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PubMed2005

Effects of 1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on human leukemia cells in vitro and in vivo.

1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantine (DPD), a new cytostatic and differentiation inducing agent, was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Previously, we demonstrated that DPD inhibited the growth of human colon cancer cell lines both in vitro and in vivo. In this study, we examined the anticancer effects of DPD on two human leukemia cells lines. DPD exerted growth inhibitory activities in vitro against two human leukemia cell lines, the promyeloid line HL-60 and the lymphoblastic line Molt-3. The in vivo effect of tumor growth suppression by DPD was also observed in mouse xenografts. No acute toxicity was observed after an intra-peritoneal challenge of DPD in "severe combined immune-deficiency" (SCID) mice twice a week. The in vitro study showed HL-60 was more sensitive to DPD than Molt-3 through induction of G(0)/G(1) cell-cycle arrest with the appearance of a hypodiploid DNA fraction. The increased superoxide (O(2)(-)), dissipation of the mitochondrial membrane potential, activation of caspase 3, and increase in annexin V binding were evident before apoptosis in DPD-treated cells. The superoxide dismutase 1 (SOD1) mRNA expression was also decreased in DPD-treated HL-60 and Molt-3 cells. Thus, it appeared that inhibition of SOD might be the major cause for the production of cellular superoxide with concomitant decrease of H(2)O(2) in DPD-treated cells. Addition of antioxidant can reduce DPD-induced mitochondrial damage, caspase activation, and annexin V binding in HL-60 cells. The results suggest that the cellular generation of O(2)(-) plays a role in initiating and coordinating DPD-mediated growth arrest and apoptosis of HL-60 cells. Importantly, addition of arsenic trioxide, a compound capable of reactive oxygen species (ROS) generation, significantly enhanced the in vitro activity of DPD. These results suggest that DPD appears to be a potential new modality in human leukemia therapy.

Adamantane↗
PubMed2002

Role of the Multidrug Resistance Protein 1 in protection from heavy metal oxyanions: investigations in vitro and in MRP1-deficient mice.

The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Metabolism and excretion of orally and intraperitoneally administered gallium arsenide in the hamster.

This study deals with the metabolism of gallium arsenide (GaAs). GaAs was shown to be soluble in various media. Since this compound could dissolve in aqueous solvents, in vivo dissolution was investigated. Hamsters were used to study the dissolution and subsequent pharmacokinetics of any liberated arsenic species. The fecal and urinary excretion data following oral and intraperitoneal administration showed that GaAs, when administered orally, is mostly excreted in the feces but poorly in the urine, and that the compound, when administered intraperitoneally, is poorly excreted in both the feces and urine. Analysis of tissues for arsenic levels yielded concentrations in the ppb range, which further verified this fact. Most interesting was the fact that dimethylarsinic acid (DMAA) and methylarsonic acid (MAA) along with inorganic arsenic were found in the urine and tissues. GaAs was shown to dissolve in vivo and the released arsenic species were metabolized as other inorganic arsenics were found in the urine and tissues. GaAs was shown to dissolve in vivo and the released arsenic species were metabolized as other inorganic arsenic containing compounds. The low solubility and poor oral absorption may make this compound less toxic than other inorganic arsenic compounds.

Administration, Oral↗
PubMed1991

[Clinical and hygienic aspects of the effect of antimony ore on workers in the Far North].

The clinical and hygienic studies performed at the antimonite ore extraction mines in Yakutia revealed that the workers were exposed to high concentrations of polymetallic dusts, containing chromium dioxide, antimony, arsenic and their compounds. 11% of the workers exhibited dust bronchitis, changes in the blood and immune reactivity indices which were due to reactions of adaptation to the Far North climatic conditions and the occupational factors' toxic effects.

Air Pollutants, Occupational↗
PubMed1964

EFFECTS OF ACIDIC AZOPROTEINS ON PLASMA TRIGLYCERIDE LEVELS AND ON THE HEPARIN-ACTIVATED CLEARING SYSTEM.

When injected into the rabbit 3 acidic azoproteins produced marked changes in the blood triglyceride levels. 4-Arsonophenylazoproteins, which were found to act similarly in 2 other mammalian species, produced a gross and prolonged hyperlipemia. 4-sulfono- and 4-carboxyphenylazoproteins in the rabbit produced an initial elevation and later lowering in blood triglyceride levels. The correlation between these changes and the action of the azoproteins on clearing factor lipase provides further evidence for the importance of this enzyme in fat transport mechanisms. 4-Arsonophenylazoprotein is powerfully inhibitory to the lipase. 4-Carboxy- and 4-sulfonophenylazoprotein in vivo initially inhibit the enzyme and later produce a heparin-like activation.

Albumins↗
PubMed2004

[Exposure to metals, metalloids and their compounds in heavy metals refining].

BACKGROUND: In the process of heavy metals refining, workers are first of all exposed to metals, metalloids (As, Se) and their compounds. Moreover, they are exposed to sulphuric acid and dusts (about 2% SiO2). MATERIALS AND METHODS: Several dozen workers in two Polish plants were studied (Cu, Pb, Cd, Zn, and Ag refining processes, production of Ni sulphate and production of Se). Cd, Ni, Se, Cu, Pb, As and Ag were determined by atomic absorption spectrometry (AAS) with graphite tube, whereas ZnO (as Zn) by AAS with air-acetylene flame. Sulphuric acid was determined by the method given in PN-91/Z-04056/02, and dust (total and respirable fraction) by gravimetric methods. RESULTS: High concentrations of lead were found in the workplace air in both plants. Occupational exposure indicators for lead were much higher than the Polish MAC value. Exposure to arsenic and its compounds was a serious problem in one of the plants. Concentrations of the other chemical agents were generally below the Polish MAC values. CONCLUSIONS: Even though in many cases no risk is posed by individual metals and metalloids, total exposure is another matter. The total exposure indicator for present metals and metalloids at most workstations in both plants was higher than 1. In general, risk posed by metals and metalloids is high or even very high in the heavy metal refining industry.

Air Pollutants, Occupational↗
PubMed2006

Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats.

Arsenic and its compounds cause adverse health effects in humans. Current treatment employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised by number of limitations due to their lipophobic nature, particularly in case of chronic poisoning. Combination therapy is a new approach to ensure enhanced removal of metal from the body, reduced doses of potentially toxic chelators, and no redistribution of metal from one organ to another, following chronic metal exposure. The present study attempts to investigate dose-related effects of two thiol chelators, DMSA and one of its new analogues, monoisoamyl dimercaptosuccinic acid (MiADMSA), when administered in combination with the aim of achieving normalization of altered biochemical parameters suggestive of oxidative stress and depletion of inorganic arsenic following chronic arsenic exposure. Twenty-five adult male Wistar rats were given 25 ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 0.3 mmol/kg (orally) when administered individually or 0.15 mmol/kg and 0.3 mmol/kg (once daily for 5 consecutive days), respectively, when administered in combination. Arsenic exposure led to the inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and depletion of glutathione (GSH) level. These changes were accompanied by significant depletion of hemoglobin, RBC and Hct as well as blood superoxide dismutase (SOD) acitivity. There was an increase in hepatic and renal levels of thiobarbituric acid-reactive substances, while GSH:GSSG ratio decreased significantly, accompanied by a significant increase in metallothionein (MT) in hepatocytes. DNA damage based on denaturing polyacrylamide gel electrophoresis revealed significant loss in the integrity of DNA extracted from the liver of arsenic-exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.

Animals↗
PubMed2003

Arsenic sensing and resistance system in the cyanobacterium Synechocystis sp. strain PCC 6803.

Arsenic is one of the most important global environmental pollutants. Here we show that the cyanobacterium Synechocystis sp. strain PCC 6803 contains an arsenic and antimony resistance operon consisting of three genes: arsB, encoding a putative arsenite and antimonite carrier, arsH, encoding a protein of unknown function, and arsC, encoding a putative arsenate reductase. While arsB mutant strains were sensitive to arsenite, arsenate, and antimonite, arsC mutants were sensitive only to arsenate. The arsH mutant strain showed no obvious phenotype under the conditions tested. In vivo the arsBHC operon was derepressed by oxyanions of arsenic and antimony (oxidation state, +3) and, to a lesser extent, by bismuth (oxidation state, +3) and arsenate (oxidation state, +5). In the absence of these effectors, the operon was repressed by a transcription repressor of the ArsR/SmtB family, encoded by an unlinked gene termed arsR. Thus, arsR null mutants showed constitutive derepression of the arsBHC operon. Expression of the arsR gene was not altered by the presence of arsenic or antimony compounds. Purified recombinant ArsR protein binds to the arsBHC promoter-operator region in the absence of metals and dissociates from the DNA in the presence of Sb(III) or As(III) but not in the presence of As(V), suggesting that trivalent metalloids are the true inducers of the system. DNase I footprinting experiments indicate that ArsR binds to two 17-bp direct repeats, with each one consisting of two inverted repeats, in the region from nucleotides -34 to + 17 of the arsBHC promoter-operator.

Antimony↗
PubMedDate not supplied

2,3-Dithioerythritol, a possible new arsenic antidote.

British antilewisite (2,3-dimercaptopropanol; BAL) has long been used as an arsenic antidote, but its therapeutic efficacy is limited by its inherent toxicity. We synthesized two less toxic derivatives of BAL and investigated their potential as antidotes to organic arsenic. The new compounds, 2,3-dithioerythritol (DTE) and 2,2-dimethyl-4-(hydroxymethyl)-1,3-dithiolane (isopropylidene derivative of BAL), react readily with phenyldichloroarsine (PDA) to yield the expected corresponding cyclic 1,3-dithioarsolanes. The BAL derivatives were compared to BAL in terms of their cytotoxicity and their ability to rescue PDA-poisoned mouse lymphoma cells in culture. The dithiolane was not a good antidote in the cultured cell system. In contrast, DTE was less toxic than BAL or DMSA and was superior at improving cell survival in PDA-exposed cells.

Animals↗
PubMed1994

Binding of ArsR, the repressor of the Staphylococcus xylosus (pSX267) arsenic resistance operon to a sequence with dyad symmetry within the ars promoter.

arsR, the first gene of the Staphylococcus xylosus (pSX267) arsenic/antimonite resistance (ars) operon encodes a negative regulatory protein, ArsR, which mediates inducibility of the resistances by arsenic and antimony compounds. ArsR, which has no obvious DNA-binding motif in its primary structure, was purified from an ArsR-overproducing Escherichia coli strain and identified as a DNA-binding protein by its behaviour in gel mobility shift assays. ArsR had a specific affinity for a 312 bp DNA restriction fragment carrying the ars promoter; the minimum sequence complexed by ArsR was a 75 bp polymerase chain reaction (PCR) fragment, which mainly comprised the -35 and -10 regions of the promoter. The effect of inducers on the DNA-binding activity of ArsR was examined by in vitro induction assays; only arsenite inhibited DNA-binding of the repressor. DNase I footprinting revealed two protected regions within the promoter region, spanning 23 and 9 nucleotides, respectively. Furthermore, a new cleavage site for DNase I between the protected regions was made accessible by binding of the repressor. The footprints cover a region of three inverted repeats located between the -35 and -10 motifs of the ars promoter. By high resolution footprinting with the hydroxy radical, five sites of close contact between the protein and DNA were identified.

Antimony↗
PubMed1987

Metal toxicity in the central nervous system.

The nervous system is the principal target for a number of metals. Inorganic compounds of aluminum, arsenic, lead, lithium, manganese, mercury, and thallium are well known for their neurological and behavioral effects in humans. The alkyl derivatives of certain metals--lead, mercury and tin--are specially neurotoxic. Concern over human exposure and in some cases, outbreaks of poisoning, have stimulated research into the toxic action of these metals. A number of interesting hypotheses have been proposed for the mechanism of lead toxicity on the nervous system. Lead is known to be a potent inhibitor of heme synthesis. A reduction in heme-containing enzymes could compromise energy metabolism. Lead may affect brain function by interference with neurotransmitters such as gamma-amino-isobutyric acid. There is mounting evidence that lead interferes with membrane transport and binding of calcium ions. Methylmercury produces focal damage to specific areas in the adult brain. One hypothesis proposes that certain cells are susceptible because they cannot repair the initial damage to the protein sythesis machinery. The developing nervous system is especially susceptible to damage by methylmercury. It has been discovered that microtubules are destroyed by this form of mercury and this effect may explain the inhibition of cell division and cell migration, processes that occur only in the developmental stages. These and other hypotheses will stimulate considerable experimental challenges in the future.

Animals↗
PubMed2006

Seafood arsenic: implications for human risk assessment.

Concerns about the adverse effects of chronic arsenic exposure have focused on contaminated drinking water and airborne workplace exposures; the risks of naturally occurring arsenic in foods have received less attention. About 90% of the arsenic in US diets comes from seafood, of which only a small proportion occurs in inorganic forms; the great majority consists of complex organic compounds that generally have been regarded as non-toxic. However, recent studies of seafood have documented formation of metabolites carcinogenic in some rodents. To calculate the risks of ingested seafood arsenic, therefore, it is necessary to identify the nature and quantity of arsenic species present and the metabolites formed by expected metabolic activities. We review the nature and quantities of the various arsenical compounds found in dietary seafood and discuss their metabolic processing and fate. Based on conservative dose estimates and the likelihood that arsenic's carcinogenic mechanisms follow sub-linear dose-response curves, we estimate a margin of exposure of at least 10(3)-10(4) between carcinogenic doses used in rodent studies and those expected after human consumption of large quantities of seafood.

Animals↗
PubMed1992

Plasmid mediated metal and antibiotic resistance in marine Pseudomonas.

Pseudomonas sp isolated from the Bay of Bengal (Madras coast) contained a single large plasmid (pMR1) of 146 kb. Plasmid curing was not successful with mitomycin C, sodium dodecyl sulfate, acridine orange, nalidixic acid or heat. Transfer of mercury resistance from marine Pseudomonas to Escherichia coli occurred during mixed culture incubation in liquid broth at 10(-4) to 10(-5) ml(-1). However, transconjugants lacked the plasmid pMR1 and lost their ability to resist mercury. Transformation of pMR1 into E. coli competent cells was successful; however, the efficiency of transformation (1.49 x 10(2)Hgr transformants microsgm-1 pMR1 DNA) was low. E. coli transformants containing the plasmid pMR1 conferred inducible resistance to mercury, arsenic and cadmium compounds similar to the parental strain, but with increased expression. The mercury resistant transformants exhibited mercury volatilization activity. A correlation existed between metal and antibiotic resistance in the plasmid pMR1.

DNA, Bacterial↗
PubMed1997

Alternate energy coupling of ArsB, the membrane subunit of the Ars anion-translocating ATPase.

The arsenical resistance (ars) operon of the conjugative R-factor R773 confers resistance to arsenical and antimonial compounds in Escherichia coli, where resistance results from active extrusion of arsenite catalyzed by the products of the arsA and arsB genes. Previous in vivo studies on the energetics of arsenite extrusion showed that expression of both genes produced an ATP-coupled arsenite extrusion system that was independent of the electrochemical proton gradient. In contrast, in cells expressing only the arsB gene, arsenite extrusion was coupled to electrochemical energy and independent of ATP, suggesting that the Ars transport system exhibits a dual mode of energy coupling depending on the subunit composition. In vitro the ArsA-ArsB complex has been shown to catalyze ATP-coupled uptake of 73AsO2(-1) in everted membrane vesicles. However, transport catalyzed by ArsB alone has not previously been observed in vitro. In this study we demonstrate everted membrane vesicles prepared from cells expressing only arsB exhibit uptake of 73AsO2(-1) coupled to electrochemical energy.

Adenosine Triphosphatases↗
PubMed2002

Molecular mechanisms of in vivo metal chelation: implications for clinical treatment of metal intoxications.

Successful in vivo chelation treatment of metal intoxication requires that a significant fraction of the administered chelator in fact chelate the toxic metal. This depends on metal, chelator, and organism-related factors (e.g., ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, route of administration, bioavailability, metabolism, organ and intra/extracellular compartmentalization, and excretion). In vivo chelation is not necessarily an equilibrium reaction, determined by the standard stability constant, because rate effects and ligand exchange reactions considerably influence complex formation. Hydrophilic chelators most effectively promote renal metal excretion, but they complex intracellular metal deposits inefficiently. Lipophilic chelators can decrease intracellular stores but may redistribute toxic metals to, for example, the brain. In chronic metal-induced disease, where life-long chelation may be necessary, possible toxicity or side effects of the administered chelator may be limiting. The metal selectivity of chelators is important because of the risk of depletion of the patient's stores of essential metals. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have gained more general acceptance among clinicians, undoubtedly improving the management of many human metal intoxications, including lead, arsenic, and mercury compounds. Still, development of new safer chelators suited for long-term oral administration for chelation of metal deposits (mainly iron), is an important research challenge for the future.

Biological Availability↗