A toxicology study to evaluate the embryotoxicity of metformin compared with the hypoglycemic drugs, the anticancer drug, the anti-epileptic drug, the antibiotic, and the cyclo-oxygenase (COX)-2 inhibitor

作者：Li, Li; Zhang, Xing; Wang, Lei; Chai, Zhenhai; Shen, Xiuping; Zhang, Zongpeng; Liu, Changxiao^*

来源：Journal of Diabetes, 2015, 7(6): 839-849.

DOI：10.1111/1753-0407.12251

• cytotoxicity
• embryonic stem cell test
• embryotoxicity
• hypoglycemic drugs
• metformin

BackgroundThe safe use of medications in pregnant females, their embryos and in offspring is important. The aim of the present study was to evaluate embryotoxicity of metformin (MET) compared with other hypoglycemic drugs (rosiglitazone [RSG] and glimepiride [GLIM]), the anticancer drug 5-fluorouracil (5-FU), the anti-epileptic drug diphenylhydantoin (DPH), the antibiotic penicillin G (PenG), and the cyclo-oxygenase (COX)-2 inhibitor nimesulide (NIM) in an embryonic stem cell test (EST).
MethodsDifferences in the expression of developmental marker genes following treatment with the test compounds during the course of differentiation (from embryonic stem cell D3 (D3 cells) to myocardial cells) were determined using real-time quantitative polymerase chain reaction. In these studies, 5-FU was used as a positive control and PenG was used as a negative control. The cytotoxicity of these drugs against D3 cells and 3T3 fibroblasts was determined by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Embryotoxicity was classified according to the prediction model of EST.
ResultsAt concentrations >800g/mL MET had a greater cytotoxic effect on D3 cells than 3T3 fibroblasts. At the highest concentration of MET (5mg/mL), the cell viability of D3 cells and 3T3 fibroblasts was <10% and >30%, respectively. The size of the embryonic body (EB) differentiation area was almost the same over the concentration range 50-200g/mL MET, and there was no significant difference in EB differentiation area until a concentration of 400g/mL MET. At a concentration of 800g/mL MET, the size of EB outgrowth was significantly reduced. The same assays revealed GLIM, RSG, and NIM to be weakly embryotoxic substances.
ConclusionsBased on the EST, MET can be classified as a weakly embryotoxic substance, which suggests that it should be prescribed with caution to pregnant women with gestational diabetes.

• 出版日期2015-11
• 单位天津药物研究院有限公司; 沈阳药科大学; 天津中医药大学