Preparation, toxicity and mutagenicity of 1-methyl-2-nitrosoimidazole. A toxic 2-nitroimidazole reduction product.
1-Methyl-2-nitrosoimidazole (INO), the 2-electron reduction product of 1-methyl-2-nitroimidazole (INO2), was prepared by electrochemical reduction of INO2 to 2-hydroxylamino-1-methyl-imidazole (INHOH), followed by back oxidation with iodine. Although stable in crystalline form, INO reacted in water, phosphate-buffered saline, and mammalian cell growth medium. Half-lives for decay were determined by UV-visible spectroscopy. INO was found to be highly toxic towards Chinese hamster ovary (CHO) cells, concentrations of 10-60 microM producing significant cytotoxicity. The rate of INO decay was found to be increased in the presence of CHO cells. INO was also toxic and mutagenic towards Salmonella typhimurium TA-100. When compared on a molar basis to the parent nitro compound INO2, and the 4- and 6-electron reduction products INHOH and 2-amino-1-methylimidazole (INH2), INO was by far (two orders of magnitude) the most toxic under aerobic conditions. These results suggest that the nitroso reduction product of 2-nitroimidazoles may be the reduced species responsible for hypoxic cell selective toxicity of 2-nitroimidazoles.
Noss
M B
MB
Physics Division, Ontario Cancer Institute, Toronto, Canada.
Panicucci
R
R
McClelland
R A
RA
Rauth
A M
AM
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D007093:Imidazoles / Q000138:chemical synthesis / Q000302:isolation & purification / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000302:isolation & purification / Q000633:toxicity*; D013057:Spectrum Analysis
D007093:Imidazoles; D009153:Mutagens; D009603:Nitroso Compounds; C056496:1-methyl-2-nitrosoimidazole