We have utilized cDNA probes and in vitro translation analysis to quantitate the levels of rat liver glutathione transferase (glutathione S-aralkyltransferase; RX:glutathione R-transferase, EC 2.5.1.18) and DT-diaphorase [NAD-(P)H:quinone-acceptor oxidoreductase, EC 1.6.99.2] mRNAs in persistent hepatocyte nodules induced by chemical carcinogens. Our results indicate that within the nodules, glutathione transferase mRNAs specific for the Ya/Yc and Yb subunits are increased 3-fold and 5-fold, respectivqly, over the levels observed in normal liver or in the liver tissue surrounding the nodules. Similarly, the level of DT-diaphorase mRNA is increased 5-to 7-fold within the nodules as compared to surrounding liver tissue or normal liver. When animals were administered 3-methylcholanthrene, a typical inducer of these nRNAs in normal animals, a further increase in the glutathione transferase Yb mRNA(s) and DT-diaphorase mRNA was observed in the nodules; however, the Ya/Yc mRNA levels remained unaffected. Our data indicate that during chemically induced neoplastic transformation, the mRNA levels for the Yb subunit of glutathione transferase and DT-diaphorase arp increased in the nodules but still retain the capacity to be regulated by 3-methylcholanthrene. Although the glutathione transferase Ya/Yc mRNAs are also increased in the nodules, they lost their ability to be regulated by 3-methylcholanthrene.These latter data suggest that within the nodules there is a specific defect in the regulatory mechanism(s) that leads to an induction of the Ya/Yc mRNAs in normal tissue by xenobiotics.The administration of a single initiating dose of diethylnitrosamine to rats followed by a low level of 2-acetylaminofluorene plus a partial hepatectomy induces foci of altered hepatocytes, which have been referred to as persistent hepatocyte nodules, hyperplastic nodules, or preneoplastic nodules (1). Persistent hepatocyte nodules are thought to represent precursors for the subsequent development of hepatocellular carcinomas and, thus, have been utilized as a model system to study chemically induced neoplastic transformation (1, 2). Biochemically the nodules have elevated levels of various drug-metabolizing enzymes {e.g., glutathione transferases (glutathione S-aralkyltransferase; RX:glutathione R-transferase, EC 2.5.1.18), DT-diaphorase [NAD(P)H:quinone-acceptor oxidoreductase, EC 1.6.99.2], and epoxide hydrolase}; however, cytochrome P-450 levels appear to be depressed (3-11). The elevated levels of some phase II drugmetabolizing enzyme activities and a decreased level of cytochrome P-450 are consistent with the observation that persistent hepatocyte nodules are more resistant to the cytotoxic effects of carcinogens as compared to normal liver (12). In fact, Farber (2) has hypothesized that an early or even first biological cellular event in liver carcinogenesis is the induction in a rare hepatocyte of resistance to the cytotoxic effect of carcinogens.In order to understand the mechanisms of chemical carcinogenesis, a basic unde...