Mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) when activated by hamster pancreatic duct epithelial cells: A chemopreventive role for glutathione

We have shown a role for glutathione (GSH) in the detoxification of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using mutagenicity in V79 cells as the end-point. Immortalized hamster pancreas duct epithelial cells (CK cells) were used to metabolize PhIP in this assay. Intracellular GSH concentrations were lowered by treatment with buthionine sulfoximine (BSO) and were raised by treatment with sodium sulfite. BSO treatment (10 mM, 4 h) reduced the GSH concentration in V79 cells from 18 ± 1 to 6 ± 1 nmol/mg protein, 4 h after treatment. The mutation frequency of PhIP in these V79 cells rose from 15 ± 2 to 34 ± 4 mutants/10⁶ survivors in BSO-treated V79 cells. In a related experiment both CK and V79 cells were treated with sulfite. Sulfite treatment (2 mM, 4 h) produced a greater reduction in PhIP mutagenicity when the V79 cells were treated with sulfite (from 15 ± 2 to 3 ± 1 mutants/10⁶ survivors) than when the CK cells were treated (from 15 ± 2 to 7 ± 2 mutants/10⁶ survivors). These data show a relationship between intracellular GSH concentration and the mutagenicity of PhIP.