RESISTANCE OF HEPATIC NODULES TO OROTIC ACID-INDUCED ACCUMULATION OF URIDINE NUCLEOTIDES

It has been hypothesized that erotic acid (OA) promotes rat liver carc inogenesis by a differential mitoinhibitory mode. Consistent with this hypothesis, hepatic nodules are relatively resistant to OA-induced mi toinhibition. OA-induced mitoinhibition is dependent on the metabolism of OA to uridine nucleotides. The present studies investigate the upt ake and metabolic pathway of OA, both in viva and in vitro, as a possi ble basis for the resistance of hepatic nodules to OA-induced mitoinhi bition. Rats bearing hepatic nodules exposed to 1% dietary OA exhibite d increased levels of uridine nucleotides in the surrounding non-nodul ar liver (from 0.44 to 0.70 mg/g liver) but not in the hepatic nodules . Further, following administration of [H-3]OA i.p., nodules have sign ificantly lower levels of acid-soluble radioactivity compared to the n on-nodular surrounding tissue. Furthermore, most of the acid-soluble r adioactivity was present as uridine nucleotides, suggesting that the O A taken up was converted to uridine nucleotides. similarly, hepatocyte s from nodules in primary culture incubated with radiolabeled OA, have significantly lower levels (46-60%) of acid-soluble radioactivity. Th ese results suggest that the decreased uptake of OA by hepatic nodules may be a factor contributing to the observed resistance of hepatic no dules to the mitoinhibitory effects of OA.