title: Cytogenetic study of metronidazole and three metronidazole analogues in cultured human lymphocytes with and without metabolic activation.
abstract: Metronidazole (MTZ) and other nitroimidazole derivatives have been extensively used to treat infections caused by protozoa and anaerobic bacteria. However, the need for new derivatives with similar therapeutic activity but lower toxicity to human beings prevails. On this purpose, three metronidazole analogues were synthesized, namely: 1-(p-methylphenacyl)-2-methyl-4-nitro imidazole (CPMe), 1-(p-methoxyphenacyl)-2-methyl-4-nitroimidazole (CPMeO), and 1-(p-fluorphenacyl)-2-methyl-4-nitroimidazole (CPF), which at low concentrations (0.5-2 microg/ml) showed a higher activity against Entamoeba histolytica than MTZ (3-6 microg/ml). The aim of this work was to investigate the cytogenetic effect of the three MTZ analogues on human lymphocyte cultures with and without metabolic activation in vitro, using the sister chromatid exchange test (SCE), comparatively with MTZ. The effect of the compounds on the cell proliferation kinetics (CPK) measured by the replication index (RI) and the cytotoxic effect in the mitotic index (MI) was evaluated as well. The SCE frequencies with and without S9 metabolic activation in treated and control lymphocytes showed no significant statistical differences. However when metabolic activation was involved a significant increase in the amount of third division metaphases provoked the CPK increased significantly with all the tested compounds. The RI showed similar behaviour, except for compound CPF.
authors.affiliation: Laboratorio de Citogenética Ambiental, Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán 04510 DF Mexico.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gómez-Arroyo
authors.forename: Sara
authors.initials: S
authors.lastname: Melchor-Castro
authors.forename: Rafael
authors.initials: R
authors.lastname: Villalobos-Pietrini
authors.forename: Estela Meléndez
authors.initials: EM
authors.lastname: Camargo
authors.forename: Héctor
authors.initials: H
authors.lastname: Salgado-Zamora
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Campos Aldrete
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020732:Cytogenetic Analysis; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000633:toxicity*; D008940:Mitotic Index; D012854:Sister Chromatid Exchange
chemical_list: C500177:1-(p-fluorphenacyl)-2-methyl-4-nitroimidazole; C500178:1-(p-methoxyphenacyl)-2-methyl-4-nitroimidazole; C500176:1-(p-methylphenacyl)-2-methyl-4-nitro imidazole; D000890:Anti-Infective Agents; D008795:Metronidazole