Possible role of dimethylarsinous acid in dimethylarsinic acid-induced urothelial toxicity and regeneration in the rat.
Dimethylarsinic acid (DMA(V)) 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 (microg/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 (DMA(III)) is involved in the induction of the cytotoxicity. To evaluate the possibility that DMA(V) 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 DMA(V) (100 ppm) for 2 weeks to groups of female Fischer F344 rats. Based on light and scanning electron microscopy, and bromodeoxyuridine labeling index, DMA(V) 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 DMA(V) were high concentrations of DMA(V) (66.4 +/- 2.7 microM) itself and the pentavalent organic arsenical trimethylarsine oxide (TMAO) (73.2 +/- 9.5 microM). Co-administration with DMPS led to an increase in DMA(V) (507 +/- 31 microM) with a decrease in TMAO (2.8 +/- 0.4 microM) excretion. The formation of TMAO from DMA(V) mechanistically suggests formation of the intermediate trivalent metabolite, DMA(III). In a second experiment evaluating fresh void urines collected on study days 1, 71, and 175, we detected DMA(III) in the urine of DMA(V) and DMA(V) plus DMPS-treated rats at approximately micromolar concentrations. Using rat (MYP3) and human (1T1) urothelial cells, cytotoxicity for trivalent arsenicals, sodium arsenite, monomethylarsonous acid (MMA(III)), and DMA(III) was demonstrated at 0.4-4.8 microM concentrations, whereas MMA(V), DMA(V), and TMAO were cytotoxic at millimolar concentrations. The presence of DMA(III) at micromolar concentrations in the urine of rats fed 100 ppm DMA(V) suggests that DMA(III) produced in vivo may be involved in the toxic effects in the rat urinary bladder after dietary administration of DMA(V).
Cohen
Samuel M
SM
Department of Pathology and Microbiology and Eppley Institute for Cancer Research, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA. scohen@unmc.edu
Arnold
Lora L
LL
Uzvolgyi
Eva
E
Cano
Martin
M
St  John
Margaret
M
Yamamoto
Shinji
S
Lu
Xiufen
X
Le
X Chris
XC
D000818:Animals; D001835:Body Weight; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000633:toxicity* / Q000652:urine; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008855:Microscopy, Electron, Scanning; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration / Q000187:drug effects; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D019459:Urothelium / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure
D002273:Carcinogens; C472511:dimethylarsinous acid; D002101:Cacodylic Acid