Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver.

Abstract

Arsenicals are epidemiologically 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 preneoplastic 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.

• Authors: H Wanibuchi, T Hori, V Meenakshi, T Ichihara, S Yamamoto, Y Yano, S Otani, D Nakae, Y Konishi, S Fukushima
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 88 Issue 12 Pg. 1149-54 (Dec 1997) ISSN: 0910-5050 [Print] Japan
• PMID: 9473732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Herbicides
• 8-Hydroxy-2'-Deoxyguanosine
• DNA
• Cacodylic Acid
• Ornithine Decarboxylase
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Cacodylic Acid (toxicity)
• Carcinogens (toxicity)
• DNA (chemistry)
• Deoxyguanosine (analogs & derivatives, biosynthesis)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Herbicides (toxicity)
• Liver (drug effects, enzymology)
• Liver Neoplasms, Experimental (chemically induced, enzymology)
• Male
• Ornithine Decarboxylase (genetics, metabolism)
• Rats
• Rats, Inbred F344