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

Abstract

C[complementary]DNA probes and in vitro translation analysis were utilized 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] mRNA in persistent hepatocyte nodules included by chemical carcinogens. Within the nodules, glutathione transferase mRNA specific for the Ya/Yc and Yb subunits are increased 3- to 5-fold, respectively, over the levels observed in normal liver or in the liver tissue surrounding the nodules. The level of DT-diaphorase mRNA is increased 5-7-fold within the nodules as compared to surrounding liver tissue or normal liver. When animals were administered 3-methylcholanthrene, a typical inducer of these mRNA 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. During chemically induced neoplastic transformation, the mRNA levels for the Yb subunit of glutathione transferase and DT-diaphorase are evidently increased in the nodules but still retain the capacity to be regulated by 3-methylcholanthrene. Although the glutathione transferase Ya/Yc mRNA are also increased in the nodules, they lost their ability to be regulated by 3-methylcholanthrene. Within the nodules there may be a specific defect in the regulatory mechanisms(s) that leads to an induction of the Ya/Yc mRNA in normal tissue by xenobiotics.