| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We had reported that dimethylarsinic acid (DMA) induced mitotic arrest and tetraploids or aneuploids in Chinese hamster V79 cells, cultured human lymphocytes or bone marrow cells (in vivo). In this study we revealed that DMA inhibits normal assembly of tublin in vitro and also inhibits normal development of spindles in V79 mitotic cells, DMA inhibits tublin's GTP activity. These results suggest that DMA disturbs normal assembly of tublin by lowering tublin's GTP activity and induces mitotic arrest. Next we found that cysteine enhances strongly cytotoxicity and induction of chromosome aberration of DMA. This result suggest that cysteine participates in carcinogenicity of DMA.
We attempted to clarify the mechanism of production of unknown metabolites, M-1 and M-2, which were excreted in urine after long-term oral administration of DMA in rats. Glutathione (GSH) depletion decreased in TMAO elimination, suggesting that GSH plays important roles in the methylation of DMA to TMAO in rats. The amounts of urinary elimination of either M-1 or M-2 in GSH-depleted rats were higher than controls after a single oral administration, suggesting that M-1 and M-2 cannot be formed during methylation in the liver. The amounts of elimination of M-1 and M-2 were less after intraperitoneal administration than after oral administration.
A new unidentified metabolite, M-3, was detected in feces as a metabolite of DMA after 20-week exposure to DMA. The unidentified metabolites M-1, M-2, and M-3 were excreted mainly as fecal metabolites along with unmetabolized DMA. In vitro study showed that two strains of E. coli isolated from rat ceca metabolized DMA to M-2 or M-3 and TMAO to M-1. These findings suggest that M-1, M-2, and M-3 might be produced in the intestinal tract. Cysteine was required for metabolism of DMA by the intestinal bacteria.
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