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/10(6) 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/10(6) survivors) than when the CK cells were treated (from 15 +/- 2 to 7 +/- 2 mutants/10(6) survivors). These data show a relationship between intracellular GSH concentration and the mutagenicity of PhIP.
Lawson
T
T
Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Kolar
C
C
Reyes
T
T
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity; D010183:Pancreatic Ducts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013447:Sulfites / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009153:Mutagens; D013447:Sulfites; D019328:Buthionine Sulfoximine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D005978:Glutathione; C025026:sodium sulfite