Around 3000 proteins are thought to bind zinc in vivo, which corresponds to ~10% of the human proteome. Zinc plays a pivotal role as a structural, catalytic, and signaling component that functions in numerous physiological processes. It is more widely used as a structural element in proteins than any other transition metal ion, is a catalytic component of many enzymes, and acts as a cellular signaling mediator. Thus, it is expected that zinc metabolism and homeostasis have sophisticated regulation, and elucidating the underlying molecular basis of this is essential to understanding zinc functions in cellular physiology and pathogenesis. In recent decades, an increasing amount of evidence has uncovered critical roles of a number of proteins in zinc metabolism and homeostasis through influxing, chelating, sequestrating, coordinating, releasing, and effluxing zinc. Metallothioneins (MT) and Zrt- and Irt-like proteins (ZIP) and Zn transporters (ZnT) are the proteins primarily involved in these processes, and their malfunction has been implicated in a number of inherited diseases such as acrodermatitis enteropathica. The present review updates our current understanding of the biological functions of MTs and ZIP and ZnT transporters from several new perspectives.

Oral drug administration is the most convenient and common for drug therapy and it is, therefore, very important and useful to estimate the absorbability of drugs and to predict the plasma concentration profile of drugs after oral administration for the development of novel drugs and/or novel dosage form and the designation of the dosage regimen. Generally, the absorbability of drugs has been estimated by in-situ recirculation studies, in-situ closed loop studies or the analysis by the simple compartment model. The information which can be obtained from these approaches is usually an absorption rate constant, ka. The ka value is generally the averaged one throughout the intestinal tract. However, there is the site-difference in drug absorbability [1][2][3][4] and variable residence time of drugs in each segment must make the contribution of each segment to drug absorption changed, resulting in the different absorbability as a whole. As for the drug absorption after oral administration, the gastrointestinal (GI) transit of a drug is also an important factor to determine the drug absorption and is so variable, as was influenced by not only individual differences, 5) but also the dosage conditions like meals, 6) disease states 7) and so on. Therefore, the absorbability and the residence time in each segment are the major determining factors for drug absorption after oral administration and very important for the analysis of drug absorption kinetics and the estimation of, and the prediction of plasma concentration profiles of drugs. However, the analysis and the estimation of drug absorption after oral administration have been usually performed by a simple compartment model, where even a process of gastric emptying is not included often. This kind of simple model cannot describe the irregular shape in the plasma concentration, which is often observed. Therefore, several models were proposed to analyze the plasma profile, [8][9][10][11] but they are not necessarily based on the practical phenomena, i.e. GI transit and site-different drug absorbability.We have developed a GI-Transit-Absorption (GITA) Model containing the GI transit and absorption processes to analyze and predict the plasma concentration profile after oral administration of aqueous drug solution.12) Although several efficient methods to estimate the absorption of orally administered drug by analyzing the GI disposition following oral administration (GI disposition analysis) have been reported, some are only focused on the gastric emptying based on a model having a stomach and an intestine compartment. 13,14) The other one estimated the intestinal transit of a drug using polyethylene glycol 4000 as a nonabsorbable marker, 10) but the actual data of intestinal transit were not utilized enough to analyze and predict the drug absorption kinetics. Although the analytical procedures for plasma profile of a drug absorbed from successive absorption sites along the GI tract have been also reported, [16][17][18] they just showed the concept and/or simulation stu...

Antiviral activities of insoluble solid-state and soluble ionic copper and silver compounds were evaluated against influenza A virus (A/PR8/H1N1) possessing a viral envelope and bacteriophage Qβ lacking an envelope. The viral solutions were exposed on glass samples uniformly loaded with copper and silver compounds. Exposure to solid-state cuprous oxide (Cu2O) efficiently inactivated both influenza A virus and bacteriophage Qβ, whereas solid-state cupric oxide (CuO) and silver sulfide (Ag2S) showed little antiviral activity. Copper ions from copper chloride (CuCl2) had little effect on the activity of bacteriophage Qβ in spite of the fact that copper ions strongly inactivate influenza A in previous studies. Silver ions from silver nitrate (AgNO3) and silver(I) oxide (Ag2O) in solution showed strong inactivation of influenza A and weak inactivation of bacteriophage Qβ. We also investigated the influence of the compounds on the function of two influenza viral proteins, hemagglutinin and neuraminidase. Silver ions from AgNO3 and Ag2O remarkably decreased enzymatic activity of neuraminidase through the breakage of disulfide (SS) bonds, corresponding to the selective inactivation of influenza A virus. By contrast, exposure to Cu2O markedly reduced the activity of hemagglutinin rather than neuraminidase. These findings suggest that solid-state Cu2O disrupts host cell recognition by denaturing protein structures on viral surfaces, leading to the inactivation of viruses regardless of the presence of a viral envelope.

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Mammalian metallothionein (MT) genes are transcriptionally activated by the essential metal zinc as well as by environmental stresses, including toxic metal overload and redox fluctuations. In addition to playing a key role in zinc homeostasis, MT proteins can protect against metal-and oxidant-induced cellular damage, and may participate in other fundamental physiologic and pathologic processes such as cell survival, proliferation, and neoplasia. Previously, our group reported a requirement for metal-responsive transcription factor-1 (MTF-1) in hypoxia-induced transcription of mouse MT-I and human MT-IIA genes. Here, we provide evidence that the protumorigenic hypoxia-inducible transcription factor-1A (HIF-1A) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1A are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1A, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1A seems to function as a coactivator of MT-I gene transcription by interacting with MTF-1 during hypoxia. Coimmunoprecipitation studies suggest interaction between MTF-1 and HIF-1A, either directly or as mediated by other factors. It is proposed that association of these important transcription factors in a multiprotein complex represents a common strategy to control unique sets of hypoxia-inducible genes in both normal and diseased tissue. (Mol Cancer Res 2008;6(3):483 -90)