title: 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.
abstract: BACKGROUND
  The 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).
  
  
  METHODS
  Differences 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.
  
  
  RESULTS
  At concentrations >800 μg/mL MET had a greater cytotoxic effect on D3 cells than 3T3 fibroblasts. At the highest concentration of MET (5 mg/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 50-200 μg/mL MET, and there was no significant difference in EB differentiation area until a concentration of 400 μg/mL MET. At a concentration of 800 μg/mL MET, the size of EB outgrowth was significantly reduced. The same assays revealed GLIM, RSG, and NIM to be weakly embryotoxic substances.
  
  
  CONCLUSIONS
  Based 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.
authors.affiliation: Shenyang Pharmaceutical University, Shenyang, China.|Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.|Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.|Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Chai
authors.affiliation: Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Shen
authors.affiliation: Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.
authors.forename: Zongpeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shenyang Pharmaceutical University, Shenyang, China.|State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000927:Anticonvulsants / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008687:Metformin / Q000633:toxicity*; D051379:Mice; D010406:Penicillins / Q000633:toxicity; D010672:Phenytoin / Q000633:toxicity; D018570:Risk Assessment; D000077154:Rosiglitazone; D013449:Sulfonamides / Q000633:toxicity; D013453:Sulfonylurea Compounds / Q000633:toxicity; D045162:Thiazolidinediones / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D007004:Hypoglycemic Agents; D010406:Penicillins; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010672:Phenytoin; C057619:glimepiride; D008687:Metformin; D005472:Fluorouracil; C012655:nimesulide
keywords: cytotoxicity; embryonic stem cell test; embryotoxicity; hypoglycemic drugs; metformin; 关键词：细胞毒性，胚胎干细胞试验，胚胎毒性，降糖药，二甲双胍