OVEREXPRESSION OF GLUCOSE-6-PHOSPHATE-DEHYDROGENASE IN RAT HEPATIC PRENEOPLASIA AND NEOPLASIA

Abundance of messenger RNA (mRNA) and activity of glucose-6-phosphate dehydrogenase (G6PDH), the rate limiting enzyme of the oxidative pento se phosphate pathway, were studied in preneoplastic foci of altered he patocytes (FAH) and hepatocellular carcinomas (HCC) induced in rats by limited oral exposure to N-nitrosomorpholine (NNM-stop model). Northe rn blot analysis revealed increased amounts of G6PDH-mRNA in 9/10 HCC, which are apparently not due to structural alterations of the G6PDH g ene as studied by Southern blot analysis. In four additional HCC eleva ted expression of G6PDH was demonstrated by in situ hybridization to a ntisense-mRNA and by catalytic enzyme histochemistry. This correlative molecular genetic and enzyme histochemical approach was also used to study G6PDH expression in FAH of different phenotypes, namely glycogen storage foci (GSF), mixed cell foci (MCF) acid basophilic cell foci ( BCF), representing early (GSF) and advanced (MCF, BCF) stages of hepat ic preneoplasia. mRNA level and activity of G6PDH were closely correla ted in all types of lesions and increased from GSF to MCF/BCF and HCC. These results suggest a predominantly transcriptional regulation of t he increasing expression of G6PDH during hepatocarcinogenesis in the r at.