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, using linolenic acid or linoleic acid, or microsomal membranes as substrates, and in situ in cultured human hepatoma cells. Mutagenicity of Salmonella and lipid peroxidation occurs in the presence of 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 H2O2. The effects of antioxidants and free radical scavengers on mutagenicity and lipid peroxidation induced by other sulfhydryls, such as D- and L-cysteine has been studied. The results suggest that these thiols are mutagenic via the same mechanisms as GSH, i.e., through the formation of H2O2. Preliminary studies have shown that 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.
