Mammalian cell toxicity and bacterial mutagenicity of nitrosoimidazoles.
It is currently believed that the biological activity of such therapeutic 5-nitroimidazoles as metronidazole is mediated by a short-lived, highly toxic species that arises from nitro group reduction. We found that the 5-nitroimidazole, 1-methyl-4-phenyl-5-nitroimidazole (5-NO2), is at least 1000-fold less cytotoxic for CHO cells and mutagenic for Ames tester strain TA100 than its homologous nitroso compound, 1-methyl-4-phenyl-5-nitrosoimidazole (5-NO). Such evidence, along with previous work showing a similar relative bactericidal potency of these compounds, is consistent with the labile nitrosoimidazole being a biologically active species of the nitroimidazole, and indicates that mammalian cells are very susceptible to such an active form. The high potency of both 5-NO and 1-methyl-4-nitroso-5-phenylimidazole (4-NO), in contrast to the lack of potency of 1-methyl-4-nitro-5-phenylimidazole (4-NO2) relative to 5-NO2, is additional evidence to support the suggestion that the activity of a nitroimidazole is determined mainly by the ease with which it is reduced.
Ehlhardt
W J
WJ
Department of Nutrition, Harvard School of Public Health, Boston, MA.
Beaulieu
B B
BB
Goldman
P
P
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D009593:Nitroimidazoles / Q000633:toxicity*; D009603:Nitroso Compounds / Q000633:toxicity; D013329:Structure-Activity Relationship
D009593:Nitroimidazoles; D009603:Nitroso Compounds