1-Methyl-2-nitrosoimidazole: cytotoxic and glutathione depleting capabilities.
We tested 1-methyl-2-nitrosoimidazole (INO), the two electron reduction product of 1-methyl-2-nitroimidazole (INO2) for its in vitro cytotoxicity and glutathione (GSH) depleting capabilities. The half life of INO was shown to be dependent on cell concentration above 10(5) cells/ml, decreasing with increasing cell concentration up to 2 X 10(6) cells/ml. For a 10-fold decrease in cell concentration, from 10(6) to 10(5) cells/ml, the toxicity curve shifted 10-fold towards lower concentrations. At 10(6) cells/ml, INO depleted GSH, in the range of concentrations where toxicity was observed, down to a plateau of 15% of the control level at a concentration of 100 microM INO. Oxidized glutathione (GSSG) levels were not elevated significantly above control cultures at this concentration. INO2, 1000 microM, did not deplete GSH under similar exposure conditions while 2-hydroxylamino-1-methylimidazole (INHOH) depleted GSH minimally at this same concentration. The nitroso intermediate may play a central role in the toxicity and GSH depleting capabilities of 2-nitroimidazoles in mammalian cells.
Noss
M B
MB
Ontario Cancer Institute, University of Toronto, Canada.
Panicucci
R
R
McClelland
R A
RA
Rauth
A M
AM
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*
D007093:Imidazoles; D009603:Nitroso Compounds; C056496:1-methyl-2-nitrosoimidazole; D005978:Glutathione