DRUG-METABOLIZING ENZYME-ACTIVITIES IN FRESHLY ISOLATED OVAL CELLS AND IN AN ESTABLISHED OVAL CELL-LINE FROM CARCINOGEN-FED RATS

The activities of several different phase I and phase II drug-metaboli zing enzymes were measured in freshly isolated oval cells from rats fe d a choline-deficient/DL-ethionine-supplemented diet for 6 weeks and a lso in vitro in the established oval cell line OC/CDE 6. No cytochrome P450 was spectrophotometrically measurable in both preparations and t wo cytochrome P450-dependent monoxygenase activities, aminopyrine N-de methylase and ethoxyresorufin O-deethylase, could not be detected in t he oval cells of both sources. However, cytosolic glutathione transfer ase, microsomal epoxide hydrolase and UDP-glucuronosyltransferase acti vities were clearly measurable in oval cells. Similar enzyme activitie s were found in freshly isolated and cultured oval cells. The highest activities of these three enzymes were detected during the exponential growth phase of the cultured cells; thereafter the activities decreas ed until the cells reached confluency. Changes in phenol UDP-glucurono syltransferase (UGT1A1) mRNA levels paralleled the variations in UDP-g lucuronosyltransferase activity, i.e. they were high in exponentially growing oval cells and low in confluent cell cultures. Taking into acc ount that oval cells are able to proliferate in the livers of rats con tinuously fed a choline-deficient/DL-ethionine-supplemented diet and t hat none of the analyzed drug metabolizing enzymes are involved in the activation or detoxication of DL-ethionine, the described pattern mig ht be part of a more general, nonspecific, protection mechanism enabli ng these cells to overcome the cytotoxic effects of a variety of carci nogens and to proliferate even in their presence. Furthermore, the exp ression of microsomal epoxide hydrolase, cytosolic glutathione transfe rase and UDP-glucuronosyltransferase appears to depend on the prolifer ative status of the cells.