Copper is an essential trace metal. Proteins exploit the unique redox nature of this metal to undertake a series of facile electron transfer reactions using copper as a cofactor in a select number of critical enzymatic pathway. The signs and symptoms of copper deficiency are the results of impaired function of these cuproenzymes. Copper homeostasis is maintained entirely by gastrointestinal absorption and biliary excretion. Biliary copper is not absorbed from the gastrointestinal tract, so there is no enterohepatic circulation of this metal. Wilson disease and Menkes disease are inherited metabolic disorders of copper transport. Each disease results from the absence or dysfunction of homologous copper-transporting ATPase present in the trans-Golgi networt of cells. The Wilson disease ATPase transports copper into the hepatocyte secretary pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, individuals with this autosomal recessive disease present with signs and symptoms arising from impaired biliary copper excretion. The Menkes disease ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two disease, the respective ATPase function in precisely the same fashion within the cell. The unique clinical features of each disease are the results of the tissue specific expression of these ATPase. Aceruloplasminemia is an autosomal recessive disease characterized by absent serum ceruloplasmin and progressive neurodegeneration of the basal ganglia in association with specific inherited mutation in the ceruloplasmin gene. Although the basal ganglia symptoms and a lack of serum ceruloplasmin may lead to diagnostic confusion with Wilson disease, magnetic resonance imaging reveals the presence of iron the basal ganglia.
In this article, the connection modes between cancer immunity and trace elements are reviewed, with a focus on the three wide fields of the carcinogenesis, the tumor progress and the tumor suppression, as an immunoenvironment surrounding the tumor, on the basis of recent data. The table of contents is as follows : Introduction, 1. The Carcinogenesis and Trace Elements, 2. The Progress of Tumor and Trace Elements, 3. The Suppression of Tumor and Trace Elements, Conclusion. To sum up this article, there are several aspects in the connection mode of trace elements with cancer immunity. In the field of carcinogenesis, there are two cases as follows; 1) the induction of the facility of carcinogenesis by the disorder in the general intracellular metabolism, the disorder in the activation modulating systems of enzyme, hormone, cytokine etc which are induced by the deficiency or the excessive exposure of trace elements and the disorder in the immune response. 2) under the conditions rising the carcinogenic sensibility, the induction of carcinogenesis by cancer-causing substances (carcinogenic trace elements etc)-induced several DNA damage and the functional injury of a gene associated with proliferation/differentiation. In the field of the tumor progress, there are several cases as follows; 3) with the progress of tumor, a break-down of essential roles of trace elements in an immunity system. Conversely, 4) the promotion of tumor progress by this break-down. Further, 5) an increase in the demand of certain trace elements needed for the proliferation of cancerous cells or 6) an increase in the level of certain trace elements acting suppressively on the proliferation of cancerous cells. In the field of the tumor suppression, most of cases are 7) the action as an anticancer agent administered from the outside of a body, except for the suppression of proliferation of tumor cells by zinc-deficiency and selenium-deficiency and by accumulation of aluminum at the tumor site.
Functionally altered proteins are reported to be present in various organs of aged animals. The accumulation of such proteins is implicated in the mechanism of age-associated deterioration of the physiological functions of tissues. However, the mechanisms of the generation of altered proteins are not fully understood. Protein carbonylation has been regarded as a marker of oxidative damage to proteins and an increase in the amount of such oxidized protein has been reported in many experimental aging models. It has been suggested or shown that protein carbonyls drive from the direct oxidation of side chains of amino acid residues or the reaction of lipid peroxidation products with amino acid residues or non-enzymatic glycation phenomena. Interestingly, the rates of these chemical modifications of proteins are often enhanced in the presence of metal ions such as iron and copper. Because age-related accumulation of iron but not copper appears to be a common phenomenon in different tissues of various animals, including humans, iron may acts as a major catalyst which promotes direct or indirect protein carbonylation in vivo during aging. Furthermore, it has been shown that decreased iron stores and low iron diet extend the life span of animals. These findings suggest that iron withholding or removal can possibly prevent age-related dysfunctions and certain diseases caused by iron-mediated oxidative damage.
It is recognized that longevity is longer in females than in males in almost all countries. Prevalence of intractable diseases is larger in females than in males. From the aspect of trace element research the difference between females and males is considered. When male and female mice were given Mg deficient diet, mice died between 1 and 4 weeks without sex difference. When Mg and K deficient diet, male mice died before female mice. Mg concentrations in various organs of mice fed Mg and K deficient diet for one week, Mg concentrations in plasma, erythrocytes, and bone of both males and females were significantly lower, and those in brain, liver, and muscle of males were significantly lower than corresponding controls. Mg concentrations in kidney and heart were kept the normal values. In various element concentrations in liver of mice fed Mg and K deficient diet, changing ranges were smaller in females than in males. It is clear that female homeostasis is stronger than males. Element concentrations in follicular fluid samples were analyzed. Concentrations of Mg, P, Se, and As had positive correlations with age, and negative correlation with blood estradiol concentration, and Mn concentration had negative correlation with age, and positive correlation with blood estradiol. Element concentrations of human breast milk were analyzed. Na and K concentrations were high soon after delivery, and gradually became steady state. Se concentration was not largely changed.
Requirements of trance elements during childhood are larger than other period. There are higher possibilities to be deficient for trace elements in this period. Zinc, copper, and iodide are most important among those elements. The causes for the deficiency have been changed in recent years. Nutritional deficiency is still the major cause in the developing countries, however, in Japan, skewed food at home based on various reasons lead to unexpected deficiency of specific trace elements.
Although arsenic (As) pollution has been indicated in groundwater of Vietnam, there is no detailed information on pollution by other trace elements in Vietnam. In the present study, concentrations of As and other trace elements were determined in groundwater collected from Gia Lam District and Thanh Tri District, suburban areas of Hanoi, Vietnam in September 2001. Concentrations of As in the groundwater ranged from <0.10 to 330 μg/l. These levels were lower than those in other As-contaminated areas, but about 40 % of these samples exceeded the World Health Organization (WHO) drinking water guideline of 10 μg/l. Interestingly, 76 % and 12 % of groundwater samples had also higher concentrations of manganese (Mn) and barium (Ba) than WHO drinking water guidelines, respectively. To our knowledge, this study indicates for the first time that the people in Red River Delta may be exposed not only to As but also to Mn and Ba from groundwater.
Seven elements, Co, Cr, Cu, Mn, Ni, Se, and Zn, in the whole blood of a total of 94 healthy individuals (36 males and 58 females), ranging from 30 to 79 years of age, were measured by the coupled plasma-mass spectrometer (ICP-MS) method. Gender differences were found only in Cu (p <0.05). By age bracket, low values were measured for Cu in the 70s, Co in the 60-70s, Cr, Ni and Se in the 60s, Zn in the 40s, and Mn in the 30s and 60s. These results reveal that there is a trend for many elements that are involved in antioxidation, except for Zn, to decrease with ageing.
A two-dimensional (2D) HPLC/ICP-MS hyphenated system was developed and applied to speciation of biometals in salmon egg cell cytoplasm. The 2D HPLC was based on the combination of surfactant-mediated HPLC and size exclusion chromatography (SEC). In the present experiment, an ODS column coated with CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate), which is a zwitterionic bile acid derivative, was employed as a separation column in the first-dimensional surfactant-mediated HPLC. The surfactant-mediated HPLC allowed simultaneous separation of large and small molecules. In the second-dimensional HPLC, proteins thus separated from inorganic salts in the first dimension were further separated by the SEC column. The present 2D HPLC/ICP-MS system was available for the improvement of resolution in SEC separation of metalloproteins in salmon egg cell cytoplasm. Metalloproteins including Fe and Zn in salmon egg cell cytoplasm were detected as only one large peak at the volume of total exclusion limit of SEC column (>300 kDa), when analyzed by SEC/ICP-MS. However, these metalloproteins could be detected as two peaks in the present 2D HPLC/ICP-MS measurements; the molecular weights of Fe-proteins were >300 kDa and 100 kDa, and those of Zn-proteins were >300 kDa and 150 kDa.
Treatment methods of hepatocellular carcinoma (HCC) in human have been developed. However, it is desired to diagnose the HCC in early stages. We previously found that metallothionein (MT) and zinc levels in HCC tissues were significantly lower, in contrast, copper levels in the tissues were significantly higher than those of the control. Then we examined whether the monitoring of these serum parameters such as MT, copper, and zinc levels are useful in diagnosing HCC or not. On the other hand, MT has been reported to present in two isoforms, MT-1 and MT-2, in the liver and serum. We recently reported that MT-1 is related to the metabolism or detoxification of toxic metals such as cadmium, and in contrast, MT-2 is responsible for the homeostasis of essential metals such as copper. Thus, we tried to separate and determine MT isoforms in human liver by using capillary zone electrophoresis (CZE) with a polyacrylamide-coated tube at neutral pH, and compared the ratio of MT-1 and MT-2 to try to find diagnostic method.
In recent years, some metal ions and their complexes have been found to treat diabetes mellitus (DM) in not only experimental animals but also humans. Among them, vanadyl(IV) and zinc(II) ions as well as their complexes have been shown to be the most expectant agents. Then, the differences in the insulin-mimetic effects of vanadyl(IV) and zinc(II) ions as well as their complexes were investigated. In vitro insulin-mimetic activities of the compounds were estimated by both glucose uptake enhancing effect and inhibitory effect of free fatty acid (FFA) release in isolated rat adipocytes treated with epinephrine. Vanadyl(IV) compounds exhibited the higher glucose uptake enhancing activities than zinc(II) compounds, however, vanadyl(IV) compounds showed the lower inhibitory activities of FFA release than zinc(II) compounds. Next, we examined the blood glucose lowering effects of the compounds in both streptozotocin (STZ)-induced type 1 DM mice and type 2 DM KK-Ay mice by intraperitoneal injection of the compounds. Vanadyl(IV) compounds lowered the high blood glucose levels in both types of DM mice. In contrast, zinc(II) showed the blood glucose lowering effects in KK-Ay mice.
Trace metals in commercially-available 18 mineral waters were determined by ICP-MS, where a chelating resin-packed minicolumn was applied to separate matrix elements as well as to preconcentrate trace metals in the samples. The 25-fold concentration for trace metals was obtained by preconcentrating 50 ml of mineral water to 2.0 ml of final analysis solution. At the same time, matrix elements were substantially eliminated, so that trace metals could be determined by ICP-MS on the multielement basis. The validation of the present analytical method was examined by determining trace metals in river water reference material (JAC 0032). In addition, trace metals in tap water from Nagoya city were determined by the present method, and their concentrations were compared to those in mineral water.
Di-(2-ethylhexyl) phthalate (DEHP) is the most common plasticizer for plastics such as polyvinyl chloride. However, recent studies have demonstrated toxic effects of DEHP on the testes and liver in rodents. In this study, the effects of nicotinic acid on the testicular toxicity of DEHP and metal concentrations in the atrophic testes were examined in 4-week-old SD rats. The rats were fed a diet containing 1% (w/w) DEHP and water supplemented with 0.5% (w/w) nicotinic acid for a week. In rats given the DEHP diet, testicular atrophy accompanied by aspermatogenesis developed. By co-administration of nicotinic acid, testicular atrophy by DEHP was definitely inhibited. However, hypertrophy in the liver was not prevented. In the atrophic testes, zinc was slightly decreased, while iron, copper and calcium were higher than those in normal testes. Strong negative correlations were found between testicular weight and testicular iron, copper, and calcium concentrations.
Serum selenium decreased by long-term administration of conventional enteral liquid foods such as MA-8 and PN-Hi (Clinico) in elderly inpatients, who were suffered from dysphagia by cerebrovascular events. To these inpatients with low levels of serum selenium new enteral liquid foods such as L-6PM plus® or L-8 (Asahi Kasei Pharma) were administrated through nasogastric or gastric tube, which contained 40 μg of selenium per 1, 000 kcal. Fasting blood samples were obtained early in the morning. Sixteen inpatients (4 men, 12 women) aged 75 ± 13 years (M ± SD) had received long-term conventional enteral liquid foods and showed 7.1 ± 1.9 μg/dl of serum selenium (normal range 10.6 to 17.4 μg/dl). They were then changed to L-6PM plus® and L-8 from conventional liquid foods. Serum selenium increased significantly from low levels to normal range by L-6PM plus® and L-8 during 6 months. From these finding 40 μg of selenium per 1, 000 kcal were estimated to be adequate in elderly bedridden inpatients.
Hypocupremia occurred often by long-term administration of copper (Cu) — poor conventional liquid foods in elderly inpatients with cerebrovascular events. Therefore, new enteral liquid foods such as L-6PM plus and L-8 (Asahi Kasei Pharma) were administrated to improve hypocupremia. 10 inpatients (2 men, 8 women) aged 73 ± 15 years (M ± SD) were recruited, who had received conventional enteral liquid foods. Of these 10 inpatients 6 ones showed hypocupremia and 4 ones showed normocupremia. For 6 ones with hypocupremia L-8 increased significantly to normocupremia during 2 to 6 months of observation (Fig. 1). For 4 ones with normocupremia L-8 made serum Cu within normal range during 6 months (Fig. 1). Serum ceruloplasmin (CEP) showed almost same tendency as serum Cu by administration of L-8 (Fig. 2). The inpatients with hypocupremia as base line ingested daily mean 950 kcal and mean 0.76 mg of Cu for 6 months, when ones with normocupremia ingested 975 kcal and 0.78 mg of Cu. However, serum zinc (Zn) and iron (Fe) did not change significantly for 6 months by L-8. From these above findings daily 0.8 mg of Cu per 1, 000 kcal was estimated to be adequate in elderly bedridden inpatients with cerebrovascular events.
In Japan cadmium (Cd) concentration in rice is higher than other countries. Therefore daily cadmium intake is larger than the case of other countries. So in this study, we tried to extrapolate the results of animal experiments to estimate the level of tolerable daily Cd intake of human. Female Wistar rats (6 weeks old) were given Cd at a dose of 2, 5, 10, 20, 30 and 60 mgCd/kg (as CdCl2) by a gastric tube daily for conductive 6 days a week for 60 weeks. Animals were sacrificed at 0, 5, 10, 30, 40 and 60 weeks after oral Cd administration. Cd concentration in the kidney, urinary excretion of enzymes (NAG, AAP, GST), serum enzymes (GGT, ALP), amino acid, protein, glucose, and calcium were determined. The urinary excretion of Pyridinoline (Pry) and Deoxypridinoline (Dpry) was also determined. Benchmark dose (BMD) was calculated from our experimental data by power model of BMD software ver. 1.3.2 that was released from U.S. Environmental Protection Agency (EPA). The dose to estimate BMD was set two ways renal Cd concentration and oral Cd administration dose. Tolerable daily intake was estimated as 10%BMD divided by uncertainly factors (UFs). Namely, 10%BMD for the kidney was calculated as 32.8ug/g-tissue. On the other hand, the case of oral Cd administration dose was calculated as 2.52mgCd/kg-bw/day at the 60 weeks after Cd administration. The relationship between oral Cd dose and the cumulative renal Cd concentration calculated 0.9mg/kg-bw/day and 32.8ug/g-tissue at the 60 weeks. The value of UFs is determined as 1000. As the result, tolerable daily intake of Cd was estimated respectively as 0.9ug/kg-bw/day from the renal Cd concentration, and as 2.5ug/kg-bw/day from the oral Cd administration dose.
Iron is an essential element for all living organisms. It is a key functional component of oxygen transporting and storage molecules and of many enzymes. It is well established that the bioavailability of non-heam iron from foods is enhanced by the presence of meat. Carnosine (β-alanyl-L-histidine) is found in millimolar concentrations in the skeletal muscle and brain of animals. Carnosine was reported to act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Thus, to investigate the effects of carnosine for the absorption of iron, we determined the change of serum iron concentration in rats administered ferrous sulfate and carnosine using cannulation system. We further determined the effect of carnosine for the gastric secretion in rats. The serum iron concentration in rats administered with ferrous sulfate in the presence of carnosine was significantly higher than that in rats administered with ferrous sulfate after treatment for 15 min. Furthermore, the carnosine-administered rats exhibited a significant increase in pepsine activity and output. These results suggest that carnosine may facilitate the velocity of iron absorption by enhancing iron solubility.
The content of lithium in seaweed has been investigated for estimating the dietary intake of lithium, which has been known as a remedy medicine of manic-depressive psychosis. In this work, 46 samples of seaweed were divided into 5 groups; Hijiki 13, Wakame 15, Konbu 12, Arame 4 and Mekabu 4 samples. Lithium content was determined by flame photometry after the decomposition of a seaweed sample (∼1 g) with the mixture of nitric and perchloric acids. It was found that lithium content was obviously higher in “Hijiki” (3400±626 ng/g, n=13) than in other seaweed samples; “Wakame” (2000±1020 ng/g, n=15) and “Konbu” (1210±492 ng/g, n=12). It was indicated that lithium was present in seaweed “Hijiki” as insoluble salt associated with calcium or calcium complexes from the results of both lithium and calcium in chemical leaching experiments using water, 0.1 mol/l HCl, 6 mol/l HCl, 0.1 mol/l CH3COOH, 1 mol/l CH3COOH and 0.01 mol/l EDTA as a leaching solution.