Promotion of Rat Hepatocarcinogenesis by Dimethylarsinic Acid: Association with Elevated Ornithine Decarboxylase Activity and Formation of 8‐Hydroxydeoxyguanosine in the Liver

Abstract

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