Dimethylarsinic acid (DMAV) is carcinogenic to the rat urinary bladder when administered at high doses in the diet or drinking water. At a dietary dose of 100 ppm (μg/g), it produces cytotoxicity within 6 h and increased proliferation (hyperplasia) by 7 days of administration. We hypothesize that formation of the reactive organic intermediate dimethylarsinous acid (DMAIII) is involved in the induction of the cytotoxicity. To evaluate the possibility that DMAV administration produces urothelial toxicity and regeneration by the formation of trivalent arsenicals, 2,3-dimercaptopropane-1-sulfonic acid (DMPS, 5600 ppm), a chelator of trivalent arsenicals, was co-administered with DMAV (100 ppm) for 2 weeks to groups of female Fischer F344 rats. Based on light and scanning electron microscopy, and bromodeoxyuridine labeling index, DMAV produced cytotoxicity and regenerative hyperplasia of the urothelium which was inhibited by co-administration with DMPS. The major forms of arsenic in the 24-h urine of rats administered DMAV were high concentrations of DMAV (66.4 ± 2.7 μM) itself and the pentavalent organic arsenical trimethylarsine oxide (TMAO) (73.2 ± 9.5 μM). Co-administration with DMPS led to an increase in DMAV (507 ± 31 μM) with a decrease in TMAO (2.8 ± 0.4 μM) excretion. The formation of TMAO from DMAV mechanistically suggests formation of the intermediate trivalent metabolite, DMAIII. In a second experiment evaluating fresh void urines collected on study days 1, 71, and 175, we detected DMAIII in the urine of DMAV and DMAV plus DMPS-treated rats at approximately micromolar concentrations. Using rat (MYP3) and human (1T1) urothelial cells, cytotoxicity for trivalent arsenicals, sodium arsenite, monomethylarsonous acid (MMAIII), and DMAIII was demonstrated at 0.4-4.8 μM concentrations, whereas MMAV, DMAV, and TMAO were cytotoxic at millimolar concentrations. The presence of DMAIII at micromolar concentrations in the urine of rats fed 100 ppm DMAV suggests that DMAIII produced in vivo may be involved in the toxic effects in the rat urinary bladder after dietary administration of DMAV.
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