Effect of nitroimidazoles on the oxygen consumption rate and respiratory control ratio of beef heart mitochondria

The neurotoxic effect of the nitroimidazole radiosensitizers misonidazole (MISO) and desmethylmisonidazole (DMM) has seriously compromised their clinical effectiveness. The authors compare here the effect of MISO and DMM on oxygen consumption in purified beef heart mitochondria. MISO has been found to significantly increase the oxygen consumption rate and decrease the respiratory control ratio in isolated mitochondria when incubated in the presence of the NAD+ dependent substrate, β-hydroxybutyrate. DMM has a similar but less pronounced effect than MISO on these respiratory parameters. When mitochondria were incubated in the presence of these radiosensitizers for 8, 15, 30, 45, and 60 minutes, the oxygen consumption rate was decreased when succinate, a FAD dependent substrate, was added following the incubation. This decrease, which is both time and dosage dependent, is equivalent for MISO and DMM