Biphasic early changes in rat liver gamma-glutamyl transpeptidase in response to aflatoxin B1

The present study was designed to examine the earliest changes in gamma-glutamyl transpeptidase (GGT) in response to administration of the hepatocarcinogen aflatoxin B1 (AFB1). Male Fischer 344 rats were either fed a diet containing 4 p.p.m., or received a single i.p. injection (0.72 or 1.73 mg/kg) of AFB1. GGT levels were determined histochemically and by quantitative fluorimetric assay. In livers of animals receiving 4 p.p.m. AFB1, GGT activity showed a biphasic response during a 15 week period. During the first 4 weeks the increasing activity was localised predominantly in the bile duct epithelial cells and some periportal hepatocytes. At 4 weeks the first foci of GGT-positive hepatocytes, characteristic of the very early carcinogenic changes began to appear. As feeding continued there was an overall temporary decrease in GGT, during which time biliary hyperplasia regressed but the number of foci gradually increased. The second phase of increased activity corresponded to increase in size and number of foci, so that by 15 weeks most of GGT was present in hepatocytes. Single injections of AFB1 produced dose-dependent increases in GGT which bore a linear relationship to biliary hyperplasia.