EFFECT OF OROTIC-ACID ON INVIVO DNA-SYNTHESIS IN HEPATOCYTES OF NORMAL RAT-LIVER AND IN HEPATIC FOCI NODULES

One of the proposed mechanisms by which orotic acid (OA) promotes live r carcinogenesis is by differentially mito-inhibiting the normal hepat ocytes while permitting the initiated ones to respond to growth stimul i to form foci/nodules. In an attempt to examine this hypothesis, the present study was designed to determine (i) whether OA inhibits DNA sy nthesis in normal hepatocytes in vivo, and (ii) whether hepatocytes fr om hepatic foci/nodules are relatively resistant to the mito-inhibitor y 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 peri od by which the implanted tablet disappeared-the hepatocytes resumed D NA synthesis. Exposure to OA results in an accumulation of uridine nuc leotides and a decrease in adenosine nucleotides. Creation of such an imbalance in nucleotide pools appears to be important for OA to inhibi t DNA synthesis. Adenine (a tablet of 300 mg), an agent that inhibits the metabolism of OA to uridine nucleotides, counteracted the mito-inh ibitory effects of OA. To determine whether the hepatocytes in foci/no dules are resistant to the mito-inhibitory effects of OA, rats were in itiated 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 or absence of OA (300 mg tablet). The results indicated that, in contrast to hepatocyte s in normal or surrounding non-nodular liver, a subpopulation of hepat ocyte foci/nodules appear to be relatively resistant to the mito-inhib itory effects of OA. These findings support the hypothesis that differ ential mito-inhibition is a possible component in the promoting effect of OA. However, whether this is the mechanism by which OA promotes li ver carcinogenesis needs to be further investigated.