Evaluation of the genotoxic activity of metronidazole and dimetridazole in human lymphocytes by the comet assay.
The genotoxicity of metronidazole (MZ) and dimetridazole (DZ) has been evaluated in human lymphocytes using the comet assay. The test has been performed using 3 doses (58.4, 175.2 and 292.1 microM for MZ; and 70.9, 212.6 and 354.3 microM for DZ) under 3 experimental protocols: aerobiosis, anaerobiosis (90% N2, 10% CO2) and with the presence of the microsomal fraction S9 mix. The effects of 4 antioxidants (8-hydroxyquinoline (8HQ), vitamin C (VitC), catalase (CAT) and superoxide dismutase (SOD), have been investigated on DNA damage generated by fixed concentrations of MZ (292.1 microM) and DZ (354.4 microM). In aerobic conditions, MZ and DZ produced significant dose-response relationships. The dose-related effects of both drugs decreased or were abolished in anaerobic conditions or in presence of S9 mix. 8HQ, VitC, CAT and SOD induced dose-related protective responses against DNA damage due to MZ and DZ. These findings suggest that MZ and DZ induce DNA damage in human lymphocytes through the futile cycle. The one-electron reduction of the drugs leads to the production of nitro radical anions. In the presence of oxygen, these radicals are reoxidized and generate oxygen-activated species.
Ré
J L
JL
Laboratoire de Biogénotoxicologie et Mutagénèse Environnementale (EA 1784), Faculté de Pharmacie, Marseille, France.
De Méo
M P
MP
Laget
M
M
Guiraud
H
H
Castegnaro
M
M
Vanelle
P
P
Duménil
G
G
D000818:Animals; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004131:Dimetridazole / Q000494:pharmacology*; D004587:Electrophoresis, Agar Gel / Q000379:methods; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
D009153:Mutagens; D008795:Metronidazole; D013482:Superoxide Dismutase; D004131:Dimetridazole