Correlation between metabolic reduction rates and electron affinity of nitroheterocycles.
Nitroheterocyclic compounds can selectively sensitize hypoxic (tumor) cells to radiation damage in vitro. However, results in vivo have generally been less optimistic, inasmuch as metabolic reduction of these drugs not only limits effective lifetime but also produces metabolic intermediates with marked cytotoxic and carcinogenic activity. With three reducing systems in vitro, E. coli B/r, mouse L-929 cells, and mouse liver microsomes, the rate of nitroreduction of several nitroheterocycles was found to be proportional to their electron affinity (half-wave reduction potential). Relative to the rate of nitrofurazone reduction in each system, metronidazole (Flagyl), N-hydroxyethyl-3,5-dinitropyrrole, misonidazole, nifuroxime, nitrofurantoin, and furylfuramide were metabolized about 200, 20, 2, 1.4, and 1.2 times less rapidly, while 3,5-dinitrobenzonitrile, 2,5-dinitrophenol, and 5-nitro-2-furaldehyde diacetate were reduced 2, 3, and 4 times more rapidly. Since nitroreduction has previously been correlated with subsequent cytotoxicity, DNA damage, and mutagenicity, the present results suggest that improvements in the therapeutic efficacy of nitroheterocycles (i.e., sensitization without toxicity and carcinogenicity) will be dependent on development of drugs with more appropriate pharmacological properties.
D000818:Animals; D004583:Electrons; D004926:Escherichia coli / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism*; D066298:In Vitro Techniques; D007739:L Cells / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism*; D010084:Oxidation-Reduction; D011838:Radiation-Sensitizing Agents / Q000378:metabolism
D006571:Heterocyclic Compounds; D009574:Nitro Compounds; D011838:Radiation-Sensitizing Agents