[Assays of phosphorus compounds in the presence of arsenic compounds in medicinal preparations].
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Arsenic↗
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The retention behavior of arsenic compounds on PRP-X100 column under alkaline condition.
A systematical investigation of the retention behaviour of arsenic compounds (arsenite, arsenate, methylarsonic acid, dimethylarsinic acid, arsenobetaine etc.) on PRP-X100 column under alkaline condition was carried out. The dependence of the retention times of arsenic compounds on pH with two mobile phases: 20 mmol/L ammonium bicarbonate, 2.5 mmol/L p-hydroxybenzoic acid/1.0 mmol/L benzoic acid was studied, and the optimal separations of these five arsenic compounds were achieved.
Arsenicals↗
Unexpected arsenic compounds in low-rank coals.
Nine low-rank coal samples from three different coal basins (Velenje and Trbovlje basins, Slovenia, and Sokolov basin, Czech Republic) were analyzed for their elemental composition and the presence of arsenic compounds. Total arsenic concentrations in the samples were 1.59-5.77 microg g(-1) with one exception, 142 microg g(-1) for a sample from the Sokolov basin. A methanol/water mixture (1:1) extracted 15.1 - 38.7% of the total arsenic from Velenje basin samples but only 2.2-7.1% from Sokolov and Trbovlje basin samples. Extracts from the Velenje basin samples contained mainly the tetramethylarsonium ion (0.14 - 0.92 microg g(-1)) with considerable amounts of arsenate (0.15 - 0.85 microg g(-1)) and monomethyl arsonic acid 0.04 - 0.27 microg g(-1)). In methanol/water extracts from samples from the Sokolov and Trbovlje basins inorganic arsenic (arsenate) prevailed (0.26 - 37.1 microg g(-1)), but at least trace amounts of organic arsenic compounds were found as well. It is likely that biogeochemical degradation of organic material is related to the unexpected organoarsenic compounds found in low-rank coals. However, it should also not be ruled out that abiogenic synthesis could have taken place in the carbon-rich environment under the harsh conditions present (elevated temperature and pressure).
Arsenic↗
Capillary electrophoresis of arsenic compounds with indirect fluorescence detection.
A capillary electrophoresis (CE)-indirect fluorescence detection method for arsenic compounds is described. The five arsenic species, viz., arsenite (As(III)), arsenate (As(V)), monomethylarsonate (MMA), dimethylarsinate (DMA) and phenylarsonate (PhA), were efficiently separated by CE in 8 min with an 1.5 mM fluorescein solution at pH 9.8. Fluorescein also functioned as a background fluorophore for the indirect detection of these nonfluorescent arsenic species. Linearity (r> or =0.996) of more than two orders of magnitude was generally obtained. The relative standard deviation (RSD) values were in the ranges 0.4-0.7% and 2.2-8.2% for migration times and peak areas, respectively. The concentration limits of detection (CLODs) for the arsenic compounds studied were between 0.04 and 0.16 microg/mL (as arsenic). The detection sensitivity was generally dependent upon the transfer ratio (TR, defined as the number of moles of fluorescein ions displaced by one mole of analyte ions) of each arsenic species. The applicability of the method for the analysis of ground water was examined.
Arsenicals↗
Tumorigenicity of inorganic arsenic compounds following intratracheal instillations to the lungs of hamsters.
The tumorigenicity of arsenic trioxide (As2O3), calcium arsenate (Ca3(AsO4)2) and arsenic trisulfide (As2S3) was studied in male Syrian golden hamsters which received arsenic compounds containing a total dose of 3.75 mg arsenic by means of intratracheal instillations once a week for 15 weeks. As controls, some hamsters were treated with only the vehicle, phosphate buffer solution. During the animals' total life span, one lung adenocarcinoma was seen in the 17 hamsters in the As2O3 group, one lung adenocarcinoma and 6 lung adenomas in the 25 hamsters in the Ca3(AsO4)2 group, one lung adenoma in the 22 hamsters in the As2S3 group and one lung adenosquamous carcinoma in the 21 hamsters in the control group. From these results, we conclude that calcium arsenate is tumorigenic to the lungs of Syrian golden hamsters. The results concerning the other 2 arsenic compounds were not conclusive.
Animals↗
Arsenic compounds as anticancer agents.
In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.
Antineoplastic Agents↗
Induction of chromosomal aberrations in cultured human fibroblasts by inorganic and organic arsenic compounds and the different roles of glutathione in such induction.
Clastogenic effects of a variety of arsenic compounds were examined on cultured human fibroblasts. The following compounds were tested: inorganic arsenicals (arsenite and arsenate), the major metabolites of inorganic arsenicals in human and experimental animals [methylarsonic acid (MAA), dimethylarsinic acid (DMAA) and trimethylarsine oxide (TMAO)], and water-soluble organoarsenic derivatives [2', 3'-dihydroxypropyl-5-deoxy-5-dimethylarsinoyl-beta-D-riboside (arsenosugar), arsenocholine, arsenobetaine and tetramethylarsonium iodide] found in marine organisms. Arsenic compounds induced mainly chromatid gaps and chromatid breaks. The rank order of compounds in terms of clastogenic potency was arsenite > arsenate > DMAA > MAA > TMAO. DMAA was very potent and caused chromosome pulverizations in most metaphases when present at doses higher than 7 x 10(-3) M. Arsenosugar, arsenocholine, arsenobetaine and tetramethylarsonium iodide were less effective. Depletion of cellular glutathione (GSH) with L-buthionine-SR-sulfoximine (BSO), increased the incidence of chromosomal aberrations induced by arsenite, arsenate and MAA, and markedly suppressed the clastogenic effects of DMAA. DMAA was highly clastogenic even in GSH-depleted cells when the cells were incubated with DMAA in the presence of GSH (5 and 10 mM). These results suggest that GSH might play a role in protecting cells against the clastogenic effects of arsenite, arsenate and MAA. GSH might be involved in the expression of clastogenic actions of DMAA.
Arsenicals↗
Contact sensitivity to arsenical compounds. Clinical and experimental studies.
Two arsenic compounds (sodium arsenate and sodium arsenite) were included in our standard patch test series and 2 of 379 tested dermatitis patients reacted. They had not experienced any exposure to arsenicals and showed concomitant reactions to nickel and cobalt. In the guinea pig maximization test (GPMT) the compounds were found to be Grade-I-allergens. There are some convincing case reports in the literature on contact sensitivity to arsenicals and the discrepancy between these reports and the results from the GPMT should be further evaluated by clinical studies on workers with arsenical dermatitis.
Animals↗
Genotoxicity of two arsenic compounds in germ cells and somatic cells of Drosophila melanogaster.
Two arsenic compounds, sodium arsenite (NaAsO2) and sodium arsenate (Na2HAsO4), were tested for their possible genotoxicity in germinal and somatic cells of Drosophila melanogaster. For germinal cells, the sex-linked recessive lethal test (SLRLT) and the sex chromosome loss test (SCLT) were used. In both tests, a brood scheme of 2-3-3 days was employed. Two routes of administration were used for the SLRLT: adult male injection (0.38, 0.77 mM for sodium arsenite; and 0.54, 1.08 mM for sodium arsenate) and larval feeding (0.008, 0.01, 0.02 mM for sodium arsenite; and 0.01, 0.02 mM for sodium arsenate). For the SCLT the compounds were injected into males. Controls were treated with a solution of 5% sucrose which was employed as solvent. The somatic mutation and recombination test (SMART) was run in the w+/w eye assay as well as in the mwh +/+ flr3 wing test, employing the standard and insecticide-resistant strains. In both tests, third instar larvae were treated for 6 hr with sodium arsenite (0.38, 0.77, 1.15 mM), and sodium arsenate (0.54, 1.34, 2.69 mM). In the SLRLT, both compounds were positive, but they were negative in the SCLT. The genotoxicity of both compounds was localized mainly in somatic cells, in agreement with reports on the carcinogenic potential of arsenical compounds. Sodium arsenite was an order of magnitude more toxic and mutagenic than sodium arsenate. This study confirms the reliability of the Drosophila in vivo system to test the genotoxicity of environmental compounds.
Animals↗
Comparison of mild extraction procedures for determination of plant-available arsenic compounds in soil.
In this work three mild extraction agents for determination of plant-available fractions of elements in soil were evaluated for arsenic speciation in soil samples. Pepper (Capsicum annum, L.) var. California Wonder was cultivated in pots, and aqueous solutions of arsenite, arsenate, methylarsonic acid, and dimethylarsinic acid, at a concentration of 15 mg As kg(-1) soil, were added at the beginning of the experiment. Control pots (untreated) were also included. Deionized water, 0.01 mol L(-1) CaCl2, and 0.05 mol L(-1) (NH4)2SO4 were used to extract the plant-available fraction of the arsenic compounds in soil samples collected during the vegetation period of the plants. Whereas in control samples the extractable arsenic fraction did not exceed 1% of total arsenic content, soil amendment by arsenic compounds resulted in extraction of larger amounts, which varied between 1.4 and 8.1% of total arsenic content, depending on soil treatment and on the extracting agent applied. Among arsenic compounds determined by HPLC-ICPMS arsenate was predominant, followed by small amounts of arsenite, methylarsonic acid, and dimethylarsinic acid, depending on the individual soil treatment. In all the experiments in which methylarsonic acid was added to the soil methylarsonous acid was detected in the extracts, suggesting that the soil bacteria are capable of reducing methylarsonic acid before a further methylation occurs. No significant differences were observed between analytical data obtained by using different extraction procedures.
Arsenic↗
Enzymatic methylation of arsenic compounds. VII. Monomethylarsonous acid (MMAIII) is the substrate for MMA methyltransferase of rabbit liver and human hepatocytes.
Inorganic arsenite is methylated by some, but not all, animal species to dimethylarsinic acid (DMA). The monomethyl compound containing arsenic in an oxidation state of +3 has been proposed as an intermediate. Using highly purified arsenic methyltransferase from rabbit liver and the partially purified enzyme from Chang human liver hepatocytes, the activity of methylarsonic acid (MMAV) and methylarsonous acid (MMAIII) as a substrate has been characterized by Michaelis-Menten kinetics. The rabbit liver enzyme has a greater affinity for MMAIII (Km = 0.92 x 10(-5) M) than MMAV (Km = 7.0 x 10(-5) M) since the smaller the Km the greater the affinity. In addition, a dithiol, reduced lipoic acid or dithiothreitol, appears to be more active than GSH in satisfying the thiol requirement of the enzyme. Although investigators have been unable to detect the arsenic methyltransferase in surgically removed human liver, its presence in Chang human hepatocytes now has been established. The Km for MMAIII, 3.04 x 10(-6), using MMAIII methyltransferase from Chang human hepatocytes was not greatly different from that of the rabbit liver enzyme.
Animals↗
Pattern of excretion of arsenic compounds [arsenite, arsenate, MMA(V), DMA(V)] in urine of children compared to adults from an arsenic exposed area in Bangladesh.
Urinary arsenic is generally considered as the most reliable indicator of recent exposure to inorganic arsenic and is used as the main bio-marker of exposure. However, due to the different toxicity of arsenic compounds, speciation of arsenic in urine is generally considered to be more convenient for health risk assessment than measuring total arsenic concentration. Additionally, it can give valuable information about the metabolism of arsenic species within the body. In our study, for exposed group--42 urine samples were collected from Datterhat (South) village of Madaripur district, Bangladesh and an average arsenic concentration in their drinking water was 376 microg/L (range 118 to 620 microg/L). For control group, 27 urine samples were collected from a non-affected district, Badhadamil village of Medinipur district, West Bengal, India, where arsenic concentration in their drinking water is below 3 microg/L. The arsenic species in the urine were separated and quantified by using HPLC-ICP-MS. The sum of inorganic arsenic and its metabolites was also determined by FI-HG-AAS. Results indicate that average total urinary arsenic metabolites in children's urine is higher than adults and total arsenic excretion per kg body weight is also higher for children than adults. For arsenic species between adults and children, it has been observed that inorganic arsenic (In-As) in average is 2.36% and MMA is 6.55% lower for children than adults while DMA is 8.91% (average) higher in children than adults. The efficiency of the methylation process is also assessed by the ratio between urinary concentration of putative product and putative substrate of the arsenic metabolic pathway. Higher values mean higher methylation capacity. Results show the values of the MMA/In-As ratio for adults and children are 0.93 and 0.74 respectively. These results indicate that first reaction of the metabolic pathway is more active in adults than children. But a significant increase in the values of the DMA/MMA ratio in children than adults of exposed group (8.15 vs. 4.11 respectively) indicates 2nd methylation step is more active in children than adults. It has also been shown that the distribution of the values of DMA/MMA ratio to exposed group decrease with increasing age (2nd methylation process). Thus from these results we may infer that children retain less arsenic in their body than adults. This may also explain why children do not show skin lesions compared to adults when both are drinking same contaminated water.
Adult↗
Quantification of seven arsenic compounds in seafood products by liquid chromatography/electrospray ionization-single quadrupole mass spectrometry (LC/ESI-MS).
A liquid chromatography/electrospray ionization-single quadrupole mass spectrometry (LC/ESI-MS) method was developed to quantify seven arsenic compounds: arsenate (As(V)), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), arsenobetaine (AB), trimethylarsine oxide (TMAO), arsenocholine (AC) and tetramethylarsonium ion (TEMA), widely found in seafood. The arsenicals separated by anion- or cation-exchange LC were all readily identified under the optimized ESI-MS conditions. Linear calibration curves constructed by plotting the peak area counts of molecular ions against the arsenic concentrations were obtained for all seven arsenic compounds. The limits of quantification (S/N = 10) were 800, 600, 50, 10, 5, 5 and 5 ng ml-1 for As(V), MMA, DMA, AB, TMAO, AC and TEMA, respectively. The LC/ESI-MS method was found to be useful to quantify arsenic compounds in seafood by model experiments using the mid-gut gland and muscle of a shellfish (Buccinid whelks). Spiking experiments verified the accuracy of the method.
Animals↗
Resistance to arsenic compounds in microorganisms.
Arsenic ions, frequently present as environmental pollutants, are very toxic for most microorganisms. Some microbial strains possess genetic determinants that confer resistance. In bacteria, these determinants are often found on plasmids, which has facilitated their study at the molecular level. Bacterial plasmids conferring arsenic resistance encode specific efflux pumps able to extrude arsenic from the cell cytoplasm thus lowering the intracellular concentration of the toxic ions. In Gram-negative bacteria, the efflux pump consists of a two-component ATPase complex. ArsA is the ATPase subunit and is associated with an integral membrane subunit, ArsB. Arsenate is enzymatically reduced to arsenite (the substrate of ArsB and the activator of ArsA) by the small cytoplasmic ArsC polypeptide. In Gram-positive bacteria, comparable arsB and arsC genes (and proteins) are found, but arsA is missing. In addition to the wide spread plasmid arsenic resistance determinant, a few bacteria confer resistance to arsenite with a separate determinant for enzymatic oxidation of more-toxic arsenite to less-toxic arsenate. In contrast to the detailed information on the mechanisms of arsenic resistance in bacteria, little work has been reported on this subject in algae and fungi.
Arsenic↗
Inorganic arsenic compounds and methylated metabolites induce morphological transformation in two-stage BALB/c 3T3 cell assay and inhibit metabolic cooperation in V79 cell assay.
We have performed two-stage transformation assay using BALB/c 3T3 cells to determine initiating and promoting activities of disodium arsenate, sodium arsenite, monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA). Treatment with these arsenic compounds at the initiating stage induced significant numbers of transformed foci when cells were post-treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Disodium arsenate was active at the concentrations of 15-30 microM, sodium arsenite 5-20 microM, and DMAA 1-2 mM. MMAA required 10 mM to induce cell transformation. The concentrations of these compounds (except DMAA) that induced transformation were highly growth-inhibitory (more than 50%). DMAA induced transformation foci at growth inhibition levels of 66 to 84%. In experiments on promoting activity, cells pretreated with a sub-threshold dose of 20-methylcholanthrene (MCA, 0.2 microg/ml) or sodium arsenite (10 microM) were used. Transformation was enhanced by post-treatment with disodium arsenate (1-10 microM), sodium arsenite (0.5-2 microM), and MMAA (200-1000 microM), but not with DMAA. Studies of gap junctional intercellular communication using the V79 cell metabolic cooperation assay showed that the arsenic compounds (except DMAA) exhibited inhibitory activity. Thus, most arsenicals were shown to have not only initiating activity, but also promoting activity. In addition, inorganic arsenicals, especially trivalent sodium arsenite, were more active than organic ones and exhibited promoting activity at one-order of magnitude lower than initiating activity. These results suggest that from the viewpoint of human hazard, more attention should be paid to the tumor promoting activity of inorganic arsenic compounds.
Animals↗
Inorganic and methylated arsenic compounds induce cell death in murine macrophages via different mechanisms.
We demonstrate in this study the cytotoxic effects of inorganic arsenicals, arsenite and arsenate, and organic arsenic compounds, monomethylarsonic acid (MAA), dimethylarsinic acid (DMAA), and trimethylarsine oxide (TMAO), which are metabolites of inorganic arsenicals in human bodies, using murine macrophages in vitro. Inorganic arsenicals, both arsenite and arsenate, are strongly toxic to macrophages, and the concentration that decreased the number of surviving cells to 50% of that in untreated controls (IC50) was 5 or 500 microM, respectively. These inorganic arsenicals mainly caused necrotic cell death with partially apoptotic cell death; about 80% of dead cells were necrotic, and 20% were apoptotic. The inorganic arsenicals also induced marked release of an inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), at cytotoxic doses. This strong cytotoxicity of an inorganic arsenical, arsenite, might be mediated via active oxygen and protease activation because it was inhibited by the addition of some antioxidant reagents, such as superoxide dismutase (SOD), catalase, and GSH, or by a peptide inhibitor of interleukin-1 beta-converting enzyme (ICE). It is likely that these immunotoxic effects of inorganic arsenicals may evoke both immunosuppression and inflammation, and they may be central factors causing carcinogenesis and severe inflammatory responses, such as hepatomegaly and splenomegaly, in chronic arsenicosis patients who daily ingested arsenic-contaminated well water. In contrast, the cytotoxic effects of methylated arsenic compounds were lower than those of inorganic arsenicals. The IC50 value of DMAA was about 5 mM, and MAA and TMAO had no toxicity even at concentrations over 10 mM. Additionally, these methylated chemicals suppressed the TNFalpha release from macrophages. DMAA induced mainly apoptotic cell death in macrophages as indicated by cellular morphological changes, condensed nuclei, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and DNA fragmentation. However, the cytotoxicity of DMAA might be induced via a different mechanism from that of inorganic arsenicals because it was not abolished by the additions of SOD, catalase, or ICE inhibitor. Conversely, GSH enhanced the toxicity of DMAA. These data suggest that methylation of inorganic arsenicals in mammals plays an important role in suppression of both severe immunosuppression and inflammatory responses caused by inorganic arsenicals.
Animals↗
Occurrence of arsenic in plaice (Pleuronectes platessa), nature of organo-arsenic compound present and its excretion by man.
The arsenic content in 255 samples of plaice (Pleuronectes platessa) varied between 3 and 166 mg/kg. About 65% of the samples had an arsenic content above 10 mg/kg. High (low) arsenic concentration in the fillet corresponds with a high (low) concentration in milt or roe. An excretion experiment with eight human volunteers showed that after the consumption of plaice, 69-85% of the ingested arsenic was excreted in the urine within five days. The organo-arsenic compound present in plaice was isolated by means of extraction, ion-exchange and thin-layer chromatography. Field desorption mass spectrometry of the isolate showed that arsenic was present as arsenobetaine, (CH3)3AsCH2C00-.
Animals↗
Effects of cysteine on the cytotoxicity of arsenic compounds.
Effects of cysteine on the cytotoxicity of arsenic compounds, such as arsenite, arsenate, methylarsonic acid (MMA), and dimethylarsinic acid (DMA), were investigated in cultured human HL-60 cells. Using adenosine triphosphate bioluminescence assay, the rank order of the mixtures of arsenicals with cysteine was: DMA > arsenite > arsenate > MMA. The IC50 of DMA with equimolar cysteine was approximately 7.7 microM, nearly two orders of magnitude lower than that of DMA alone. Apoptotic cells were examined by the TUNEL method, and cysteine was found to enhance the induction of apoptosis by arsenicals. Using LC-ICP-MS, trivalent arsenic was detected in the mixtures of arsenate, DMA, and MMA with cysteine. These results suggested that the trivalent arsenic in the mixtures of arsenicals with cysteine might account for the enhanced cytotoxicity as well as apoptosis, and that cysteine is involved in induction of the adverse effects of arsenicals in humans.
Adenosine Triphosphate↗