According to early studies on the transport of cadmium (Cd), it was suggested that iron (Fe) or calcium (Ca) transport system is important in Cd incorporation into cells based on the evidence that dietary Fe or Ca deficiency enhanced intestinal Cd absorption. Transporter of Fe, divalent metal transporter, was shown to be capable of permeating other divalent metals including Cd. On the other hand, L-type Ca channel was also shown to be responsible at least in part, for cellular Cd uptake. In addition to Ca and Fe, it was suggested that the transporter for cellular incorporation of manganese (Mn) and zinc (Zn) may also be involved in Cd uptake by using Cd-resistant metallothionein null cells. Recently, two members of ZIP family, ZIP8 (Slc39a8) and ZIP14 (Slc39a14) have been suggested as the candidates for Cd transporter. ZIP8 was found to be the determinant for the sensitivity to Cd-induced testicular hemorrhage. ZIP14 was down-regulated in Cd-resistant metallothionein null cells. Further characterization of the roles of ZIP8 and ZIP14 in the transport of Cd, Mn and Zn is needed to clarify Cd transport system in mammals.

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Selenocysteine lyase (SCL) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that specifically acts on L-selenocysteine to yield L-alanine and selenium. The enzyme does not act on L-cysteine at all. We have recently found that RNAi-mediated depletion of SCL results in significant reductions in activities and protein levels of the selenoproteins glutathione peroxidase and thioredoxin reductase, suggesting an important cellular role of SCL in selenoprotein synthesis. Therefore, the strict discrimination between selenium and sulfur by SCL may be a key step in the specific seleniumdelivery pathway for selenoprotein synthesis. However, the mechanism for the discrimination between selenium and sulfur by SCL remains unclear. In this review, we describe function and mechanism of SCL involved in the biosynthesis of selenoprotein. We also discuss the catalytic properties of the SCL-related enzymes, cysteine desulfurases.

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We investigated the in vitro and in vivo effects of metal ions on the activity of an alpha-glucosidase (Saccharomyces sp.). CuSO₄, ZnSO₄, and VOSO₄ significantly inhibited the alpha-glucosidase activity in vitro. Additionally, we examined their effects on the blood glucose level by performing oral carbohydrate tolerance tests in both normal ddY mice and streptozotocin-induced diabetic mice. After oral administration of these three metal compounds, the elevation in the blood glucose levels in mice administered disaccharide (sucrose) was significantly suppressed in comparison with untreated mice. On the other hand, the elevation in the blood glucose levels in mice administered monosaccharide (glucose) was not suppressed when such compounds or a vehicle was administered. The results suggested that some metal ions suppress disacharide digestion probably due to the inhibition of the alpha-glucosidase activity in the epithelium of the small intestine.

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Inorganic arsenicals (iAs) are metabolized and excreted mainly in urine as dimethylarsinic acid (DMA^V). Glutathione (GSH) plays an important role in the metabolism of iAs. In rat bile, the major metabolites of iAs have been reported to be arsenic-glutathione (As-GSH) complexes, such as arsenic triglutathione (ATG) and methylarsenic diglutathione (MADG). Recently, we proposed a new metabolic pathway of iAs in which As-GSH complexes are substrates for S-adonosyl-L-methionine (SAM)-dependent arsenic methyltransferase, Cyt19. Arsenite (iAs^III) forms a complex with GSH producing ATG, and ATG is methylated to MADG by Cyt19, and finally As-GSH complexes excreted into hepato-enteric and/or hepato-blood circulation. We showed that both ATG and MADG were unstable in both bile and phosphate buffer (PBS) and were hydrolyzed to iAs^III and monomethylarsonous acid (MMA^III). Furthermore, MMA^III appeared to be oxidized to MMA^V in bile faster than in PBS. Cytotoxicity of MMA^III and dimethylarsinous acid (DMA^III) were higher than that of iAs. The concentration of biliary GSH increased in As-treated rats, and synthetic As-GSH complexes were stabilized by GSH. Very recently, we reported that dimethylarsenic glutathione (DMAG) generated volatile arsenicals when GSH exists in culture medium at low concentration, and GSH inhibited cellular uptake of DMAG and generation of volatile arsenicals at high concentration. The volatile arsenicals dissolved into solution and formed an unstable arsenical and finally converted DMA^V. These results suggested that GSH plays an important role in preventing hydrolysis of As-GSH complexes and the generation of toxic trivalent arsenicals, and that the oxidation of trivalent arsenicals plays an important role in the detoxification of arsenicals.

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Organotin compounds have been widely used as agricultural fungicides, rodent repellents, and molluscicides and in antifouling paints for ships and fishing nets. These widespread uses have resulted in the release of increasing amounts of organotins into the environment. In aquatic invertebrates, particularly marine gastropods, organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), induce irreversible sexual abnormality in females which is termed “imposex” at very low-concentrations. Although it has been theorized that these compounds act as potential competitive inhibitors for aromatase, which converts androgen to estrogen, and then increase levels of unconverted androgens in gastropods, their effective concentrations of aromatase inhibition are high. In addition to wildlife, organotins may have various undesirable effects on human health. In human ovarian granulosa cells, these compounds suppress aromatase activity at the nanomolar level. Contrary to this, in human choriocarcinoma cells, these compounds markedly enhance estrogen biosynthesis along with the increase of aromatase activity at the same low concentrations. Although there are many reports describing the potential toxicity of organotins, the critical target molecules for the toxicity of organotin compounds remain unclear. New data identify TBT and TPT as nanomolar agonist ligands for retinoid X receptor (RXR) and peroxisome proliferatoractivated receptor (PPAR) γ, which are members of the nuclear receptor superfamily. Here, we review the potential toxicity of organotin compounds via these nuclear receptors in mammals.

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With the increasing detection of patients with malignant mesothelioma among residents living near factories and facilities handling asbestos in the past, asbestos-related diseases have become a big medical, social and political issue in Japan. Therefore, we should seriously consider what we, as researchers into the biological effects of asbestos in the field of preventive medicine, can do to clarify the problem and which type of investigations may eliminate the anxiety of Japanese people. One answer is to establish biomarkers for asbestos exposure, since most people do not know for sure whether or not they were exposed to asbestos 30 to 40 years ago. In addition, we should develop markers to detect asbestos-induced malignancies such as lung cancer and malignant mesothelioma. Moreover, the establishment of the markers for molecular prevention of asbestos-induced carcinogenesis would be much appreciated news to persons feeling anxiety about the uncertainty of past exposure to asbestos.

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Malignant mesothelioma is a highly lethal and particularly refractory tumor for which treatments have been far from satisfactory in achieving clinical responses. Mesothelioma has a strong etiological relationship with asbestos exposure. The incidence is rising and expected to continue to increase into the next decade in Japan. However, strict prohibitions on the use of asbestos started in the early 1970s lead to a decline in the incidence in Sweden, New Zealand, and in US. In June 2005, several inhabitants of Amagasaki, Hyogo prefecture, lived within one kilometer of the asbestos factory, suffered from mesothelioma, whose environmental exposures to asbestos were clarified to trigger off social and medico-legal problems of asbestos-related diseases in Japan. Japan was one of the greatest consumers of chrysotile asbestos and one of the largest producers of asbestos-containing products. Considering the long latent period of about 40 years and more than 300,000 tons of asbestos used between 1973 and 1977, the incidence can be expected to increase dramatically hereafter, may be from 2010. Mesothelioma is a disease which has been poorly responsive to chemotherapy, and there is as yet no standard chemotherapy regimen. Diffuse nature of mesothelioma makes it difficult for surgeon to perform a radical resection, however, combined modality treatments have been attempted in order to reduce local recurrence and systemic spread. Mesothelioma is no longer considered a rare tumor, the peak incidence of this tumor is not reached in Japan.

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Zinc exists in high densities in the giant boutons of hippocampal mossy fibers. Zinc decreases extracellular glutamate concentration in the hippocampus, suggesting inhibitory modulation of glutamatergic neurotransmitter system by zinc. Zinc-specific fluorescent (ZnAF-2) signals are increased in both extracellular and intracellular compartments in the mossy fiber terminals during the delivery of tetanic stimuli to the dentate granule cell layer. It is likely that zinc released from mossy fibers is immediately retaken up by mossy fibers and taken up into postsynaptic CA3 neurons. In mossy fiber terminals preferentially double-stained with zinc and calcium indicators, the increase in calcium orange signal during delivery of tetanic stimuli to the dentate granule cell layer is enhanced by addition of CaEDTA, a membrane-impermeable zinc chelator, while suppressed by addition of zinc. The decrease in FM4-64 signal (vesicular exocytosis) during tetanic stimulation, which induces mossy fiber long-term potentiation, is also enhanced in mossy fiber terminals by addition of CaEDTA and is suppressed by addition of zinc. Zinc released from mossy fibers may serve as a negative-feedback factor of presynaptic activity.

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We have analyzed the copper-transporting P-type ATPase (ATP7B) gene responsible for Wilson's disease to provide an explanation for the early onset of acute hepatitis. The ATP7B coding sequence, including the intron-exon boundaries, has been screened for mutations by direct sequence analysis. The genetic data in this study indicate that the patient has been proven to carry both R778L and 2871del.C, each as one of the known disease-causing mutations. The R778L and 2871del.C were inherited from the father and the mother, respectively. Therefore, the patient was confirmed as a compound heterozygote for these mutations. This compound heterozygous mutation resulted in severe disruption of the ATP7B function. In sibs, however, the suspicion of Wilson's disease could be rejected because the compound heterozygous mutation was not found in them. The evidence suggests that the familial genetic analysis provides integral information to the genetic counseling for the disease in families with these patients.

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In the present study, lead concentrations were determined in human blood collected from cities, dumping sites and reference sites in South India, North Vietnam and Cambodia. To evaluate human health effect of lead exposure, the δ-aminolevulinic acid dehydratase (ALAD) activities were also measured. Concentrations of lead in human blood ranged from 2.33 μg/dl to 27.4 μg/dl. Especially, concentrations in blood of residents from Perungudi (waste dumping site) and Palaverkadu (farming village) in South India were higher than those from other regions or those reported previously. Concentrations of lead in blood of some residents exceeded the threshold levels which can induce hypertension in adult and inhibit development of intelligence in fetus. Furthermore, significant negative correlations between blood lead levels and ALAD activities were observed in the residents from all the three countries, indicating possible suppression of that heme biosynthesis by lead in these residents.

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The immune system is a target of dibutyltin (DBT) intoxication. We evaluated the effects of DBT dichloride in macrophages using the murine macrophage cell line, J774.1. Cultured J774.1 cells were exposed to DBT dichloride at 0, 0.5, 1.0, 1.5 or 2.0 μM in 24-well plates. After 18 hours, lipopolysaccharide was added to each well. The cells were incubated for an additional 6 hours or 24 hours. At the ends of the incubations, the cell viability was determined by the trypan blue exclusion method. Total RNA was extracted from the cells after an additional 6 hours of incubation. Real- time polymerase chain reaction (PCR) was used to analyze the mRNA expression for tumor necrosis factor α (TNFα), interleukin 1β (IL-1β) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (housekeeping gene) in J774.1 cells. The supernatants were sampled after an additional 24 hours of incubation. The concentrations of TNFα and IL-1β in the supernatants were determined by ELISA. The mean values of cell viabilities in the DBT-exposed groups were significantly lower than that of respective control both after the additional 6 and 24 hours of incubation. The mean relative mRNA expression of TNFα was higher than that in the control only in the 0.5 μM group. There were no significant differences in IL-1β relative mRNA expression among the groups. The mean concentrations of TNFα in the supernatant in the 1.0, 1.5 and 2.0 μM groups were significantly lower compared to that in the control. The mean concentrations of IL-1β in the supernatant in the DBT-exposed groups were also significantly lower than that of the control. The concentrations of cytokines in the supernatants were marked low and not fully explained by the low cell viability of the DBT-exposed groups. Since the mRNA expressions of cytokines in the higher dose groups were similar to that in the control, the translation from mRNA may be inhibited by DBT.

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Low-molecular-weight selenocompounds without selenol groups, N-methyl, N-phenyl-(2-selenomethyl)benzoylamide, N-phenyl-(2-selenoallyl)benzoylamide, N-phenyl-(2-selenopropyl)benzoylamide, and bis[1-methyl-2-(N-phenylcarboxamido)ethyl] diselenide, dibenzyl diselenide, were synthesized and their antioxidant activities were evaluated. Among the synthesized selenocompounds, N-phenyl-(2-selenoallyl)benzoylamide had the highest glutathione peroxidase(GPx)-like activity, and the activity increased depending on the concentration. The activity of N-phenyl-(2-selenoallyl)benzoylamide was several times higher than that of selenomethionine, though it was about 1/10 of ebselen. These results suggest that selenocompounds which don't have selenol groups can also behave as a GPx-like reductant, where a different reaction mechanism from that for selenocompounds with selenol groups is present. Spectrophotometric studies also supported this suggestion. It may be possible that selenium atom located between two carbon atoms in the molecule is oxidized to selenoxide by an oxidant and then selenoxide is reduced to selenium by reduced form of gluta-thione, thus GPx-like reduction of hydrogen peroxide by selenocompounds without selenol groups occurs. N-phenyl-(2-selenoallyl)benzoylamide had superoxide anion scavenging activity, although it was comparatively low. These results indicated that selenocompounds without selenol groups such as N-phenyl-(2-selenoallyl)benzoylamide can be reductants against peroxide or other oxidant species possibly by forming selenoxide, though their antioxidant activity may not be high.

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Inorganic agents, such as Cu, Zn, and Ag compounds, are known to be relatively safe, and these agents are used in many kinds of products. However, regions treated with metal compound agents and their concentration are not indicated in most commercially available products. In this study, to establish a simple method of measuring the concentration of metals in product regions, we evaluated screening methods using non-destructive X-ray fluorescence spectrometry (XFS). Qualitative analysis by XFS and quantitative analysis by inductively coupled plasma atomic emission spectroscopy (ICPAES) were performed in the same regions, and the results were compared. Inorganic antimicrobial agents used in 40 antimicrobial products (96 regions) were analyzed. As the result, (1) XFS was useful for the screening of Cu and Zn, but was not suited for the screening of Ag. (2) Use of inorganic antimicrobial treatment was indicated on 11 products, but actually, 25 products were treated with inorganic antimicrobial agents. (3) Cu was detected in 12 products. (4) In 19 products, Zn was used for the antimicrobial treatment. (5) Ag was detected in 5 products, in which Cu or Zn were contained at higher concentrations. The combination of Ag and Cu or Zn may enhance antimicrobial effects. (6) Inorganic antimicrobial agents were detected in 4 of the 13 products for infants. Although 2 products indicated the treatment with chitosan, Zn was detected. In these products, antimicrobial effects may have been obtained by the combination of chitosan and Zn or Zn alone.

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In Europe, the standard levels of heavy metals eluted with artificial sweat and saliva are specified in the self-imposed safety criteria (OEKOTEX Standard) for textile products. To establish standard values in Japan, we prepared metal zeolites (Ag, Cu, Zn, and Cr) and standard cloths processed with these zeolites and a silver antimicrobial agent, AG300. The agents, standard processed cloths, and regions of commercial textile products in which metals were detected at a high concentration were subjected to metal elution with artificial sweat (JIS L 0848: 2004), saliva (BS 6684: 1987), and ultrapure water according to the JIS shake-flask antimicrobial test method (JIS L 1902-1900). The metal concentrations in the extracts were measured using an inductively coupled plasma-mass spectrometer (ICP-MS). A similar tendency was noted in elution from the agents, standard processed cloths, and commercial textiles. Small amounts of metals were eluted with water alone, while large amounts were eluted with artificial sweat and saliva. Large amounts of Cu and Zn were eluted, while the elution of Ag was low, and almost no Cr was eluted. Furthermore, antimicrobial activity of the standard processed cloths was evaluated by the standard test (JIS L 1902) using Staphylococcus aureus and Klebsiella pneumoniae. Cu- and Ag (Ag zeolite and AG300)-processed cloths exhibited high antimicrobial activities against both bacteria. Zn-processed cloth also showed antimicrobial activity against S. aureus.

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The occurrence of mycosis due to an imbalance in indigenous microorganisms on the skin through the excessive use of antimicrobial processing agents is a matter of concern. We investigated the relationship between the amounts of metals eluted with artificial sweat and saliva from antimicrobial agents and processed cloths and their influences on indigenous microorganisms on skin. The relationships between 4 bacterial species (Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, and Propionibacterium acnes) and 3 fungal species (Candida albicans, Trichophyton mentagrophytes, and Aspergillus niger van tieghem), the metal concentrations in artificial sweat and saliva, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) were investigated. (1) MIC: The MIC values against Candida and Trichophyton were similar to the bacteria, and were lower than that against Aspergillus. (2) MBC: Although survival rates varied among the microorganisms, fungi survived at a higher metal concentration. In the MBC measurement, microorganisms were exposed to metal ions for a specified time (2 or 24 hours), and then their survival was investigated by culture under conditions appropriate for each microorganism. Since the conditions were close to those of exposure of coexisting microorganisms on skin, these findings suggest that fungi survive at a metal concentration that kills bacteria, up setting the balance of indigenous microorganisms naturally present on skin, which may cause mycosis.

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