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Studies on liver tumor promotion in the rat by orotic acid: dose and minimum exposure time required for dietary orotic acid to promote hepatocarcinogenesis
Department of Pathology, Medical Sciences Building, University of Toronto Toronto, Ontario, Canada M5S 1A8
1Department of Oncological Pathology Cancer Center, Nara Medical College Nara 634, Japan
2Istituto di Patologia Sperimentale, Universita di Cagliari 09100 Cagliari, Italy
3To whom correspondence and reprint requests should be addressed
Our earlier studies indicated that orotic acid, a precursor for pyrimidine nucleotide biosynthesis, exerts a promoting effect on rat hepatocarcinogenesis. The present study was designed to determine the optimum conditions of exposure to orotic acid required for promotion of hepatocarcinogenesis in the initiated rats. The first series of experiments was designed to determine the optimum dose of orotic acid needed to exert its liver tumor promoting effect. Accordingly male Fischer rats were given diethylnitrosamine (200 mg/kg, i.p.) or 0.9% NaCl. One week later carcinogen-injected rats were divided into six groups and fed either basal diet or the same diet containing 0.1, 0.5, 1, 2 or 4% orotic acid. Rats given 0.9% NaCl were fed 4% orotic acid. Two-thirds partial hepatectomy was performed on all animals 10 weeks after starting on their respective diets, and all groups were killed 3 weeks thereafter. Analysis of 
-glutamyltransferase-positive foci and nodules revealed that 0.5–1% orotic acid in the diet is sufficient to exert a significant promoting effect on the selective growth of initiated hepatocytes, while higher concentrations of orotic acid were only marginally more effective. No -glutamyl-transferase-positive foci were observed in animals given 4% orotic acid diet following saline injection. Using 1% orotic acid as the promoting regimen, in the next series, the minimum exposure time required for dietary orotic acid to promote liver carcinogenesis was determined. Male Fischer 344 rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or 0.9% NaCl 18 h after 2/3 partial hepatectomy. After 1 week of recovery one group of rats was continued on a semisynthetic basal diet, while others were transferred to the same basal diet containing 1% orotic acid. Rats that were on the 1% orotic acid diet were progressively transferred to the basal diet after 5, 10, 20, 29 and 40 weeks of exposure. All rats were sacrificed 54 weeks after the beginning of the experiment. The results indicate that 100% of the initiated rats developed hepatic nodules whether or not they were exposed to an orotic acid-containing diet. However, the incidence of hepatocellular carcinoma was greatly increased in animals exposed to the orotic acid diet, with 42% incidence in initiated rats given orotic acid diet for 10 weeks and up to 75% in those exposed to this diet for 40 weeks. Further, promotion by orotic acid exhibited a high metastatic potential with 33–60% metastasis to the lungs. On the other hand, initiated rats exposed to the basal diet developed only a 21% incidence of hepatocellular carcinoma, with no metastasis to the lungs. These results indicate that a minimum of 10–20 weeks of exposure to orotic acid diet was found to be sufficient to induce maximum liver tumor promoting effect. Further, initiated rats, whether or not exposed to orotic acid, exhibited a higher incidence of extra-hepatic tumors. However, their significance cannot be assessed because of low frequency of incidence at any given site.
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