title: Metformin's performance in in vitro and in vivo genetic toxicology studies.
abstract: Metformin is a hypoglycemiant drug prescribed for the treatment and control of the type 2 diabetes mellitus. Recently, the potential efficacy of this antidiabetic drug as an anticancer agent has been demonstrated in various mammalian cancer cells. This report evaluates the mutagenic as well as the recombinogenic potentials of the metformin drug in therapeutically relevant plasma concentrations (12.5 µM, 25.0 µM or 50.0 µM). Since the loss of heterozygosity is a process associated with carcinogenesis, the recombinogenic potential of such a drug was evaluated by the homozygotization assay using a heterozygous diploid strain of Aspergillus nidulans. The homozigotization indices (HI) for the genetic markers from the metformin-treated diploids were not statistically different from the negative control (non-treated diploids). For the first time, this indicated a lack of recombinogenic activity of the antidiabetic drug. The mutagenic potential of the metformin drug was evaluated by the chromosome aberrations and the micronuclei tests in human lymphocytes cultures. The metformin drug did not show any significant increase either in the numerical or in the structural chromosome aberrations and did not affect significantly the mitotic index when compared to the negative control. In the in vitro micronucleus test, the drug did not increase the number of micronuclei or nuclear buds when compared with the negative control. The data in this study suggest that the metformin drug is not a secondary cancer inducer, since it has neither showed recombinogenic nor mutagenic activities when used in pharmacological concentrations.
authors.affiliation: Laboratório de Genética de Microorganismos e Mutagênese, Departamento de Biotecnologia, Genética e Biologia Celular, Universidade Estadual de Maringá, 87020-900, Maringá, PR, Brazil.
authors.forename: Juliane R
authors.initials: JR
authors.lastname: Sant'Anna
authors.forename: Joana Paula R S
authors.initials: JP
authors.lastname: Yajima
authors.forename: Lúcia J
authors.initials: LJ
authors.lastname: Rosada
authors.forename: Claudinéia C S
authors.initials: CC
authors.lastname: Franco
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Prioli
authors.forename: Valter A
authors.initials: VA
authors.lastname: Della-Rosa
authors.forename: Paulo Cezar F
authors.initials: PC
authors.lastname: Mathias
authors.forename: Marialba A A
authors.initials: MA
authors.lastname: Castro-Prado
mesh_terms: D000328:Adult; D001233:Aspergillus nidulans / Q000166:cytology / Q000187:drug effects; D002842:Chromatids / Q000378:metabolism; D002869:Chromosome Aberrations / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects; D033481:Chromosomes, Mammalian / Q000378:metabolism; D004171:Diploidy; D005260:Female; D006238:Haploidy; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000633:toxicity*; D015162:Micronucleus Tests; D008940:Mitotic Index; D009153:Mutagens / Q000633:toxicity*; D055815:Young Adult
chemical_list: D009153:Mutagens; D008687:Metformin
keywords: Aspergillus nidulans; Genotoxicity; chromosome aberrations; homozygotization assay; micronucleus assay; mutagenicity