Enzymes of glutathione metabolism as biochemical markers during hepatocarcinogenesis.

Enzymes of glutathione metabolism, particularly gamma-glutamyltransferase (GGT) and glutathione S-transferase (GST), play a role in multistage hepatocarcinogenesis. The enhanced expression of these enzymes in preneoplastic altered hepatic foci, nodules, and hepatocellular carcinomas has been demonstrated after treatment with a variety of initiating and promoting agents. Glutathione is necessary for the detoxification of xenobiotics and carcinogens and for cell replication. Induction of GGT in altered hepatocytes may permit these cells to utilize extracellular glutathione to preserve their internal glutathione levels. GST induction allows glutathione utilization for the protection of the altered hepatocyte in an environment of exposure to xenobiotics, such as promoting agents. Thus, the combined effects of GGT and GST, in a toxic environment, may provide for the enhanced proliferation observed in preneoplastic hepatocytes. New clinical and research opportunities may involve the use of GGT and the placental isozyme of GST (PGST) as markers of preneoplasia and neoplasia in humans. Many factors, such as hormones, diet, and exposure to initiating and promoting agents, influence GGT and GST expression. The recent cloning of cDNAs to GGT and PGST offers opportunities for the study of factors involved in the genetic expression of these two enzymes. Coupled with the use of hepatocyte culture and transplantation, the factors involved at the molecular level in the creation of hepatocellular neoplasia may be discovered.