Effect of orotic acid on in vivo DNA synthesis in hepatocytes of normal rat liver and in hepatic foci/nodules.

Abstract

One of the proposed mechanisms by which orotic acid (OA) promotes liver carcinogenesis is by differentially mito-inhibiting the normal hepatocytes while permitting the initiated ones to respond to growth stimuli to form foci/nodules. In an attempt to examine this hypothesis, the present study was designed to determine (i) whether OA inhibits DNA synthesis in normal hepatocytes in vivo, and (ii) whether hepatocytes from hepatic foci/nodules are relatively resistant to the mito-inhibitory effects of OA. The results of this study indicate that OA given i.p. as a tablet of 300 mg at the time of partial hepatectomy (PH) almost completely inhibited liver DNA synthesis. Three days later--a time period by which the implanted tablet disappeared--the hepatocytes resumed DNA synthesis. Exposure to OA results in an accumulation of uridine nucleotides and a decrease in adenosine nucleotides. Creation of such an imbalance in nucleotide pools appears to be important for OA to inhibit DNA synthesis. Adenine (a tablet of 300 mg), an agent that inhibits the metabolism of OA to uridine nucleotides, counteracted the mito-inhibitory effects of OA. To determine whether the hepatocytes in foci/nodules are resistant to the mito-inhibitory effects of OA, rats were initiated with diethylnitrosamine (DENA; 150 mg/kg) and promoted by the resistant-hepatocyte model. Fourteen weeks after the administration of DENA, the rats were subjected to PH in the presence of absence of OA (300 mg tablet). The results indicated that, in contrast to hepatocytes in normal or surrounding non-nodular liver, a subpopulation of hepatocyte foci/nodules appear to be relatively resistant to the mito-inhibitory effects of OA. These findings support the hypothesis that differential mito-inhibition is a possible component in the promoting effect of OA. However, whether this is the mechanism by which OA promotes liver carcinogenesis needs to be further investigated.