TY - JOUR
T1 - Cytogenetic study of metronidazole and three metronidazole analogues in cultured human lymphocytes with and without metabolic activation
AU - Gómez-Arroyo, Sandra
AU - Melchor-Castro, Sara
AU - Villalobos-Pietrini, Rafael
AU - Camargo, Estela Meléndez
AU - Salgado-Zamora, Héctor
AU - Campos Aldrete, Ma Elena
PY - 2004/6
Y1 - 2004/6
N2 - 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 μg/ml) showed a higher activity against Entamoeba histolytica than MTZ (3-6 μg/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.
AB - 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 μg/ml) showed a higher activity against Entamoeba histolytica than MTZ (3-6 μg/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.
KW - ANOVA
KW - Analysis of variance
KW - BrdU
KW - Bromodeoxyuridine
KW - CPK
KW - Cell proliferation kinetics
KW - Metronidazole
KW - Nitroimidazole derivatives
KW - Replication index and mitotic index
KW - SCE
KW - Sister chromatid exchange
KW - Sister chromatid exchange test;
UR - http://www.scopus.com/inward/record.url?scp=1642303816&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2003.09.006
DO - 10.1016/j.tiv.2003.09.006
M3 - Artículo
C2 - 15046779
SN - 0887-2333
VL - 18
SP - 319
EP - 324
JO - Toxicology in Vitro
JF - Toxicology in Vitro
IS - 3
ER -