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Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India.

A speciation technique for arsenic has been developed using an anion-exchange high-performance liquid chromatography/inductively coupled argon plasma mass spectrometer (HPLC/ICP MS). Under optimized conditions, eight arsenic species [arsenocholine, arsenobetaine, dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), arsenite (As(III)), and arsenate (As(V))] can be separated with isocratic elution within 10 min. The detection limit of arsenic compounds was 0.14-0.33 microg/L. To validate the method, Standard Reference Material in freeze-dried urine, SRM-2670, containing both normal and elevated levels of arsenic was analyzed. The method was applied to determine arsenic species in urine samples from three arsenic-affected districts of West Bengal, India. Both DMA(III) and MMA(III) were detected directly (i.e., without any prechemical treatment) for the first time in the urine of some humans exposed to inorganic arsenic through their drinking water. Of 428 subjects, MMA(III) was found in 48% and DMA(III) in 72%. Our results indicate the following. (1) Since MMA(III) and DMA(III) are more toxic than inorganic arsenic, it is essential to re-evaluate the hypothesis that methylation is the detoxification pathway for inorganic arsenic. (2) Since MMA(V) reductase with glutathione (GSH) is responsible for conversion of MMA(V) to MMA(III) in vivo, is DMA(V) reductase with GSH responsible for conversion of DMA(V) to DMA(III) in vivo? (3) Since DMA(III) forms iron-dependent reactive oxygen species (ROS) which causes DNA damage in vivo, DMA(III) may be responsible for arsenic carcinogenesis in human.

Arsenic↗

[A new series of antiparasitic organic arsenicals: the spiroarsoranes. Experimental trypanocidal activity].

Arsenical compounds are the main therapeutic way, effective in the neurological phase of trypanosomiasis. Unfortunately, their important toxicity prevents their easy administration. Structural cyclization of arsonic acid derivatives has led to a class of non-toxic compounds: spiroarsoranes. A 47 compound primary screening on an in vivo murine model of Trypanosoma brucei brucei resulted in the isolation of a very effective derivative after a single subcutaneous injection of 30 mg.kg-1 body weight (Chemotherapeutic Index = 21). In this study, trypanocidal activity of this compound was evaluated on an in vivo sheep model of trypanosomiasis by T. brucei brucei, according to experimental model of the Institute of Neurological Epidemiology and Tropical Neurology of Limoges (France). A single subcutaneous injection of 30 and 100 mg.kg-1 b.w., and 30 and 60 mg.kg-1 b.w. was given respectively during first and second phase of trypanosomiasis. Ovine pharmacokinetics of this compound will be evaluated in a further study.

Animals↗

The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds.

Excess intake of arsenic is known to cause vascular diseases as well as skin lesions and cancer in humans. Recent reports suggest that trivalent methylated arsenicals, which are intermediate metabolites in the methylation process of inorganic arsenic, are responsible for the toxicity and carcinogenicity of environmental arsenic. We investigated acute toxicity and accumulation of monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), trimethylarsine oxide (TMAO), and monomethylarsonous acid diglutathione (MMA(III) (GS)(2)) in rat heart microvessel endothelial (RHMVE) cells. MMA(V) (LC(50) = 36.6 mM) and DMA(V) (LC(50) = 2.54 mM) were less toxic than inorganic arsenicals (cf. LC(50) values for inorganic arsenite (iAs(III)), and inorganic arsenate (iAs(V)) was reported to be 36 and 220 microM, respectively, in RHMVE cells. TMAO was essentially not toxic. However, MMA(III) (GS)(2) was highly toxic (LC(50) = 4.1 microM). The order of cellular arsenic accumulation of those four organic arsenic compounds was MMA(III) (GS)(2) >> MMA(V) > DMA(V) > TMAO. MMA(III) (GS)(2) was efficiently taken up by the cells and cellular arsenic content increased with the concentration of MMA(III) (GS)(2) in culture medium. N-acetyl-l-cysteine (NAC) reduced cellular arsenic content in DMA(V)-exposed cells and also decreased the cytotoxicity of DMA(V), whereas it changed neither cellular arsenic content nor the viability in MMA(V)-exposed cells. mRNA levels of heme oxygenase-1 (HO-1) were decreased by NAC in DMA(V)-exposed, but MMA(V)-exposed cells. Buthionine sulfoximine (BSO), a cellular glutathione (GSH) depleting agent, enhanced the cytotoxicity of MMA(V). However, BSO reduced, rather than enhanced, the cytotoxicity of DMA(V). These results suggest that intracellular GSH modulated the toxic effects of arsenic in opposite ways for MMA(V) and DMA(V). Even though intracellular GSH decreased the cytotoxicity of MMA(V), extracellularly added GSH enhanced the cytotoxicity of MMA(V). The use of high-performance liquid chromatography (HPLC)-inductively coupled plasma mass spectrometric analyses suggested that a small amount of MMA(V) was converted to MMA(III) (GS)(2) in the presence of GSH. These results suggest that MMA(III) (GS)(2) is highly toxic compared to other arsenic compounds because of faster accumulation of this species by cells, in addition to having the toxic nature of methylated trivalent organic arsenics.

Animals↗

Influence of inorganic and organic arsenicals on intestinal transfer of nutrients.

The effects of organic (oxophenylarsine, PhAsO 2.5-50 mumol/l) and inorganic arsenicals (As2O3 2.5-250 mumol/l; As2O5 2.5-2500 mumol/l) on intestinal transfer of water, sodium, glucose and leucine was investigated in vitro using isolated jejunal segments of male Sprague Dawley rats. All three arsenicals decreased in a dose-dependent manner the transfer of water, sodium, glucose and leucine. At the highest concentrations investigated the amount absorbed was reduced to some 10-20% of the respective control values. For both glucose and leucine the concentration ratio between absorbate and perfusate was about 3.5-4 in controls. It decreased to about 2 for leucine and to near unity for glucose. As assessed from the concentration ratio between intestinal tissue and perfusate the arsenic compounds inhibited the uptake of glucose and leucine into the tissue. There was a marked difference with respect to the potency of arsenicals, PhAsO being about 10 times more potent than As2O3 which in turn was about 5 times more potent than As2O5.

Animals↗

The effects of some drugs--pentamidine, stibocaptate, Hoechst 33258, F 151, compound 'E' and Nifurtimox--on Onchocerca volvulus in chimpanzees.

Several drugs were investigated for action against Onchocerca volvulus in chimpanzees. Pentamidine at 4 mg/kg daily for 16 days had no filaricidal action; nor did stibocaptate at 10 mg/kg monthly for 8 months. Hoechst 33258, a substituted bis-benzamidazole, showed micro- and macrofilaricidal activity; F151 (an arsenical compound) showed a purely macrofilaricidal action; and Compound E (a reaction product of Hoechst 33258 and F151) was micro- and macrofilaricidal. The toxicity of the three last-mentioned compounds was high, and further trials were not made. Nifurtimox, at doses of up to 40 mg/kg for 10 days, was shown not be microfilaricidal, but there was a suggestion that this drug may have some macrofilaricidal action.

Animals↗

Herpes zoster during treatment with arsenic trioxide.

In vitro data suggest that arsenic compounds can suppress cell-mediated immunity by inducing apoptosis of T helper lymphocytes. We describe an occurrence of herpes zoster during treatment with arsenic trioxide (ATO) in two patients who were already in remission from acute promyelocytic leukemia and received ATO as consolidation treatment. During this complication, their leukocyte counts and differentials were within normal limits. Our report suggested the immunosuppressive effect of ATO in vivo. Both patients responded well to an oral antiviral. Clinicians should be aware of this complication during treatment with ATO since early antiviral treatment may help avoid complications including post-herpetic neuralgia.

2-Aminopurine↗

Transactivation of RARE and GRE in the cellular response to arsenic.

Arsenic compounds are a somewhat unique class of metals, which have been considered as both carcinogens and chemotherapeutic agents for cancers. Tumor promotion effects of arsenic are believed to be associated with its transactivational activities on transcription factors, such as AP-1 and NFkappaB, while the induction of cell apoptosis and differentiation by arsenic is considered to be a mechanism for the chemotherapeutic effects of arsenic. Here, we found that exposure of cells to arsenite and arsenate leads to transactivation of retinoic acid response elements (RARE) and glucocorticoid response elements (GRE) in mouse epidermal JB6 cells. These inductions occur in a time-dependent manner. Furthermore, induction of RARE activity by arsenic was synergistically enhanced by co-treatment of cells with retinoic acid, while GRE activation by arsenic was not affected by combined treatment of cells with fluocinolone acetonide (FA). In consideration of the important role of RARE and GRE in induction of cell differentiation, we speculate that transactivation of RARE and GRE by arsenic may be involved in its induction of cell differentiation and anti-cancer activities in addition to its induction of apoptosis.

Animals↗

Determination and speciation of arsenic in human urine by ion-exchange chromatography/flow injection analysis with hydride generation/atomic absorption spectroscopy.

A flow injection-hydride generation/atomic absorption spectroscopic method for the measurement of total urinary arsenic and for the selective determination of inorganic arsenic, monomethylarsonic acid (MMAA), and dimethylarsinic acid (DMAA) was developed. Destruction of the organic matrix is necessary to measure total arsenic content of urine samples. Digestion of this matrix with HNO3-H2SO4-H2O2 is described. The separation of inorganic, monomethylated, and dimethylated arsenic compounds in urine was performed with ion-exchange chromatography on AG 50 W-X8 resin. Detection limits of 2 ppb for each arsenic form and of 3 ppb for total arsenic in urine analyzed after mineralization were found. Recoveries in triplicate urine samples spiked with 10 ppb inorganic arsenic, 20 ppb MMAA, and 40 ppb DMAA were 93, 91, and 85%, respectively. The precision (relative standard deviation) of the method obtained in 10 replicate analyses of urine samples spiked with arsenic metabolites varied from 3.2 to 4.6%. This method is applicable to urine samples in studies relating to arsenic exposure and its monitoring.

Arsenic↗

Distribution of elements binding to molecules with different molecular weights in aqueous extract of Antarctic krill by size-exclusion chromatography coupled with inductively coupled plasma mass spectrometry.

The distribution of silver, arsenic, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead, selenium and zinc binding to species with different molecular weight in aqueous extract of krill was studied by on-line size-exclusion chromatography (SEC)/inductively coupled plasma mass spectrometry (ICP-MS). The extract was fractionated in three fractions with different molecular weight (MW) ranges (>20,000 relative molecular mass (rel. mol. mass), 2000-20,000 rel. mol. mass and <2000 rel. mol. mass), which were further analyzed by SEC with columns having different optimum fractionation ranges in order to obtain more detailed information about the MW distribution of the elements. Various distribution profiles for the target elements among different MW ranges were observed. The results obtained indicated that manganese, zinc, silver, cadmium and lead species were mostly distributed in the higher MW range (>20,000 rel. mol. mass). In the case of chromium, iron, cobalt, arsenic and selenium, most of them bind to species with lower MW (<2000 rel. mol. mass). Only copper and nickel species was predominantly present in middle MW range (2000-20,000 rel. mol. mass). Further speciation of arsenic compounds in the small MW fraction was carried out with anion exchange chromatography (AEC) coupled with ICP-MS. The results showed that the dominant arsenic species in this fraction is As(III) (63% of extractable arsenic), while As(V) (13%) and two unknown arsenic species (19% and 5%, respectively) are present in lower amounts.

Animals↗

[Research advances on effect of arsenic trioxide on tumor].

Arsenic compounds are natural substances that have been used medically for more than 2,400 years in China. Since 1990s, Chinese physicians have began to use arsenic trioxide in treating the patients with acute promyelocytic leukemia (APL), and the results showed that arsenic trioxide was effective on APL patients. Further study of arsenic trioxide demonstrated that arsenic trioxide was safe and effective not only on patients with leukemia, but also on patients with many other kinds of malignant cancers. Arsenic trioxide exerted its anti-cancer effects mainly by inhibiting the cell growth and angiogenesis, inducing the cell partial cytodifferentiation and apoptosis, etc. In addition, this review looked forward to the prospect of application of gene chip, a newly developed and powerful technology in analysis of gene expression profile, in elucidation of the mechanism of arsenic trioxide on tumor.

Antineoplastic Agents↗

In vitro dual effect of arsenic trioxide on hemopoiesis: inhibition of erythropoiesis and stimulation of megakaryocytic maturation.

Although the arsenic compounds are now widely utilized in clinics in the treatment of various tumors, their effects on normal hematopoiesis do not seem to have been explored. In the present study, we provide evidence that arsenic trioxide (As(2)O(3)) exerts in vitro a potent inhibitory effect on normal erythropoiesis and a stimulatory action on megakaryocytic differentiation. The effect of As(2)O(3) on erythroid and megakaryocytic differentiation was evaluated on both erythroleukemic cell lines K562 and HEL and on normal hemopoietic progenitor cells (HPCs) induced to selective erythroid or megakaryocytic differentiation. The inhibitory effect of As(2)O(3) on erythropoiesis is related to: (a) the inhibition of Stat5 activation with consequent reduced expression of the target genes Bcl-X(L) and glycophorin-A; (b) the activation of an apoptotic mechanism that leads to the cleavage of the erythroid transcription factors Tal-1 and GATA-1, whose integrity is required for erythroid cell survival and differentiation; (c) the reduced expression of heat shock protein 70, required for GATA-1 integrity. The stimulatory effect of As(2)O(3) on normal megakaryocytopoiesis is seemingly related to upmodulation of GATA-2 expression and to stimulation of MAPK activity. These observations may have implications for the patients undergoing anti-leukemic treatment with this compound.

Antineoplastic Agents↗

[Occupational exposure and malignant hemopathies: a case-control study in Lyon (France)].

A hospital based case-control study was carried out in Lyon with the aim of assessing the association between haematologic malignancies and occupational exposures to 320 compounds. Job histories were obtained by questionnaire for 118 cases (52 non Hodgkin lymphomas, 48 acute myeloid leukemia, 18 others leukaemias), and 118 controls with diseases other than cancer from the same general hospital; controls were matched for sex, age and nationality. Systematic coding of exposures based on a blind analysis of job histories, was done by a team of experts in chemistry and occupational health. Mantel-Haenszel analysis was performed. Significantly elevated odds-ratio were observed for non Hodgkin lymphomas and exposure to mineral oils (14.86; 2.76-80.0), excavation dusts (3.91; 0.94-15.95), alkali compounds (2.90; 1.09-7.68), inks (2.47; 1.09-5.17). For inks, a dose-response relation was observed. Elevated odds-ratios appeared for acute myeloid leukaemias and arsenic compounds (3.02; 0.90-10.13) and lead compounds (3.70; 1.09-13.44). When regarding industrial activities, two of them are more frequently found: food industries (14 cases/5 controls), public works (12 cases/0 control). When regarding jobs, winding (6 cases/0 control), glass workers (8 cases/1 control) and warehousemen (10 cases and 4 controls) are more often seen among cases.

Adult↗

Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds.

Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds--such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine--in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the alphavbeta3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin alphavbeta3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.

Angiogenesis Inducing Agents↗

[Lead and arsenic resorption in the hard tissues (crystallochemical studies)].

Histologic-analytical observations on the resorption of lead and arsenic compounds are put into relationship with crystal-chemical analogies in the composition of hard tissue and the structure of calcium phosphate apatites with lead and arsenic substitution. Chemical analyses and x-ray diffraction of calcium and lead apatites with phosphate and arsenate represented as mixed precipitates in solution equilibrium show that - with the exception of calcium arsenate apatite - linear diadochocinetic substitution conditions are existing. The composition of calcium arsenate apatite is clearly shown to contain much less arsenic. This result is explained by the crystallographic laws of substitution in the crystal lattice (diadochocinetic laws). The clinical and physiological findings in lead and arsenic resorption are confirmed by the found distributional equilibria.

Apatites↗

Bacterial release of arsenic ions and organoarsenic compounds from soil contaminated by chemical warfare agents.

The objective of this paper was to investigate possible participation of microorganisms in the release of soluble arsenical compounds from organoarsenic warfare agents in contaminated soil. A number of bacterial strains were isolated with high resistance against As3+ and As5+ ions which are able to degrade the water insoluble compounds triphenylarsine (TP) and triphenylarsineoxide (TPO). These strains belong to different genera of bacteria. Release of arsenic ions and soluble organoarsenic compounds from soil by the activity of autochthonic soil bacteria and a mixture of the isolated pure cultures was demonstrated by percolation experiments with undisturbed soil samples (core drills) from the contaminated site. This release increased after addition of nutrients (mineral nitrogen and phosphorus, sodium acetate and ethanol) and is nearly independent of the percolation temperature (5 degrees C and 22 degrees C). These results show that bacteria play an important role in the release of arsenical compounds from organoarsenic warfare agent contaminated soil. This release is limited by shortage of water and, above all, of nutrients for the microorganisms in the sandy forest soil. These results are important both for the management and security and possibly for bioremediation of military waste sites containing similar contaminations. Furthermore, this is the first report on bacterial degradation of organoarsenic warfare compounds.

Arsenicals↗