Biomedical subjects

Seiichiro Himeno

Publications and source records attributed to Seiichiro Himeno.

13 recordsLinked to original sources

PubMed2006

Chronic exposure to methylated arsenicals stimulates arsenic excretion pathways and induces arsenic tolerance in rat liver cells.

Although inorganic arsenicals are toxic and carcinogenic in humans, inorganic arsenite has recently emerged as a highly effective chemotherapeutic agent for acute promyelocytic leukemia (APL). Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAs(V)), dimethylarsinic acid (DMAs(V)), and trimethylarsine oxide (TMAs(V)O) in mammals. We examined the effects of chronic exposure to methylated arsenicals on arsenic tolerance by using rat normal liver TRL 1215 cells. TRL 1215 cells were exposed for 20 weeks to MMAs(V), DMAs(V), or TMAs(V)O at levels that produced submicromolar cellular concentrations of arsenic. On chronic exposure to these methylated arsenicals, the cells acquired tolerance to acute arsenic cytolethality. Cellular arsenic uptake was reduced in these cells compared to passage-matched control cells. The long-term arsenic exposure increased glutathione S-transferase (GST) activity and cellular glutathione (GSH) levels. Glutathione S-transferase, multidrug resistance-associated proteins (Mrps; efflux transporters encoded by Mrp genes), and P-glycoprotein [P-gp; efflux transporter encoded by multidrug resistance gene (MDR)] had also increased in these cells at the transcript and protein levels. The depletion of cellular GSH and the inhibition of Mrps and P-gp functions increased cellular arsenic uptake and reduced arsenic tolerance in these cells. These results indicate that chronic exposure to methylated arsenicals induces a generalized arsenic tolerance that is caused by increased arsenic excretion. Because accumulation of methylated arsenicals may occur in patients with chronic arsenic poisoning and arsenic-treated APL patients, this study may provide important information regarding chronic arsenic poisoning and the latent risk of developing multidrug resistance in APL therapy using inorganic arsenite.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Reduction of drug leakage by negative-balance isolated pelvic perfusion: correlation between leakage and in-out flow rate in a pig model.

PURPOSE: Isolated pelvic perfusion (IPP) therapy exposes target tissues to high doses of anticancer drugs with low systemic concentrations, but the major drawback is drug leakage into the systemic circulation, which often thwarts the increased drug concentration. In this study, the efficacy of altering the in-out flow rate during IPP in order to decrease the leakage was assessed in adult pigs. METHODS: The abdominal aorta and the infrarenal vena cava were occluded with two balloon catheters, blood in the extracorporeal circuit was circulated with twin rotary pumps, and the IPP was performed with platinum. Three sets of in-out flow rates were used, and the degree of drug leakage into the systemic circulation was evaluated. The volume of blood withdrawn was equal to the volume returned (300 ml/min; group A), 5% higher (group B), or 10% higher (group C). The platinum concentrations in the pelvic circulation, systemic circulation, and urine were measured and compared. RESULTS: The average and maximum plasma platinum concentrations in the pelvic circulation did not significantly differ among the three groups. The plasma platinum concentrations in the systemic venous circulation of the three groups significantly (P<0.01) decreased as the volume withdrawn during IPP increased. The percentage of platinum eliminated in the urine during IPP was significantly (P<0.01) lower in group B and C than in group A. CONCLUSIONS: Setting the volume withdrawn higher than the volume returned decreased leakage into the systemic circulation under isolated pelvic perfusion.

Angiography↗

PubMed2005

Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: role of NF-E2-related factor-2.

Thioredoxin reductase (TrxR) is a selenoprotein that catalyzes the reduction of the active site disulfide of thioredoxin (Trx), which regulates the redox status of the cells. In the present study, we found that TrxR1, one of the three TrxR isozymes, was induced by cadmium as well as tumor necrosis factor alpha (TNFalpha) in bovine arterial endothelial cells (BAEC), and investigated the mechanism of cadmium-induced TrxR1 expression. We here showed that cadmium, differently from TNFalpha, enhanced the promoter activity of the 5'-flanking region of human TrxR1 gene (nucleotides -1692 to +49). Deletion and site-directed mutation of antioxidant responsive element (ARE) (nucleotides -62 to -48) in this region abolished the response to cadmium. Overexpression of NF-E2-related factor-2 (Nrf2) augmented the TrxR1 promoter activity. In contrast, overexpression of the dominant negative mutant of Nrf2 suppressed cadmium-induced activation of TrxR1 promoter through the ARE. Chromatin immunoprecipitation (ChIP) assays showed that anti-Nrf2 antibody precipitated ARE from the chromatin of the cadmium-treated cells. These results indicated that cadmium-induced TrxR1 gene expression is mediated by the activation of Nrf2 transcription factor and its binding to ARE in the TrxR1 gene promoter. We further found that in addition to cadmium, the activators of Nrf2, such as diethyl maleate (DEM) and arsenite, induced both TrxR1 and Trx gene expression in BAEC. Nrf2 might play an important role in the regulation of the cellular Trx system consisting of Trx and TrxR.

5' Flanking Region↗

PubMed2005

Cytolethality of glutathione conjugates with monomethylarsenic or dimethylarsenic compounds.

Arsenicals are known to be toxic and carcinogenic in humans. Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAsV) and dimethylarsinic acid (DMAsV), which are the major pentavalent methyl arsenic metabolites. Recent reports indicate that trivalent methyl arsenicals are produced through methylation of inorganic arsenicals and participate in arsenic poisoning. Trivalent methyl arsenicals may be generated as arsenical-glutathione conjugates, such as monomethylarsonous diglutathione (MMAsIIIDG) and dimethylarsinous glutathione (DMAsIIIG), during the methylation process. It has been well known that reduced glutathione (GSH) reduces MMAsV and DMAsV in vitro, and produces MMAsIIIDG and DMAsIIIG. Some studies have shown that exogenous GSH increased cytolethality of MMAsV and DMAsV in vitro, while other studies have suggested that exogenous GSH decreased them. In this study, we examined the true effects of exogenous GSH on the cytolethality of MMAsV and DMAsV by investigating reactions between various concentrations of MMAsV or DMAsV and GSH. GSH significantly increased the cytolethality and cellular uptake of pentavalent methyl arsenicals when GSH over 25 mM was pre-incubated with mM levels of arsenicals, and this cytolethality might have been caused by arsenical-GSH conjugate generation. However, GSH at less than 25 mM did not affect the cytolethality and cellular uptake of pentavalent methyl arsenicals. These findings suggest that high concentrations of arsenicals and GSH are needed to form arsenical-GSH conjugates and to show significant cytolethality. Furthermore, we speculated that MMAsIIIDG and DMAsIIIG may separate into trivalent methyl arsenicals and glutathione, which are then transported into cells where they show significant cytolethality.

Animals↗

PubMed2005

Induction of hepatic metallothionein by trivalent cerium: role of interleukin 6.

Metallothionein (MT) is a small sulfydryl-rich protein that binds to and is inducible by heavy metals such as mercury, cadmium, zinc, and copper. However, little is known about the induction of MT by trivalent metals except for bismuth. In this study, we examined the induction of MT synthesis by cerium, a trivalent lanthanoid metal. Administration of cerium chloride (CeCl3) to mice resulted in accumulation of cerium and induction of MT in the liver in a dose-dependent manner. Distribution profiles of metals in the soluble fraction of the liver of CeCl3-treated mice analyzed by high performance liquid chromatography/inductively coupled argon plasma-mass spectrometry (HPLC/ICP-MS) demonstrated that the metal bound to MT-I and MT-II was zinc, but not cerium. Administration of CeCl3 caused increases in the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of serum amyloid A (SAA), an acute phase protein. Among inflammatory cytokines examined, interleukin 6 (IL-6) exhibited a marked increase in the serum at 3 h after the CeCl3 administration. In order to evaluate the involvement of IL-6 in the induction of MT by cerium, we examined MT induction by CeCl3 in IL-6 null mice. Both the induction of hepatic MT and the increases in SAA levels were markedly suppressed in IL-6 null mice. These results suggest that IL-6 plays an important role in the induction of hepatic MT by cerium.

Animals↗

PubMed2004

Preventive mechanism of cellular glutathione in monomethylarsonic acid-induced cytolethality.

Human pentavalent arsenic metabolic intermediate, monomethylarsonic acid (MMAs(V)), is a major arsenic type found in the blood in chronic arsenic poisoning patients, but little information is available on its toxicity potential or mechanisms of action. In this study, we investigated the molecular mechanisms of in vitro cytolethality of MMAs(V) using rat liver TRL 1215 cells. Cellular arsenic concentrations reached the nanomolar range in TRL 1215 cells when cells were exposed to millimolar levels of MMAs(V), and most of the MMAs(V) was not metabolized during the 48-h incubation. Under these conditions, MMAs(V) showed significant cytolethality when cellular reserves of reduced glutathione (GSH) were depleted. Morphological and biochemical evidence confirmed that MMAs(V) induced both necrosis and apoptosis in the cellular GSH-depleted cells. MMAs(V) significantly enhanced cellular caspase 3 activity in the cellular GSH-depleted cells, and a caspase 3 inhibitor blocked MMAs(V)-induced apoptosis. MMAs(V) also enhanced the production of cellular reactive oxygen species (ROS) in the cellular GSH-depleted cells, and addition of a membrane-permeable radical trapping reagent completely prevented both MMAs(V)-induced cellular caspase 3 activation and cytolethality in these cells. These observations suggest that MMAs(V) typically generates harmful ROS in cells, and cellular GSH prevents cytolethality by scavenging these toxic ROS. However, when cellular GSH levels are decreased, MMAs(V) induces oxidative stress in the cells, and this leads to apoptosis and/or necrosis depending on the cellular ROS/GSH ratio.

Animals↗

PubMed2004

Overexpression of thioredoxin reductase 1 regulates NF-kappa B activation.

Thioredoxin reductase (TrxR) is a flavoprotein that contains a C-terminal penultimate selenocysteine (Sec) and has an ability to reduce thioredoxin (Trx), which regulates the activity of NF-kappa B. To date, three TrxR isozymes, TrxR1, TrxR2, and TrxR3, have been identified. In the present study, we found that among these isozymes only TrxR1 was induced by tumor necrosis factor-alpha (TNF alpha) in vascular endothelial cells. Furthermore, the overexpression of TrxR1 enhanced TNF alpha-induced DNA-binding activity of NF-kappa B and NF-kappa B-dependent gene expression. The catalytic Sec residue of TrxR1, which is essential for reducing Trx, was required for this NF-kappa B activation, and aurothiomalate, an inhibitor of TrxR, suppressed TNF alpha-induced activation of NF-kappa B and the expression of NF-kappa B-targeted proinflammatory genes such as E-selectin and cyclooxygenase-2. These results suggest that TrxR1 may act as a positive regulator of NF-kappa B and may play an important role in the cellular inflammatory response.

Animals↗

PubMed2004

[Selenium].

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Biomarkers↗

PubMed2003

Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum.

Attenuation of the renal toxicity of cis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.

Administration, Oral↗

PubMed2003

Optimal administration schedule of cisplatin for bladder tumor with minimal induction of metallothionein.

PURPOSE: The metal binding protein metallothionein (MT) confers drug resistance when MT is induced in tumor tissues. Cisplatin is known to induce MT synthesis in tumor tissues, which may lead to drug resistance. We examined whether a difference in the administration schedule of cisplatin affect the efficiency of MT induction. MATERIALS AND METHODS: Balb/c nude mice were inoculated with NMB-1 human bladder tumor tissues and injected with cisplatin (total dose of 64 micromol/kg) in a single injection or fractioned daily injections. Tumor MT concentration was determined 24 hours after the last injection of cisplatin by mercury binding assay. The effect of pretreatment with ZnCl2 on antitumor activity of cisplatin was examined in NMB-1 bearing mice. RESULTS: Tumor MT levels increased significantly with the increase in the number of cisplatin injections. Pretreatment of NMB-1 bearing mice with ZnCl2 (200 micromol/kg x 2) caused the same level of MT induction (1.6-fold) as that of fractioned injections of cisplatin (4 x 16 micromol/kg). Pretreatment of NMB-1 bearing mice with ZnCl2 (200 micromol/kg x 2) depressed cisplatin antitumor activity by about 50%. CONCLUSIONS: The induction of MT to a moderate extent (1.6-fold) in NMB-1 tumor inoculated in mice conferred cisplatin resistance. This level of MT induction can be achieved by fractioned daily injections of cisplatin but not by a single injection. Therefore, it is preferable to administer cisplatin as a single injection rather than as fractioned injections to achieve effective antitumor activity with minimum MT induction.

Animals↗

PubMed2002

Application of metallothionein null cells to investigation of cadmium transport.

Metallothionein (MT) is an important factor for cadmium resistance in mammalian cells. Most Cd-resistant cell lines thus far established have shown enhanced production of MT protein. However, the presence of high concentrations of MT, which traps cellular cadmium ions efficiently, has hindered the investigation of cadmium transport in Cd-resistant cells. Utilization of MT null mice or cultured cells derived from MT null mice is a useful way to isolate and characterize non-MT factor(s) for Cd resistance. Primary cultured cells derived from embryos of MT-I/II null mouse showed an increased sensitivity to cadmium compared with control cells. Immortalization of these cells by introducing simian virus 40 large T antigen cDNA has enabled the development of Cd-resistant MT null cells. The established Cd-resistant MT null cells exhibited a reduced accumulation of cadmium due to a decreased rate of cellular cadmium uptake. Application of the multitracer technique has demonstrated that the uptake of Mn(II) was also markedly reduced in Cd-resistant MT null cells. Kinetic and competition studies on Cd(II) and Mn(II) uptake in these cells revealed that a high-affinity transport system for Mn(II) is used, at least in part, for cellular Cd(II) uptake. Thus, the utilization of MT null cells has permitted the detection of a novel cadmium transport system.

Animals↗

PubMed2002

Suppressed proliferative response of spleen T cells from metallothionein null mice.

To investigate the role of metal-binding protein, metallothionein (MT), in lymphocyte activation, the mitogen-induced proliferation of freshly isolated spleen cells was compared among MT-I, II null, and control 129/Sv mice. Spleen cells from MT null mice exhibited a markedly reduced proliferation compared with control cells when stimulated by concanavalin A or anti-CD3(epsilon) mAb, but not by lipopolysaccharide, indicating that only the response of T cells to mitogens was suppressed in MT null mice. Flow cytometric analysis of unstimulated spleen cells demonstrated no significant difference in the relative percentages of either B220+ and CD3+ cells or CD4+ and CD8+ cells between the two strains of mice. The production of interleukin (IL)-2 by MT null spleen cells after the stimulation by anti-CD3(epsilon) mAb was lower than that of control spleen cells, especially within 24 hr after the stimulation. The addition of IL-2 recovered the proliferation of MT null spleen cells to the control level. The reduced proliferative response to mitogenic stimulation of MT null T cells was confirmed by using purified splenic T cells. These results suggest that the MT expressed at basal level in the splenocytes plays an important role in T cell mitogen-induced proliferative response, probably by positively regulating the production of IL-2.

Animals↗

PubMed2002

Cellular cadmium uptake mediated by the transport system for manganese.

The mechanism of cellular cadmium (Cd) uptake has been poorly understood. Recently, we developed Cd-resistant cell lines from metallothionein null mouse cells and showed that the Cd resistance of these cells was conferred primarily by a reduced Cd accumulation. Surprisingly, the uptake rate of manganese (Mn) was also markedly reduced in Cd-resistant cells. Subsequent studies on the kinetics of Cd and Mn uptake by Cd-resistant and parental cells revealed that the Mn transport system with high affinity for Mn is used for cellular Cd uptake, and that this pathway is suppressed in Cd-resistant metallothionein null cells. This is the first indication that the transport system for Mn is used for Cd uptake in mammalian cells. Divalent metal transporter 1 (DMT1) is the only known mammalian transporter involved in the uptake of both Cd and Mn. However, the high-affinity Mn/Cd transport system we found seems to be distinct from DMT1 because of the difference in optimal pH and substrate specificity. On the other hand, various types of Mn transporters have been shown to play an important role in cellular Cd uptake in non-mammalian species such as yeast, plants and bacteria, suggesting the existence of Mn transporters other than DMT1 in mammals.

Animals↗