Gamma-glutamyltransferase in putative premalignant liver cell populations during hepatocarcinogenesis

The activity of gamma-glutamyltransferase, as measured quantitatively and by histochemical staining, was studied in different cell populations during the induction of liver cancer with 2-acetylaminofluorene (2-AAF) or diethylnitrosamine and compared with findings in fetal and in intact and regenerating adult liver. The enzyme activity is 20-fold higher in 12-week nodules than in control livers and 30-fold higher in 20-week nodules than in controls. A similar 30-fold increase in activity relative to control is present in hepatomas, induced by either 2-AAF or diethylnitrosamine, and in fetal hepatocytes. The enzyme shows increases in activity in foci of very early putative preneoplastic hepatocytes induced by a single dose of diethylnitrosamine and selected by low doses of 2-AAF plus partial hepatectomy. By 7 days, the foci show a 4-fold increase in enzyme activity, and by 3 weeks they are 40-fold higher than in the control liver. Histochemically, the foci are strongly positive for gamma-glutamyltransferase, especially in the bile canaliculi. By 21 days, the ductular (oval) cells induced by 2-AAF have disappeared. When stained for the enzyme activity, the foci stand out clearly against the negative background of the liver, allowing easy quantitation. It appears that gamma-glutamyltransferase is a useful marker for preneoplastic hepatocytes.