The interaction of reduced metronidazole with DNA bases and nucleosides

The electrochemical behavior of the 1-electron couple for the bioreductive drug metronidazole has been examined in the presence and absence of the biological target molecules, DNA bases, and nucleosides, including uracil and uridine. Using cyclic voltammetry as the investigation technique, the change in return-to-forward peak current ratio, ipr/ipf, from the control, recorded in the absence of target, was measured as a function of scan rate and biological target concentration. All target molecules, except adenosine and guanine, resulted in interaction with RNO2.-, as measured by the decrease in the ipr/ipf ratio in the following order of increasing reactivity: adenine, guanosine, thymine, uracil, uridine, and thymidine (at a metronidazole:target ratio of 1:1). No decrease in ipr/ipf was observed with cytosine or cytidine until ratios of 1:20 and 1:30, respectively, were attained. An approximately linear relationship was found between the percentage change in the CV response and log[target] allowing us to determine the sensitivity of RNO2.- to the concentration of the target species. The implication for the biological action of metronidazole and other nitro-heterocyclic drugs is discussed.