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 mutagenicit y in V79 cells as the end-point. Immortalized hamster pancreas duct ep ithelial cells (CK cells) were used to metabolize PhIP in this assay. Intracellular GSH concentrations were lowered by treatment with buthio nine sulfoximine (BSO) and were raised by treatment with sodium sulfit e. BSO treatment (10 mM, 4 h) reduced the GSH concentration in V79 cel ls 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/10(6) survivors in BSO-treated V79 cells. In a related experiment both CK and V79 cells were treated with sulfite. Sulfite tr eatment (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/10(6) survivors) than when the CK cells were treated (from 15 +/- 2 to 7 +/- 2 mutants/10(6) survivors). These data show a relation ship between intracellular GSH concentration and the mutagenicity of P hIP.