title: Assessment of genomic instability in normal and diabetic rats treated with metformin.
abstract: To examine if a single or multiple oral administration of metformin, a member of the biguanide class of anti-diabetic agents, has any genotoxic and cytotoxic potential in normal and diabetic rats, a mammalian model, cytogenetic assays through several endpoints such as induction of micronuclei, chromosome aberrations, mitotic activity of bone marrow cells, sperm-head anomaly and assays of some oxidative stress markers have been conducted by the use of standard techniques. Diabetes was induced by streptozotocin injection. Metformin was administrated to both diabetic and non-diabetic rats in single doses of 100, 500 or 2500 mg/kg along with vehicle control groups for diabetic and non-diabetic rats. The animals were killed by cervical dislocation at 24h after treatment, and then bone marrow cells were sampled. Also, a multiple dose study has done in which diabetic and non-diabetic animals were treated with 100 or 500 mg/kg of metformin daily for 4 or 8 weeks after which the animals were killed by cervical dislocation, and then bone marrow and sperm cells were collected. Concurrent control groups were also included in each experiment. The obtained results revealed that metformin was neither genotoxic nor cytotoxic for the rats in all groups at all tested doses. Moreover, metformin significantly reduced the diabetes-induced genomic instability and cell proliferation changes in somatic and germinal cells in a dose-dependent manner (2500, 500, >100mg/kg). In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including, enhanced lipid peroxidation and reduction in the reduced glutathione level. Treatment with metformin ameliorated these biochemical markers. In conclusion, metformin is a non-genotoxic or cytotoxic compound and may protect from genomic instability induced by hyperglycemia. Apart from its well-known anti-diabetic effect, the antigenotoxic effect of metformin could be possibly ascribed to its radical scavenger effect that modulated the genomic instability responses and cell proliferation changes induced by hyperglycemia.
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. attiasm@yahoo.com
authors.forename: S M
authors.initials: SM
authors.lastname: Attia
authors.forename: G K
authors.initials: GK
authors.lastname: Helal
authors.forename: A A
authors.initials: AA
authors.lastname: Alhaider
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D004334:Drug Administration Schedule; D042822:Genomic Instability / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D008938:Mitosis / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D008687:Metformin; D005978:Glutathione