DNA damage induced by reduced nitroimidazole drugs.
Five nitroimidazole drugs were reduced electrolytically and by gamma-radiolysis at fast (300 mumoles or 100% per hr) and slow (3-9 mumoles or 1-3% per hr) reduction rates in the presence of Escherichia coli DNA and single stranded or double stranded DNA from the bacteriophage phi X174. The degree of DNA damage depends upon the rate of drug reduction, where slow reduction produces more damage than fast reduction. The efficiency of damage produced is in the order metronidazole greater than ornidazole greater than azomycin greater than misonidazole greater than benznidazole which reveals a linear correlation between the one-electron reduction potential (E17) and the negative logarithm of the concentration of reduced drug at which 37% of the original DNA activity remains. Damage is not influenced by the presence of O2 at least between about 1-100 ppm. We suggest the protonated one-electron nitro radical anion as a possible candidate for the active damaging species and explain the basis of the relative cytotoxicity of these drugs under conditions of hypoxia.
Zahoor
A
A
Department of Paramedical Sciences, North East London Polytechnic, Stratford, U.K.
Lafleur
M V
MV
Knight
R C
RC
Loman
H
H
Edwards
D I
DI
D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D009593:Nitroimidazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology
D005609:Free Radicals; D009593:Nitroimidazoles; D004247:DNA; D010100:Oxygen