The formation of hydrogen peroxide (H2O2) and free radicals from glutathione (GSH) is dependent on the activity of g-glutamyltranspeptidase (GGT), an enzyme that is frequently present at high levels in preneoplastic cells. GSH, in the presence of GGT, can induce lipid peroxidation in vitro, and in situ in cultured human hepatoma cells. Mutagenicity of Salmonella and lipid peroxidation occurs at physiological concentrations of GSH, iron and copper, and endogenous chelators, such as citrate, ADP, transferrin, and ceruloplasmin. Unlike the mutagenic effect of GSH which is mediated through the formation of H2O2, lipid peroxidation appears to be effected through a free radical reaction, without the intermediate formation of H2O 2. The effects of antioxidants and free radical scavengers on mutagenicity and lipid peroxidation induced by other sulfhydryls, such as D- and L-cysteine have been studied. The results suggest that these thiols are mutagenic via the same mechanisms as GSH, i.e., through the formation of H2O2. Lipid peroxidation can be induced in GGT-rich preneoplastic foci in rodents when challenged with GSH. Histochemical studies show that areas of lipid peroxidation are contiguous with GGT-rich preneoplastic foci in the livers of rats treated with the carcinogen diethylnitrosamine, and a promoter of liver carcinogenesis. The laboratory portions of these studies have been terminated. Efforts are concentrated on the analyses of the data and preparation of publications describing the results.
