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PubMed1999

Phenylarsine oxide evokes intracellular calcium increases and amylase secretion in isolated rat pancreatic acinar cells.

The effects of the thiol reagent, phenylarsine oxide (PAO, 10(-5)-10(-3) M ), a membrane-permeable trivalent arsenical compound that specifically complexes vicinal sulfhydryl groups of proteins to form stable ring structures, were studied by monitoring intracellular free calcium concentration ([Ca2+]i) and amylase secretion in collagenase dispersed rat pancreatic acinar cells. PAO increased [Ca2+]i by mobilizing calcium from intracellular stores, since this increase was observed in the absence of extracellular calcium. PAO also prevented the CCK-8-induced signal of [Ca2+]i and inhibited the oscillatory pattern initiated by aluminium fluoride (AlF-4). In addition to the effects of PAO on calcium mobilization, it caused a significant increase in amylase secretion and reduced the secretory response to either CCK-8 or AlF-4. The effects of PAO on both [Ca2+]i and amylase release were reversed by the sulfhydryl reducing agent, dithiothreitol (2 mM). Pretreatment of acinar cells with high concentration of ryanodine (50 microM) reduced the PAO-evoked calcium release. However, PAO was still able to release a small fraction of Ca2+ from acinar cells in which agonist-releasable Ca2+ pools had been previously depleted by thapsigargin (0.5 microM) and ryanodine receptors were blocked by 50 microM ryanodine. We conclude that, in pancreatic acinar cells, PAO mainly releases Ca2+ from the ryanodine-sensitive calcium pool and consequently induces amylase secretion. These effects are likely to be due to the oxidizing effects of this compound.

Amylases↗

PubMed1996

Inorganic arsenic species in groundwater: a case study from Purbasthali (Burdwan), India.

A regional groundwater quality survey from 20 tube wells in the Purbasthali area of the Burdwan district of West Bengal province (India) identified arsenic pollution in this area. Arsenic was detected in 19 cases at a concentration level 0.5 to 135.9 micrograms/L. Speciation studies indicate that As(III) is present in only one sample and organo-arsenic compounds have not been detected. Iron, antimony and pH of such water samples were also studied to see if there is any correlation of the presence of arsenic and these parameters. A high concentration of iron (0.3 to 10.7 mg/L) has been detected. Antimony is present in all these water samples (0.03 to 0.9 microgram/L). The pH value of the groundwater in this area shows that it is more or less neutral.

Arsenic↗

PubMed1993

Pharmacology of existing drugs for animal trypanosomiasis.

Lack of much interest by the pharmaceutical industry to venture into development of new antitrypanosomal drugs has been a major stimulus to an intensification of research into the few existing drugs. Those indicated for animal trypanosomiasis include: isometamidium, homidium and diminazene, used primarily against Trypanosoma congolense, T. vivax and T. brucei; and quinapyramine, mainly indicated for use against T. evansi infections. A great deal of research effort has focused on development of pharmacological and parasitological methodologies, which have considerably advanced our understanding on the efficacy, resistance, disposition and toxicological mechanisms of these drugs. While a clinical breakthrough has been made in the recent past, in the field of chemotherapy of T. evansi infections by the introduction of a new arsenic compound, melarsenoxide cysteamine, chemotherapy of T. simiae infections in pigs still remains a major challenge because the existing drugs are either ineffective or too toxic for economic use. Further research into the existing drugs is a prerequisite for their optimal usage in the overall effort of improving animal health and productivity through control of trypanosomiasis.

Animals↗

PubMed2004

Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein.

Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As(4)S(4)). Analysis of cell proliferation and clonogenic ability showed that As(4)S(4) and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34(+) cells from the nonleukemic donors. Examination of cell cycles showed that As(4)S(4) induced G(2)/M arrest whereas imatinib induced G(1) arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As(4)S(4) triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As(4)S(4) combination on CML.

Antineoplastic Agents↗

PubMed1994

Analysis of nickel refinery dusts.

After characterization of bulk samples by inductively coupled plasma emission spectroscopic (ICP-ES) quantitative analysis and X-ray powder diffraction studies, single particle techniques using quantitative image analysis, scanning electron microscopy--energy dispersive analysis by X-ray, and finally laser beam ionization mass spectrometry analysis (LIMA) for surface analysis have been applied to historical nickel refinery dust samples from the nickel refining plant at Clydach in Wales. There were two historical samples of processed material from 1920 and 1929. These samples had a remarkably small particle size range, mean 3 microns and range, 0.75-24 microns. The most significant difference in elemental composition was the presence of 10% arsenic in the 1920 sample compared with 1% in the 1929 sample. The X-ray spectra revealed the presence of NiO in both. However, surprisingly, CuO was identified only in the 1929 sample. Of particular interest was the presence of a component, in the 1920 sample only, identified as the mineral orcelite, a copper-iron-nickel-arsenide-sulphide mineral, predominantly, Ni5-XAs2. Using the LIMA technique, it was found that in both samples, arsenic and arsenic derivative peaks are prominent, indicating the surface availability of arsenic compounds.

Arsenic↗

PubMed2004

Arsenic speciation in human urine: are we all the same?

We studied the arsenic speciation in human urine samples by using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). We investigated the arsenic speciation in the urine collected from nine volunteers during a 3-day period after a meal of blue mussels, Mytilus edulis. We also studied the effect of cooking on the arsenic speciation. Arsenobetaine and dimethylarsinic acid (DMAA) were the major arsenic metabolites found in the urine samples. Significant amounts of unknown metabolites were also detected. The excretion patterns of arsenic from individuals were generally similar except for two subjects. One of whom excreted high amounts of arsenobetaine even though no arsenic-rich food was eaten for 3 days before the experiment. The results reveal that we need a better understanding of the metabolism of arsenic compounds by human.

Animals↗

PubMed1990

Organic arsenic-induced Guillain-Barré-like syndrome due to melarsoprol: a clinical, electrophysiological, and pathological study.

A young woman suffering from sleeping sickness was treated with melarsoprol. Thirty-eight days after the first administration of this organo-arsenic compound, myalgias, distal paresthesias and rapidly progressive weakness developed in all four limbs. Electrophysiological studies were misleading for Guillain-Barré syndrome. Neuropathological data included massive distal wallerian degeneration in peripheral nerves and abnormalities in dorsal ganglia and spinal cord where vacuolation of anterior horn cells and axonal neurofilamentous masses were observed. Very high concentrations of arsenic were found in the spinal cord, contrasting with undetectable levels in peripheral nerves. Our findings are consistent with an arsenic neuronopathy manifested by initial proximal demyelination and delayed distal axonal damage. Renal and hepatic dysfunctions, which were implicated in the toxic arsenic accumulation, should be systematically detected before administration of melarsoprol. The diagnosis of Guillain-Barré syndrome must be considered with caution in patients treated with this compound.

Adult↗

PubMed1993

Effects of arsenic on DNA synthesis in human lymphocytes.

Effects of arsenic on DNA synthesis in human lymphocytes were biphasic: Either trivalent (arsenic trioxide and sodium arsenite) or pentavalent (sodium arsenate) arsenic compounds at very low concentrations enhanced DNA synthesis in human lymphocytes stimulated by phytohemagglutinin (PHA), whereas higher concentrations inhibited DNA synthesis. There were differences among individual susceptibilities to arsenic-induced DNA synthesis. Either stimulating or inhibiting effects of trivalent arsenic on DNA synthesis in PHA-stimulated lymphocytes were always stronger than those of pentavalent arsenic. Both trivalent and pentavalent arsenic could be rapidly taken up into the human lymphocytes and immediately stimulate or inhibit DNA synthesis. A possible dual effect of arsenic at very low concentrations as both comutagen and inhibitor of mutagenesis is discussed.

Arsenic↗

PubMed1993

Effects of arsenic on DNA synthesis in human lymphocytes stimulated by phytohemagglutinin.

Effects of arsenic on DNA synthesis in human lymphocytes were biphasic: either trivalent (arsenic trioxide and sodium arsenite) or pentavalent (sodium arsenate) arsenic compounds at very low concentrations enhanced DNA synthesis in human lymphocytes stimulated by phytohemagglutinin (PHA), whereas higher concentrations inhibited DNA synthesis. There were differences among individual susceptibilities to arsenic-induced DNA synthesis. Either stimulating or inhibiting effects of trivalent arsenic on DNA synthesis in PHA-stimulated lymphocytes were always stronger than those of pentavalent arsenic. It was also shown that both trivalent and pentavalent arsenic could be rapidly taken up into the human lymphocytes, and immediately stimulated or inhibited DNA synthesis. A possible dual effect of arsenic at very low concentrations as both comutagen and inhibitor of mutagenesis is discussed.

Adult↗

PubMedDate not supplied

Effect of arsenicals on biliary excretion of endogenous glutathione and xenobiotics with glutathione-dependent hepatobiliary transport.

Sodium arsenite (25-100 mumol/kg, i.v.) and arsenate (75-300 mumol/kg, i.v.) injected into anaesthetized rats increased the biliary excretion of endogenous non-protein thiols (NPSH) in a dose-dependent fashion up to 24- and 31-fold, respectively. Simultaneously with NPSH, glutathione (GS) excretion was increased to a similar extent suggesting that the increment in biliary thiol output originated from enhanced hepatobiliary transport of GS. After administration of labelled arsenicals, biliary excretion of 74As and NPSH followed similar time-courses. Biliary excretion of 74As was more efficient after arsenite than arsenate administration corresponding to the greater potency of arsenite compared to arsenate to increase biliary output of NPSH. Coadministered sulfobromophthalein (BSP) inhibited the biliary excretion of 74As and prevented the arsenical-induced increase in biliary NPSH. Thus, hepatobiliary transport of arsenic apparently proceeds coordinately with that of GS. However, excretion of each molecule of arsenic compound generates transport of several molecules of GS. Though mercuric, methylmercuric, cadmium and zinc ions are thought to be excreted into bile as complexes with GS, the marked arsenical-induced increase in GS excretion only doubled the biliary excretion of inorganic mercury and hardly influenced the transport of other metals into bile. This finding suggests that arsenicals markedly enhance biliary excretion of GS with a free thiol group but barely or not at all that of GS with a thiol group blocked by a firmly bound metal ion. Both arsenicals diminished the biliary excretion of BSP-glutathione conjugate after BSP administration presumably because they impaired conjugation of BSP with GSH due to decreased GS availability. It is assumed that arsenite, and arsenate after reduction to arsenite, forms an unstable complex with GS that is efficiently transported into bile resulting in increased biliary output of GS. It is demonstrated that arsenite-induced perturbation of hepatobiliary disposition of endogenous GS differentially affects biliary excretion of xenobiotics with GS-dependent hepatobiliary transport.

Animals↗

PubMed2002

Biotransformation of arsenate to the tetramethylarsonium ion in the marine polychaetes Nereis diversicolor and Nereis virens.

Arsenic compounds in aqueous extracts of the marine polychaetes Nereis diversicolor and Nereis virens were determined by HPLC-ICP-MS. Both polychaetes contained most of their water-soluble arsenic as arsenobetaine (approximately 60%), and the tetramethylarsonium ion was also a significant arsenic constituent (approximately 20% in N. diversicolor and approximately 30% in N. virens). Trimethylarsoniopropionate and arsenosugars were present in the Nereis species as minor constituents, and traces of arsenocholine, trimethylarsine oxide, and arsenate were also detected. When N. diversicolor and N. virens were exposed in laboratory experiments to different concentrations of arsenate in seawater (10, 50, 100, 500, and 1000 microg of As L(-1)), both species accumulated arsenic in a dose-dependent manner. Atthe highest exposure level, they achieved mean arsenic concentrations (dry mass) of approximately 70 mg of As kg(-1) (N. virens) and 90 mg of As kg(-1) (N. diversicolor), which represented about a 5-fold increase when compared with the control animals. The arsenic taken up by the polychaetes was readily methylated, and the major metabolite was the tetramethylarsonium ion (up to approximately 85% of the accumulated arsenic). Two other products of arsenic methylation, methylarsonate and trimethylarsine oxide, were also produced to a small extent; however, dimethylarsinate, another likely intermediate in the formation of the tetramethylarsonium ion, could not be detected in these experiments. The remaining accumulated arsenic was present as unchanged arsenate. This is the first report of significant biomethylation of arsenic to the tetramethyl stage and provides a ready explanation for the widespread occurrence of tetramethylarsonium ion in marine animals.

Animals↗

PubMed1999

Arsenic trioxide induces apoptosis of oesophageal carcinoma in vitro.

The arsenic compounds in traditional Chinese medicine have been recorded to have therapeutic effects on the treatment of psoriasis, syphilis, rheumatosis and a number of malignant tumours. Recent studies showed that arsenic trioxide can induce clinical remission in patients with acute promyelocytic leukemia, including those who have relapsed after retinoic acid treatment. however, the mechanism of how arsenic trioxide targets tumour cells is not clearly understood. We have examined the effects of arsenic trioxide on oesophageal carcinoma cell line EC8712. Our results demonstrated that the growth and survival of tumour cells were markedly inhibited by arsenic trioxide. The half dose effect (ED50) was at the concentration of 1 microM. Electron microscopic study demonstrated that EC8712 tumour cells treated with arsenic trioxide display a typical morphological appearance of apoptosis, including chromatin condensation and fragmentation of the nuclei. In contrast, no apoptotic features were observed in tumour cells without arsenic trioxide treatment. TUNEL assay also showed the biological features of apoptosis in cells treated with arsenic trioxide. Flow cytometry analyses showed that apoptotic peak was identified in arsenic trioxide treated cells but not in the control. Apoptotic cells in arsenic trioxide treated group account for 35% of total cell populations after three days treatment at a dose of 3 microM. In short, our results suggested that the anticancer effect of arsenic trioxide is due, at least in part, to the induction of apoptosis in cancer cells.

Antineoplastic Agents↗

PubMed2003

Speciation of arsenic in water, sediment, and plants of the Moira watershed, Canada, using HPLC coupled to high resolution ICP-MS.

High-performance liquid chromatography (HPLC) coupled with high-resolution sector field ICP-MS was applied to the speciation of arsenic in environmental samples collected from the Moira watershed, Ontario, Canada. Arsenic contamination in Moira River and Moira Lake from historic gold mine operations is of increasing environmental concern to the local community. In this study, the current arsenic contamination status in water, sediment, and plants was investigated. Elevated levels of arsenic in the surface water of up to 75 ng mL(-1) in Moira River and 50 ng mL(-1) in Moira Lake were detected, 98% of which was present as arsenate. High concentrations of arsenic (>300 ng mL(-1)), mainly present as arsenite, were detected in sediment porewaters. A sediment profile of As from the West basin of Moira Lake showed lower As concentrations compared with data from the 1990s. An optimized extraction procedure using a phosphoric acid-ascorbic acid mixture demonstrated that an unknown "As-complex" which may consist of As, sulfide and organic matter is potentially responsible for the release of arsenite from the sediment to the overlying water column. Arsenic concentrations in plant samples ranged from 2.6 to 117 mg kg(-1), dry weight. Accumulation of arsenic was observed in submerged plants collected from Moira River and Moira Lake. Only a small part of the arsenic (6.3-16.1%) in the plants was extractable with methanol-water (9:1), and most of this arsenic (70-93%) was inorganic arsenic. A variety of organic arsenic compounds, including simple methylated compounds (methylarsonic acid and dimethylarsinic acid), trimethylarsine oxide, and tetramethylarsonium cation were detected at trace levels. No arsenobetaine and arsenocholine was found in any plant sample. An unknown compound, most probably an arsenosugar was detected in the two submerged plants, coontail ( Ceratophyllum demersum) and long-stemmed waterwort ( Elatine triandra). These submerged plants are constantly exposed to high arsenic concentrations in the surrounding water. Apparently, they are able to grow in this environment without invoking the same biochemical defence known from marine algae to detoxify inorganic arsenic. The detoxification mechanism of these plants remains unknown.

Journal Article↗

PubMed2003

Oxidation and detoxification of trivalent arsenic species.

Arsenic compounds with a +3 oxidation state are more toxic than analogous compounds with a +5 oxidation state, for example, arsenite versus arsenate, monomethylarsonous acid (MMA(III)) versus monomethylarsonic acid (MMA(V)), and dimethylarsinous acid (DMA(III)) versus dimethylarsinic acid (DMA(V)). It is no longer believed that the methylation of arsenite is the beginning of a methylation-mediated detoxication pathway. The oxidation of these +3 compounds to their less toxic +5 analogs by hydrogen peroxide needs investigation and consideration as a potential mechanism for detoxification. Xanthine oxidase uses oxygen to oxidize hypoxanthine to xanthine to uric acid. Hydrogen peroxide and reactive oxygen are also products. The oxidation of +3 arsenicals by the hydrogen peroxide produced in the xanthine oxidase reaction was blocked by catalase or allopurinol but not by scavengers of the hydroxy radical, e.g., mannitol or potassium iodide. Melatonin, the singlet oxygen radical scavenger, did not inhibit the oxidation. The production of H2O2 by xanthine oxidase may be an important route for decreasing the toxicity of trivalent arsenic species by oxidizing them to their less toxic pentavalent analogs. In addition, there are many other reactions that produce hydrogen peroxide in the cell. Although chemists have used hydrogen peroxide for the oxidation of arsenite to arsenate to purify water, we are not aware of any published account of its potential importance in the detoxification of trivalent arsenicals in biological systems. At present, this oxidation of the +3 oxidation state arsenicals is based on evidence from in vitro experiments. In vivo experiments are needed to substantiate the role and importance of H2O2 in arsenic detoxication in mammals.

Allopurinol↗

PubMedDate not supplied

Arsine evolution-electrothermal atomic absorption method for the determination of nanogram levels of total arsenic in urine and water.

An arsine evolution-electrothermal atomic absorption method is described for the determination of ng/mL concentrations of total arsenic in urine and water. Organic-arsenic compounds are decomposed with nitric, sulfuric, and perchloric acids. Sodium borohydride, a redesigned hydride generator, and an electric-heated absorption tube are used for arsine evolution and its conversion to atomic arsenic. The method has a detection limit of 6 ng/mL, a sensitivity of 1 ng/mL, and is linear from 0 to 110 ng/mL of arsenic. Accuracy was established with two different National Bureau of Standards Standard Reference materials, and mean errors from 0 to -2 were obtained.

Arsenic↗

PubMed2003

Arsenic speciation in the earthworms Lumbricus rubellus and Dendrodrilus rubidus.

Two species of earthworm, Lumbricus rubellus Hoffmeister and Dendrodrilus rubidus (Savigny) collected from an arsenic-contaminated mine spoil site and an uncontaminated site were investigated for total tissue arsenic concentrations and for arsenic compounds by liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). For L. rubellus, whole-body total tissue arsenic concentrations were 7.0 to 17.0 mg arsenic/ kg dry weight in uncontaminated soil and 162 to 566 mg arsenic/kg dry weight in contaminated soil. For D. rubidus, whole-body tissue concentrations were 2.0 to 5.0 mg arsenic/kg dry weight and 97 to 321 mg arsenic/kg dry weight, respectively. Arsenobetaine was the only organic arsenic species detected in both species of earthworms, with the remainder of the extractable arsenic being arsenate and arsenite. There was an increase in the proportion of arsenic present as arsenobetaine in the total arsenic burden. Lumbricus rubellus and D. rubidus have similar life styles, both being surface living and litter feeding. Arsenic speciation was found to be similar in both species for both uncontaminated and contaminated sites, with dose-dependent formation of arsenobetaine. When L. rubellus and D. rabidus from contaminated sites were incubated in arsenic-free soils, the total tissue burden of arsenic diminished. Initially, L. rubellus from the tolerant populations (from the contaminated site) eliminated arsenic in the first 7 d of exposure before accumulating arsenic in tissues, whereas nontolerant populations (from the uncontaminated site) accumulated arsenic linearly. The tolerant and nontolerant L. rubellus eliminated tissue arsenic linearly over 21 d when incubated in uncontaminated soil.

Animals↗

PubMed2001

Cytotoxic and genotoxic effects of As, MMA, and DMA on leukocytes and stimulated human lymphocytes.

Inorganic arsenic is a human carcinogen associated with different types of cancer. Arsenic metabolism produces two methylated species: monomethylarsonic and dimethylarsinic acids. Although this metabolic route has been involved in arsenic detoxification, it is still not clear whether these methylated metabolites participate in the carcinogenic process. In this work, we studied the cytotoxic and genotoxic effects of arsenic and its metabolites. Cytotoxicity was evaluated in cultured lymphocytes from three donors. Mitotic and replication indices were the parameters analyzed. The results indicate a clear cytotoxic effect by sodium arsenite but not by its metabolites. Genotoxicity was assessed by the single cell gel electrophoresis assay. Sodium arsenite increased DNA migration in stimulated lymphocytes only at doses greater than 5 x 10(-6) M; meanwhile in leukocytes a weak response was observed. Monomethylarsonic acid produced in leukocytes a weak induction of DNA damage, while in stimulated lymphocytes, a dose-increase in DNA migration was observed. The injury caused by dimethylarsinic acid was more evident than that observed in cultures treated with sodium arsenite and monomethylarsonic acid in stimulated lymphocytes, although in leukocytes no effect on DNA migration was found. In conclusion, only sodium arsenite had the capacity to alter mitotic and replication indices, while sodium arsenite and its metabolites were capable of inducing single strand DNA breaks on stimulated human lymphocytes treated in vitro for 24 h; however, the differences observed were between individual responses, one donor being more susceptible even at the lower doses. This individual susceptibility to arsenic compounds has been repeatedly observed for different end-points and should be studied further.

Arsenic↗

PubMedDate not supplied

Mechanisms of arsenic-induced cell transformation.

Arsenic is a well-established carcinogen in humans, but there is little evidence for its carcinogenicity in animals and it is inactive as an initiator or tumor promoter in two-stage models of carcinogenicity in mice. Studies with cells in culture have provided some possible mechanisms by which arsenic and arsenical compounds may exert a carcinogenic activity. Sodium arsenite and sodium arsenate were observed to induce morphological transformation of Syrian hamster embryo cells in a dose-dependent manner. The trivalent sodium arsenite was greater than tenfold more potent than the pentavalent sodium arsenate. The compounds also exhibited toxicity; however, transformation was observed at nontoxic as well as toxic doses. At low doses, enhanced colony forming efficiency of the cells was observed. To understand the mechanism of arsenic-induced transformation, the genetic effects of the two arsenicals were examined over the same doses that induced transformation. No arsenic-induced gene mutations were detected at two genetic loci. However, cell transformation and cytogenetic effects, including endoreduplication, chromosome aberrations, and sister chromatid exchanges, were induced by the arsenicals with similar dose responses. These results support a possible role for chromosomal changes in arsenic-induced transformation. The two arsenic salts also induced another form of mutation-gene amplification. Both sodium arsenite and sodium arsenate induced a high frequency of methotrexate-resistant 3T6 cells, which were shown to have amplified copies of the dihydrofolate reductase gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗