ToxSci Advance Access originally published online on January 12, 2005
Toxicological Sciences 2005 84(2):344-351; doi:10.1093/toxsci/kfi082
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Inorganic Arsenic Compounds and Methylated Metabolites Induce Morphological Transformation in Two-Stage BALB/c 3T3 Cell Assay and Inhibit Metabolic Cooperation in V79 Cell Assay
* Safety Evaluation Center, Showa Denko K.K., Chiba 267-0056, Japan; Division of Environmental Chemistry and Exposure Assessment, National Institute of Health Science, Setagaya-ku, Tokyo 158-8501, Japan; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo-shi, Tokyo 202-8585, Japan; and Laboratory of Cellular Toxicology, Hatano Research Institute, Food and Drug Safety Center, Hadano, Kanagawa 257-0025, Japan
Received October 22, 2004; accepted January 7, 2005
We have performed two-stage transformation assay using BALB/c 3T3 cells to determine initiating and promoting activities of disodium arsenate, sodium arsenite, monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA). Treatment with these arsenic compounds at the initiating stage induced significant numbers of transformed foci when cells were post-treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Disodium arsenate was active at the concentrations of 15–30 µM, sodium arsenite 5–20 µM, and DMAA 1–2 mM. MMAA required 10 mM to induce cell transformation. The concentrations of these compounds (except DMAA) that induced transformation were highly growth-inhibitory (more than 50%). DMAA induced transformation foci at growth inhibition levels of 66 to 84%. In experiments on promoting activity, cells pretreated with a sub-threshold dose of 20-methylcholanthrene (MCA, 0.2 µg/ml) or sodium arsenite (10 µM) were used. Transformation was enhanced by post-treatment with disodium arsenate (1–10 µM), sodium arsenite (0.5–2 µM), and MMAA (200–1000 µM), but not with DMAA. Studies of gap junctional intercellular communication using the V79 cell metabolic cooperation assay showed that the arsenic compounds (except DMAA) exhibited inhibitory activity. Thus, most arsenicals were shown to have not only initiating activity, but also promoting activity. In addition, inorganic arsenicals, especially trivalent sodium arsenite, were more active than organic ones and exhibited promoting activity at one-order of magnitude lower than initiating activity. These results suggest that from the viewpoint of human hazard, more attention should be paid to the tumor promoting activity of inorganic arsenic compounds.
Key Words: arsenic compounds; BALB/c 3T3 cells; initiating activity; metabolic cooperation; tumor-promoting activity; two-stage cell transformation.
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