Comparison of the sensitivity of human and rat hepatocytes to the genotoxic effects of metronidazole.
Metronidazole (MNZ), an antiprotozoan and antibacterial agent, has been shown to yield DNA-damaging reactive species after nitroreductive biotransformation. The genotoxic effect of MNZ was studied in primary cultures of both rat and human hepatocytes. In millimolar concentrations MNZ produced DNA fragmentation, as measured by the alkaline elution technique, and unscheduled DNA synthesis, as evaluated by quantitative autoradiography, in rat hepatocytes. The amount of DNA damage was directly related to the dose and the length of exposure, was increased by hypoxia and GSH depletion, and was markedly reduced by inhibition of cytochrome P-450 activity. In the same experimental conditions human hepatocytes resulted constantly more resistant than rat hepatocytes to the genotoxic activity of MNZ. These findings suggest that the rat hepatocyte model might be an inappropriate predictor of nitroimidazoles genotoxicity.
Martelli
A
A
Institute of Pharmacology, University of Genova, Italy.
Allavena
A
A
Robbiano
L
L
Mattioli
F
F
Brambilla
G
G
D000328:Adult; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008795:Metronidazole / Q000633:toxicity*; D008875:Middle Aged; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D009153:Mutagens; D013438:Sulfhydryl Compounds; D008795:Metronidazole; D005978:Glutathione