Role of P53 functionality in the genotoxicity of metronidazole and its hydroxy metabolite.
P53 mediates several biological processes for preservation of genetic stability such as the induction of cell cycle arrest, DNA repair or apoptosis in response to DNA damage. The antiparasitic drug, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (metronidazole, MTZ) is able to increase lymphocyte proliferation inducing at the same time chromosomal aberrations. Trying to understand this unexpected event we used cell lines with different P53 functionality, determining the proliferation capacity and the induction of micronuclei (MN) after the treatment with MTZ or its hydroxy metabolite. Our results show that MTZ increased proliferation in a dose response manner in all P53 functional cell lines without inducing changes on the levels of P53 nor MN. However, MTZ hydroxy metabolite induced a dose response increase of P53 and MN, while cell proliferation was not increased. Several studies have shown that the hydroxy metabolite is more potent than MTZ itself. Only in cell lines that do not have a functional P53, MTZ and its metabolite increased both cell proliferation and MN. MTZ use is increasing and its carcinogenicity has not been discarded. Our data indicate that MTZ hydroxy metabolite is potentially a carcinogen and needs to be further studied.
Menéndez
D
D
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Bendesky
A
A
Rojas
E
E
Salamanca
F
F
Ostrosky-Wegman
P
P
D000890:Anti-Infective Agents / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008795:Metronidazole / Q000378:metabolism / Q000633:toxicity*; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D010084:Oxidation-Reduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000890:Anti-Infective Agents; D016159:Tumor Suppressor Protein p53; D008795:Metronidazole