Reduction of glutathione S-transferase P-form mRNA expression in remodeling nodules in rat liver revealed by in situ hybridization.

Glutathione S-transferase P-form (GST-P) mRNA levels and distribution were sequentially analyzed by in situ hybridization histochemistry (ISH) in rat livers during and after induction of preneoplastic foci and nodules in the Solt-Farber model. Dot blot analysis showed GST-P transcripts in the liver to be elevated coincidental with the development of GST-P-positive lesions. GST-P ISH indicated that the majority of early foci and some of the resultant lesions showed uniformly high levels of GST-P mRNA. However, the majority of foci and nodules after completion of the selection regimen exhibited a progressive loss of staining for GST-P mRNA. Similar results were obtained for gamma-glutamyltransferase (GGT) transcripts, indicating that phenotypic reversion is controlled by factors operating at the level of gene expression in both cases. Expression of GST-P mRNA was high in all hepatocellular carcinoma samples, whereas the levels of GGT transcripts varied considerably, so that the two enzymes showed a degree of independence in their regulation. The present data for transcription suggest that GST-P is a stable marker of preneoplastic and neoplastic cells, not only at the protein but also at the mRNA level, throughout hepatocarcinogenesis in the rat. The reason why transcription of GST-P mRNA is switched off as part of the reversion to a normal organization remains to be elucidated.