Arsenicals are epidemiologicaUy significant chemicals in relation to induction of liver cancer in man. In the present study, we investigated the dose‐dependent promotion potential of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenicals in mammals, in a rat liver carcinogenesis model. In experiment 1, glutathione‐S‐transferase placental form (GST‐P)‐positive foci, putative preneoplas‐tic lesions, were employed as endpoints of a liver medium‐term bioassay for carcinogens (Ito test). Starting 2 weeks after initiation with diethylnitrosamine, male F344 rats were treated with 0, 25, 50 or 100 ppm of DMAA in the drinking water for 6 weeks. All animals underwent two‐thirds partial hepatectomy at week 3 after initiation. Examination of liver sections after termination at 8 weeks revealed dose‐dependent increases in the numbers and areas of GST‐P‐positive foci in DMAA‐treated rats as compared with controls. In experiment 2, ornithine decarboxylase activity, which is a biomarker of cell proliferation, was found to be significantly increased in the livers of rats treated with DMAA. In experiment 3, formation of 8‐hydroxydeoxyguanosine, which is a marker of oxygen radical‐mediated DNA damage, was significantly increased after administration of DMAA. These results indicate that DMAA has the potential to promote rat liver carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals

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The effects of S-methylcysteine (SMC) and cysteine on the promotion stages of rodent hepatocarcinogenesis in a medium-term bioassay previously developed by Ito were examined. Initiation was induced by a single dose of diethylnitrosamine (DEN), followed by dietary administration of the promoter sodium phenobarbital (NaPB) 2 weeks later, for 6 weeks. Partial hepatectomy was conducted on all the animals at week 3. Inhibitory potential was evaluated by analyzing two markers of carcinogenesis, namely numbers of glutathione S-transferase placental form (GST-P)-positive foci, and proliferating cell nuclear antigen (PCNA). In addition, the level of ornithine decarboxylase (ODC), one of the rate-limiting enzymes of polyamine metabolism induced by promoters, was analyzed. SMC and cysteine induced significant reduction in the areas of GST-P-positive foci. A significant reduction in the PCNA index was observed in the entire liver as well as in GST-Ppositive areas. SMC also induced down-regulation of the ODC enzyme activity. Thus, SMC and cysteine were found to inhibit the promotion stage of DEN-induced hepatocarcinogenesis. No cocarcinogenic effects were evident on administration of either of these chemicals with NaPB.

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