in MT-null mice was very low as compared to WT mice during liver regeneration after injection of TAA. These results show that the liver cells of MT-null mice with no functional MT are unable to regenerate after TAA-induced hepatic injury, demonstrating an important role for MT in cellular regeneration. [Copyright &y& Elsevier]

We have shown the protection of human central nervous system (CNS) cultures by zinc (Zn) or cadmium (Cd)-pre-induced metallothionein (MT) synthesis from radiation-induced cytotoxicity (lactate dehydrogenase (LDH) release and neuronal dendritic injury). The present study is to further define the types of cell death induced by different dose levels of radiation and investigate the effect of MT induction (by Zn or Cd) on radiation-induced apoptosis in primary human CNS and astrocyte cultures. Apoptosis was detected by fragmented DNA electrophoresis, TUNEL technique, and propidium iodide staining. Expression of MT protein was examined by immunofluorescent staining. Results showed that exposure of primary human CNS cultures to 15 and 30 Gy γ-radiation predominantly induced apoptotic cell death, while exposure to 60 Gy γ-radiation predominantly induced necrotic cell death. Normal primary human CNS cultures showed weak MT staining, while primary human CNS cultures exposed to Zn or Cd showed intense MT staining. The induced apoptotic cell death by exposure to 30 Gy γ-radiation increased to a maximum level at 12 and 24 h, and was reduced significantly by Zn or Cd pre-induced MT. Using primary human astrocytes, the induction of MT protein by Zn or Cd was further confirmed. The enhanced MT expression also afforded a significant protection from 30 Gy γ-ray-induced apoptosis in the primary human astrocytes. These results suggest that MT protected human CNS cells from apoptosis following ionizing radiation, probably through its antioxidant property. [Copyright &y& Elsevier]

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]

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]

Ethnopharmocological relevance Herbo-metallic preparations have a long history in the treatment of diseases, and are still used today for refractory diseases, as adjuncts to standard therapy, or for economic reasons in developing countries. Aim of the review This review uses cinnabar (HgS) and realgar (As 4 S 4 ) as mineral examples to discuss their occurrence, therapeutic use, pharmacology, toxicity in traditional medicine mixtures, and research perspectives. Materials and methods A literature search on cinnabar and realgar from PubMed, Chinese pharmacopeia, Google and other sources was carried out. Traditional medicines containing both cinnabar and realgar (An-Gong-Niu-Huang Wan, Hua-Feng-Dan); mainly cinnabar (Zhu-Sha-An-Shen Wan; Zuotai and Dangzuo), and mainly realgar (Huang-Dai Pian; Liu-Shen Wan; Niu-Huang-Jie-Du) are discussed. Results Both cinnabar and realgar used in traditional medicines are subjected to special preparation procedures to remove impurities. Metals in these traditional medicines are in the sulfide forms which are different from environmental mercurials (HgCl 2 , MeHg) or arsenicals (NaAsO 2 , NaH 2 AsO 4 ). Cinnabar and/or realgar are seldom used alone, but rather as mixtures with herbs and/or animal products in traditional medicines. Advanced technologies are now used to characterize these preparations. The bioaccessibility, absorption, distribution, metabolism and elimination of these herbo-metallic preparations are different from environmental metals. The rationale of including metals in traditional remedies and their interactions with drugs need to be justified. At higher therapeutic doses, balance of the benefits and risks is critical. Surveillance of patients using these herbo-metallic preparations is desired. Conclusion Chemical forms of mercury and arsenic are a major determinant of their disposition, efficacy and toxicity, and the use of total Hg and As alone for risk assessment of metals in traditional medicines is insufficient. [ABSTRACT FROM AUTHOR]

Abstract: Metallothionein (MT) isoforms have not been studied in papillary thyroid cancer. We examined how the functional MT1 and MT2 isoforms were expressed in papillary thyroid cancer (KAT5) cells. We demonstrated that KAT5 cells expressed eight functional MT1 and MT2 isoforms induced by cadmium. Elevated calcium and activated ERK1/2 predated MT expression. The inhibition of either calcium or ERK1/2 significantly blocked the isoform expression. The induction of these isoforms accompanied an increased progression of cell cycle from G0/G1 to G2-M. The alternation in cell cycle disappeared when the expression of MT isoforms was blocked by calcium inhibitor or ERK1/2 inhibitor. Collectively, KAT5 cells express eight functional MT1 and MT2 isoforms in a pathway controlled by calcium and ERK1/2. The elevation of the MT isoforms contributes to the decreased G0/G1 but increased G2-M phase. These results reveal a novel pathway for the expression of the functional MT in papillary thyroid cancer. [Copyright &y& Elsevier]

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: Many biological subdisciplines that regularly assess dose–response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose–response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose–response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines. [Copyright &y& Elsevier]

Abstract: Objectives: To determine whether metallothionein (MT) protein expression is associated with clinical outcomes in patients with transitional cell carcinoma (TCC) of the bladder. Methods: Archival pathologic radical cystectomy and transurethrally resected specimens and medical charts were reviewed for 123 patients with TCC. Patients were divided into groups based on the TNM stage, tumor grade, and MT protein expression in the primary tumor. Survival and disease progression were correlated with MT expression. Results: The mean patient age was 66 years (range 41 to 92). Of the 123 tumors, 21, 13, 18, 24, 17, and 30 were pathologically staged as pTa, pT1, pT2, pT3, pT4, and pTis, respectively; 28, 15, 14, and 66 tumors had a histologic grade of X, 1, 2, and 3, respectively. On univariate analysis, TNM stage and tumor grade predicted survival and progression outcomes. MT expression was detected in 69 (56.9%) of 123 bladder cancer specimens. Greater MT protein expression was associated with worse overall survival, disease-specific survival, disease-free survival, and disease-free progression (P = 0.0004, P = 0.05, P = 0.0008, and P = 0.0005, respectively). Conclusions: MT protein expression in the primary tumor of TCC specimens appeared to be associated with overall survival, disease-specific survival, disease-free survival, and disease-free progression. This finding requires additional validation using other data sets. [Copyright &y& Elsevier]

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]

The objective of this study was to evaluate the potential role of TNF-α in the onset of acute hepatitis in the Long-Evans Cinnamon (LEC) rat, an animal model for inherited copper (Cu) toxicosis. In LEC rats, Cu is accumulated in the liver with age, and clinical signs of acute hepatitis were observed as, icterus, reduced body weight, nasal bleeding, dehydration, and reduced food intake at 12 weeks of age. Cellular changes such as apoptosis in the liver were evident in these rats with increasing age. Positive TNF-α and TNFR1 immunostainings were observed in hepatocytes and Kupffer cells in LEC rats. Hepatic levels of caspase-3 activity, TNF-α mRNA, and protein were also increased in LEC rats from 6 to 12 weeks of age as compared with control Long-Evans (LE) rats. The neutralization of TNF-α by passive immunization or the inhibition of caspase activity can block the apoptotic process initiated by TNF-α. In this study, we evaluated the effects of passive immunization of LEC rats with weekly administration of anti-rat TNF-α on Cu-induced acute hepatitis. This treatment resulted in a reduction of the percentage of apoptotic cells in the liver, decreased activity of caspase-3, and also in down-regulation of the TNF-α gene expression. Thus, these results suggest a major role for TNF-α on the pathogenesis of Cu-induced acute hepatitis in LEC rats. [Copyright &y& Elsevier]

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.

Demonstrates that high glucose concentration can induce metallothionein (MT) expression in endothelial cells through a distinct endothelin-dependent pathway. Cell viability and proliferation; Effects of high concentration of glucose on MT-2 mRNA; Effect of high concentrations of glucose on ET-1 mRNA level; Effect on MT protein induction.

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.

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.