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Orotic Acid, Nucleotide-Pool Imbalance, and Liver-Tumor Promotion: A Possible Mechanism for the Mitoinhibitory Effects of Orotic Acid in Isolated Rat Hepatocytes¹

Department of Pathology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [S. M., A. S., G. P-C., P. C., P. M. R., S. R., D. S. R. S.], and Department of Pathology, Duke University, Durham, North Carolina 27710 [P. P., G. M.]

This study was designed to determine the possible mechanism by which orotic acid exerts its mitoinhibitory effect on rat hepatocytes in primary culture. Orotic acid inhibited, dose-dependently DNA synthesis in hepatocytes induced by epidermal growth factor, transforming growth factor , hepatocyte growth factor, acidic fibroblast growth factor, or plasma from rats exposed to various liver cell-proliferative stimuli, such as two-thirds partial hepatectomy, lead nitrate, cyproterone acetate, ethylene dibromide, or a diet deficient in choline. Further, orotic acid inhibited DNA synthesis even when added 24 h after the hepatocytes were primed with transforming growth factor . Taken together, these results suggested that the target site may not be at the level of the growth-factor receptor and receptor-mediated early events. In a preliminary experiment, orotic acid inhibited the expression of the ribonucleoside diphosphate reductase gene. Exposure to orotic acid results in an imbalance in nucleotide pools characterized by an increase in uridine nucleotides and a decrease in adenosine nucleotides. It is hypothesized that this imbalance in nucleotide pools inhibits the expression of the ribonucleoside diphosphate reductase gene and, therefore, is a likely target for the mitoinhibitory effect of orotic acid.