REINVESTIGATION OF IN-VIVO GENOTOXICITY STUDIES IN MAN - I - NO INDUCTION OF DNA STRAND BREAKS IN PERIPHERAL LYMPHOCYTES AFTER METRONIDAZOLE THERAPY

Although a rodent carcinogen, metronidazole is widely used in humans f or the treatment of infections with anaerobic organisms. Metronidazole is mutagenic for microorganisms, but has a mainly negative data base for mammals and humans. Therefore, metronidazole is generally consider ed as a non-genotoxic carcinogen. Only the results of two human in viv o studies would allow the classification of metronidazole as genotoxic carcinogen: (1) the induction of DNA strand breaks; and (2) the induc tion of chromosome aberrations in peripheral lymphocytes after metroni dazole therapy. Because the classification of metronidazole as genotox ic carcinogen would imply enormous consequences with respect to its ap plication, both studies were reinvestigated very thoroughly. The prese nt report describes the reinvestigation of the induction of DNA strand breaks after metronidazole therapy. Each two probes of lymphocytes of metronidazole-treated patients (3 x 500 to 3 x 750 mg/day for 5-8 day s) were examined separately for the appearance of DNA strand breaks be fore and after treatment. In total, 400 nuclei were examined per patie nt. Immediately before the first, and 30 min to 2 h after the last app lication, 2 x 10 ml blood per patient was sampled, transported to the laboratory at 15-20 degrees C to make DNA repair more difficult, and e xamined within the next 4-7 h for DNA strand breaks. At the same time, the individual metronidazole blood plasma levels were measured. In co ntrast to the published reports, no induction of DNA strand breaks aft er metronidazole therapy could be observed in the present study. As th e applied doses (15 750 mg vs. 4800 mg) and the plasma level (up to 25 mu g/ml vs, not measured) of metronidazole were much higher than in t he published study, the relevance of the clearly negative result is ob vious. As induction of DNA strand breaks is a frequent prerequisite fo r genotoxicity, metronidazole should be considered as a non-genotoxic carcinogen, and not as a genotoxic carcinogen. (C) 1997 Elsevier Scien ce B.V.