Gamma-glutamyl transpeptidase – its role in hepatocarcinogenesis

Introduction The enzyme gamma-glutamyl transpeptidase (GGT)* is widely used as a marker in preneoplastic lesions in the liver during chemical carcinogenesis (1). The discovery of a link between GGT and liver carcinogenesis first occurred in 1972 when Fiala and co-workers reported elevated levels of the enzyme in livers of rats fed the hepatocarcinogen 3'-methyl-4dimethylaminoazobenzene and also in transplantable, chemically induced rat hepatomas (2). Using a histochemical stain for GGT, Kalengayi and co-workers found that the increased levels of the enzyme during carcinogen feeding was due to increased GGT activity in focal areas of hepatocytes (3). Further investigation by a number of laboratories revealed elevated levels of GGT in the livers of rats fed a large variety of structurally different hepatocarcinogens, including 2-acetylaminofluorene (4), diethylnitrosamine (4), N-nitrosomorpholine (5) and aflatoxin Bj (3). In livers from carcinogen-treated animals, focal areas of hepatocytes show a number of different enzymatic and pathologic alterations (1). In livers from rats initiated with a variety of hepatocarcinogens and promoted with phenobarbital, staining of serial liver sections shows that 85% of all the foci stain positively for GGT. GGT identifies more foci than any other strain used in these studies (6,7). Elevated levels of GGT during hepatocarcinogenesis are found not only in the liver of rats but in the livers of other species as well. Mouse liver tumors induced by safrole (8) or o-aminoazotoluene (9) are GGT-positive. 'Spontaneous' carcinomas in the mouse do not show elevated levels of GGT (9). However, phenobarbital feeding induces GGT preferentially in the spontaneous mouse tumors compared with the surrounding liver tissue (10,11). Human hepatocellular carcinomas also show increased levels of GGT (12,13). Gerber and Thung (12) reported eight of the ten human hepatocellular carcinomas which they examined were GGT-positive. GGT which has been released from the cell membrane can be detected in the serum (14) and measurement of the level of GGT in the serum has become a common clinical test. Elevated levels of serum GGT are most often associated with liver or pancreatic disease (15). The presence of specific GGT isoenzymes in the serum has been suggested as a means of detecting hepatocellular carcinomas at an early stage (16). There have been several proposals as to the physiological role of GGT. Meister (17) has proposed that it plays a role in amino acid transport. Recent work has led several investigators to conclude that GGT acts primarily as a glutathionase (18). This commentary is a brief review of the bio-