Abstract
Metformin (dimethyl-biguanide) is an insulin-sensitizing agent that lowers fasting plasma-insulin concentration, wherefore it's wide use for patients with a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance. During pregnancy it is a further resource for reducing first-trimester pregnancy loss in women with the polycystic ovary syndrome. We tested metformin genotoxicity in cells of Chinese hamster ovary, CHO-K1 (chromosome aberrations; comet assays) and in mice (micronucleus assays). Concentrations of 114.4 μg/mL and 572 μg/mL were used in in vitro tests, and 95.4 mg/kg, 190.8 mg/kg and 333.9 mg/kg in assaying. Although the in vitro tests revealed no chromosome aberrations in metaphase cells, DNA damage was detected by comet assaying after 24 h of incubation at both concentrations. The frequency of DNA damage was higher at concentrations of 114.4 μg/mL. Furthermore, although mortality was not observed in in vitro tests, the highest dose of metformin suppressed bone marrow cells. However, no statistically significant differences were noted in micronuclei frequencies between treatments. In vitro results indicate that chronic metformin exposure may be potentially genotoxic. Thus, pregnant woman undergoing treatment with metformin should be properly evaluated beforehand, as regards vulnerability to DNA damage.
Highlights
Metformin is an insulin-sensitizing agent that lowers fasting plasma insulin concentrations by increasing the peripheral uptake of glucose and decreasing hepatic glucose output (Nisbet et al, 2004). It is prescribed for patients suffering from a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance, obesity (Tankova et al, 2003; Rotella et al, 2006; Hirsch et al, 2009) and metabolic abnormalities associated with HIV disease (Hadigan et al, 2000; Johnson et al, 2005; Diehl et al, 2008)
The toxicity of metformin is well-known in cases of metabolic impairment due to liver and kidney diseases, its toxicity, by being mainly associated with lactic acidosis, Send correspondence to João Paulo Figueiró Longo
Metformin was shown to induce DNA damage in CHO-K1 cells. This in vitro genotoxicity was not noted in chromosome aberrations and in vivo tests
Summary
Metformin (dimethyl-biguanide) is an insulin-sensitizing agent that lowers fasting plasma insulin concentrations by increasing the peripheral uptake of glucose and decreasing hepatic glucose output (Nisbet et al, 2004). It is prescribed for patients suffering from a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance, obesity (Tankova et al, 2003; Rotella et al, 2006; Hirsch et al, 2009) and metabolic abnormalities associated with HIV disease (Hadigan et al, 2000; Johnson et al, 2005; Diehl et al, 2008). Anedda et al, (2008) showed that metformin induces oxidative stress in white adipocytes, by|through increasing the levels of reactive oxygen species, and reducing aconitase activity
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