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Our long-term oral administration of dimethylarsinic acid (DMAV) in rats revealed that three unidentified metabolites, M-1, M-2, and M-3, were detected in urine and feces. DMAV and trimethylarsine oxide (TMAO) were converted to M-2 and M-3 and M-1 by Escherichia coli strain A3-6 isolated from the ceca of DMAV-administered rats, respectively. In this study, we report on the mechanism of production and the chemical properties of these unknown metabolites. To investigate the pattern of conversion of DMAV or TMAO by A3-6 in the presence of cysteine (Cys), arsenic metabolites of DMAV or TMAO in medium after incubation with A3-6 and Cys were analyzed by liquid chromatography with inductively coupled plasma mass spectrometry (LC-ICP-MS). DMAV was reduced to dimethylarsinous acid (DMAIII) to form M-2 in the presence of Cys and A3-6, and M-2 was further converted to M-3. TMAO was rapidly converted to M-1 by A3-6. The cytotoxicity of the unidentified metabolites was investigated. M-2 was more cytotoxic than DMAV, M-1, and M-3 in V79 cells. The cytotoxicity of M-2 in HL-60 cells was decreased by the addition of superoxide dismutase, suggesting that the cytotoxicity of M-2 might be due to the production of reactive oxygen species. In addition, we examined the chemical properties of M-2 by LC-ICP-MS and LC-MS. M-2 was oxidized to DMAV by hydrogen peroxide, suggesting that M-2 may be a reduced form of DMAV. M-2 was consistent with the reactant of DMAV with metabisulfite−thiosulfate reagent but not DMAIII by analyses of LC-ICP-MS and LC-MS. The molecular weight of M-2 was 154, and M-2 was a sulfur-containing metabolite.

To selectively detect organomercurial compounds in the environment, in this study a bioluminescence biosensor for organomercurials was developed using a bacterial gene expression system for the mercury resistance determinant. merB3-Luciferase (mer-lux) transcriptional fusion plasmids pHYΔ3Lux and pHY.Δ3Lux were constructed to evaluate the gene expression system with a new organomercury lyase gene merB3 from Bacillus megaterium strain MB1, which is resistant to a broad spectrum of mercury compounds, and with its 3'end-deleted defective merB3, respectively. Another plasmid, pGR1A, encoding an operator/promoter sequence, merR1, merE, merT, merP and merA from the same bacterial strain was constructed and used as a transacting gene expression vector which combines the gene expression vector of mer-lux transcriptional fusion plasmids in the same Escherichia coli cells. The transformants that carried a set of the two plasmids were used as biological sensors for the detection of organomercurials. Transformant (E. coli DH5α/pHYB3Lux, pGR1A) is available to distinguish the organomercury from inorganic mercury, since inorganic mercurials can induce the bioluminescence of both the bacterial strain lines with pHYΔB3Lux and pHYB3Lux, whereas organomercurials can only induce the bioluminescence of the lines with pHYB3Lux. These experimental results showed that the transformant with a merB3-defective fusion plasmid, and the gene expression vector responded to only mercury chloride. On the other hand, the transformant with an intact merB3 fusion plasmid and the gene expression vector responded to mercury chloride and all organomercurials tested in the study. The sensor system responded to the existence of the phenyl mercury acetate of 50 nanomolar and was more sensitive than that of inorganic mercury (100 nanomolar). The result also indicated the capability of the system to detect bio-affecting inorganic mercury from several hundred nanomolar to several ten micromolar.

Summary:  Postoperative recovery of patients with chronic subdural haematoma (CSH) was investigated by comparing pre- and postoperative coagulant and fibrinolytic activity in the haematoma contents of 15 patients with SCH. Patients in this study were treated draining the haematoma cavity without irrigation, a procedure dubbed the closed drainage. Haematomas were collected during, and 24 hrs after, surgery. Postoperative fibrinolytic activity was lower than that observed pre-operatively. In particular, levels of tissue plasminogen activator activity (TPA), and fibrin and fibrinogen degradation products (FDP) all decreased. In contrast, coagulant activity increased postoperatively.  This paper will discuss the role of local coagulofibrinolysis in the postoperative recovery of CSH patients.

Inorganic arsenic is methylated in the mammalian body to methylarsonic acid (MMA), dimethylarsinic acid (DMA) and trimethylarsine oxide (TMA). To achieve a more precise understanding of arsenic carcinogenicity, we examined the genotoxic effects of organic arsenic compounds on human lymphocytes by assessing induction of mitotic arrest, sister chromatid exchange (SCE) and aneuploidy. MMA, DMA and TMA arrested mitosis, DMA induced hyperdiploid cells, and DMA and TMA induced tetraploid cells. Of the three arsenic metabolites tested, DMA had the strongest effects on cell mitosis and aneuploidy induction. DMA arrested mitosis and induced c‐mitosis significantly. These results suggest that DMA arrests mitosis and induces aneuploidy through spindle disruptions similar to those observed with known spindle poisons, such as colchicine or vinblastine. Since aneuploidy has been thought to be associated with tumor induction or neoplastic transformation, induction of aneuploidy by organic metabolites of arsenic may play a major role in arsenic carcinogenesis in humans. © 1997 John Wiley & Sons, Ltd.

Inorganic arsenic is methylated in the mammalian body to methylarsonic acid (MMA), dimethylarsinic acid (DMA) and trimethylarsine oxide (TMA). To achieve a more precise understanding of arsenic carcinogenicity, we examined the genotoxic effects of organic arsenic compounds on human lymphocytes by assessing induction of mitotic arrest, sister chromatid exchange (SCE) and aneuploidy. MMA, DMA and TMA arrested mitosis, DMA induced hyperdiploid cells, and DMA and TMA induced tetraploid cells. Of the three arsenic metabolites tested, DMA had the strongest effects on cell mitosis and aneuploidy induction. DMA arrested mitosis and induced c-mitosis significantly. These results suggest that DMA arrests mitosis and induces aneuploidy through spindle disruptions similar to those observed with known spindle poisons, such as colchicine or vinblastine. Since aneuploidy has been thought to be associated with tumor induction or neoplastic transformation, induction of aneuploidy by organic metabolites of arsenic may play a major role in arsenic carcinogenesis in humans. © 1997 John Wiley & Sons, Ltd.

Arsenicals are epidemiologically significant chemicals in relation to induction of urinary bladder cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMA), a major metabolite of inorganic arsenicals in mammals, for rat urinary bladder carcinogenesis. In experiment 1, 6-week-old male F344 rats were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then given one of several concentrations of DMA in their drinking water (groups 1-6: 0, 2, 10, 25, 50 and 100 p.p.m.) for 32 weeks. The development of preneoplastic lesions and tumors (papillomas and carcinomas) in the urinary bladder was enhanced by treatment with DMA in a dose-dependent manner. A significant increase in multiplicity of tumors (papillomas and carcinomas) was observed even at a low concentration of DMA (10 p.p.m.). On the other hand, no preneoplastic lesions and tumors were observed in the rats treated with DMA alone. In experiment 2, different concentrations of DMA (groups 1-4: 0, 10, 25 and 100 p.p.m.) in drinking water were administered to the rats for 8 weeks without prior initiation by BBN. A significant increase in the 5-bromo-2'-deoxyuridine labeling index and alteration of the surfaces of the urinary bladder epithelial cells, as revealed by scanning electron microscopy, provided evidence of a dose-dependent increase in cell proliferation due to the DMA treatment. These results suggest that DMA has the potential to promote rat urinary bladder carcinogenesis and one of the mechanisms involved is its stimulation of cell proliferation in the urinary bladder epithelium.