Microbial metabolite of dimethylarsinic acid is highly toxic and genotoxic

Dimethylarsinic acid [DMA.. (CH3)(2)AsO(OH)] causes cancer in the urinary bladder of rats. However, its mechanism of cancer or the ultimate carcinogenic form is not yet known. Rats administered dimethylarsinic acid excrete three unknown arsenic compounds (termed M-1, M-2, and M-3) in urine or feces, and these compounds are presumed to be produced by intestinal bacteria. Escherichia coli A3-6 isolated from a rat yielded two unknown arsenic compounds (M-2 and M-3) from dimethylarsinic acid and M-1 from trimethylarsine oxide (TMAO) in the presence of cysteine (Cys). Contents of M-2 and M-3 varied with cysteine concentration. The cytotoxicity and genotoxicity of the bacteria-free solution of dimethylarsinic acid or trimethylarsine oxide metabolized by E. coli A3-6 were studied using V79 cells. Dimethylarsinic acid (1 mM) metabolized by E. coli A3-6 in the presence of cysteine (I mM) was highly cytotoxic (50% survival reduction concentration; 2.1 muM As) in V79 cells, and the toxic substance appeared to be M-2. The metabolite solution (at 2.5-10 muM total As) induced c-mitosis and tetraploids, and caused mitotic arrest, since it increased mitotic cells at the cytotoxic dose. The metabolite solution also significantly increased sister chromatid exchange (SCE) and chromosomal aberrations, most of which were chromatid gaps and chromatid breaks. A3-6 converted 96.1% of trimethylarsine oxide to M-1 in the presence of cysteine. This metabolite solution did not exhibit cytotoxicity or genotoxicity. The reported M-2 concentration in urine of rats administered levels of DMA via drinking water known to cause bladder tumors was sufficient to exhibit cytotoxic and genotoxic effects in urinary bladder. Thus, we hypothesize that intestinal bacteria play an important role in carcinogenicity of dimethylarsinic acid. (C) 2004 Elsevier Inc. All rights reserved.