DIFFERENTIAL INDUCTION OF GAMMA-GLUTAMYL-TRANSPEPTIDASE IN PRIMARY CULTURES OF RAT AND MOUSE HEPATOCYTES PARALLELS INDUCTION DURING HEPATOCARCINOGENESIS

In carcinogen-treated rats, gamma-glutamyl transpeptidase (GGT) is ind uced in preneoplastic liver lesions and liver tumors. However, in mice , GGT is rarely detected during hepatocarcinogenesis. Data in this stu dy reveal that GGT is not induced in mouse hepatocytes when they are m aintained in vitro under the same conditions that induce GGT activity in primary cultures of rat hepatocytes. GGT activity in rat hepatocyte s increased 20-fold during the first 7 days in culture, but there was no induction of GGT in primary cultures of mouse hepatocytes. Comparis on of intracellular glutathione levels in rat and mouse liver cells sh owed that the glutathione level was higher in the mouse liver cells th an the rat. Blocking glutathione synthesis with buthionine sulfoximine reduced the intracellular glutathione concentration in mouse liver ce lls but did not trigger an induction of GGT. Analysis of the GGT mRNA in primary cultures of rat hepatocytes showed that only GGT mRNA(III) is induced. This is the same GGT mRNA species present in preneoplastic hepatic lesions and liver tumors in the rat (1-3). Therefore activati on of promoter III in the GGT gene is responsible for induction of GGT in both hepatocytes in vitro and liver tumors in vivo. These data sho w that primary cultures of rat and mouse hepatocytes provide a model s ystem with which to study interspecies differences in the regulation o f this enzyme and to better understand the role of GGT in normal and n eoplastic processes.