Glutathione Alleviates the Influence of N-Nitrosamines on the Activity of Carcinogen-Metabolizing Enzymes in the Liver of Male Mice

Most xenobiotics and carcinogens are metabolized primarily by the hepatic drug-metabolizing enzymes including cytochrome P450, cytochrome b5, arylhydrocarbon hydroxylase (AHH), and dimethylnitrosamine N-demethylase I (DMN-dI) as phase I drug-metabolizing enzymes. Therefore, changes in the activities of the above mentioned enzymes as well as free radical levels measured as thiobarbituric acid reactive substances [TBARS] were determined in the livers of sixty mice pretreated with glutathione [100 mg/kg], as antioxidant, before intraperitoneal administration of dimethylnitrosamine [DMN] [10 mg/kg], diethylnitosamine [DEN] [10 mg/kg], or methylpropylnitrosamine [MPN] [10 mg/kg] for seven consecutive days. Ten control animals received distilled water as vehicle for comparison with treated animals. The hepatic content of cytochrome P450 induced after treatment of mice with DMN, DEN and MPN while DMN, DEN, or MPN increased AHH activity. Also, cytochrome b5 content and DMN-N-dI induced after treatment with DMN or DEN. Interestingly, glutathione pretreatment restored the activities of the previously mentioned enzymes caused by DMN or DEN. On the other hand, DMN, DEN, and MPN depleted the levels of glutathione, and increased the levels of free radicals [TBARS]. DMN and DEN increased the activity of GST. Interestingly, pretreatment of mice with glutathione before administration of DMN, or DEN was found to restore the levels of TBARS and GSH to their normal levels. In addition, GSH pretreatments induced the activity of GST above the normal levels after administration of DMN or MPN except DEN did not change such activity. It was concluded that N-nitrosamines enhanced the activity of phase I & II carcinogen-metabolizing enzymes as well as increased the production of free radicals. The mechanism by which GSH restores the activity of carcinogen-metabolizing enzymes or free radical production to their normal levels is possibly due to induction of GST activity and/or a direct binding to the xenobiotic molecules.