Thiol-mediated incorporation of radiolabel from 1-[14C]-methyl-4-phenyl-5-nitrosoimidazole into DNA. A model for the biological activity of 5-nitroimidazoles.
1-Methyl-4-phenyl-5-nitrosoimidazole (5NO), which has properties consistent with the biologically active form of a 5-nitroimidazole, was radiolabeled (1-[14C]-methyl) and shown to bind to DNA, but at a rate too slow to account for its bactericidal effect. In the presence of physiological intracellular concentrations of such thiols as glutathione, however, binding was enhanced by 2-3 orders of magnitude, which is quantitatively sufficient to account for the bactericidal effect of 5NO. That 5NO binding was greater for poly[d(G-C).d(G-C)] than for poly[d(A-T).d(A-T)] suggests that the reactive species binds to nucleophilic bases on DNA, a suggestion which is also supported by our finding of a thiol-dependent reaction to form an adduct between 5NO and aniline.
Ehlhardt
W J
WJ
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115.
Goldman
P
P
D010582:Bacteriophage lambda / Q000032:analysis; D002250:Carbon Radioisotopes / Q000032:analysis*; D003545:Cysteine / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D004269:DNA, Bacterial / Q000032:analysis* / Q000302:isolation & purification; D005978:Glutathione / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism*; D007553:Isotope Labeling; D008954:Models, Biological; D009593:Nitroimidazoles / Q000032:analysis* / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D011119:Polynucleotides / Q000032:analysis*; D013056:Spectrophotometry, Ultraviolet; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D002250:Carbon Radioisotopes; D004269:DNA, Bacterial; D007093:Imidazoles; D009593:Nitroimidazoles; D009603:Nitroso Compounds; D011119:Polynucleotides; D013438:Sulfhydryl Compounds; C059089:1-methyl-4-phenyl-5-nitrosoimidazole; D004247:DNA; D005978:Glutathione; D003545:Cysteine; C052587:4-nitroimidazole