Depletion of intracellular glutathione by 1-methyl-2-nitrosoimidazole.
In addition to their ability to radiosensitize, nitroimidazoles are selectively toxic toward hypoxic cells. Reduction of the nitro group is required to observe cytotoxicity. One of the reduction products believed to play a role in this cytotoxicity is the nitroso-derivative. One-methyl-2-nitrosoimidazole (INO), chemically synthesized from one-methyl-2-nitroimidazole (INO2), has been used as a model to study the reactivity of 2-nitrosoimidazoles. The ability of INO to react rapidly with glutathione in Chinese hamster ovary cells treated with a sub-toxic and toxic level of the drug has been measured. The kinetics of GSH loss as well as oxidized GSH (GSSG) formation and loss were assessed at short times (0-15 min) after INO exposure using a high pressure liquid chromatography (HPLC) assay for GSH and GSSG. The results obtained were consistent with a model, based on previous chemical studies of the reaction of INO with GSH, whereby GSH reduces INO forming GSSG and as well reacts with a reduced form of INO to form an adduct (I-SG). These results suggest possible strategies for modifying the toxicity of reduction products of one-substituted-2-nitroimidazoles.
Bérubé
L R
LR
Ontario Cancer Institute, Toronto, Canada.
Farah
S
S
McClelland
R A
RA
Rauth
A M
AM
D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; 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