Regulation of glutathione transferase and DT-diaphorase mRNAs in persistent hepatocyte nodules during chemical hepatocarcinogenesis

Abstract

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, respectively, 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 mRNAs 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 are 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.