Li Li, Zhang Xing, Wang Lei, Chai Zhenhai, Shen Xiuping, Zhang Zongpeng, Liu Changxiao
Shenyang Pharmaceutical University, Shenyang, China.
Tianjin Center for Drug Safety Assessment and Research, Tianjin, China.
J Diabetes. 2015 Nov;7(6):839-49. doi: 10.1111/1753-0407.12251. Epub 2015 Mar 4.
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).
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.
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.
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.
药物在孕妇及其胚胎和后代中的安全使用至关重要。本研究的目的是在胚胎干细胞试验（EST）中评估二甲双胍（MET）与其他降糖药物（罗格列酮[RSG]和格列美脲[GLIM]）、抗癌药物5-氟尿嘧啶（5-FU）、抗癫痫药物苯妥英（DPH）、抗生素青霉素G（PenG）以及环氧化酶（COX）-2抑制剂尼美舒利（NIM）相比的胚胎毒性。
在分化过程中（从胚胎干细胞D3（D3细胞）到心肌细胞）用受试化合物处理后，使用实时定量聚合酶链反应测定发育标记基因表达的差异。在这些研究中，5-FU用作阳性对照，PenG用作阴性对照。通过3-（4,5-二甲基-2-噻唑基）-2,5-二苯基-2H-四氮唑溴盐（MTT）试验测定这些药物对D3细胞和3T3成纤维细胞的细胞毒性。根据EST的预测模型对胚胎毒性进行分类。
在浓度>800μg/mL时，MET对D3细胞的细胞毒性比对3T3成纤维细胞更大。在MET的最高浓度（5mg/mL）下，D3细胞和3T3成纤维细胞的细胞活力分别<10%和>30%。在50-200μg/mL MET浓度范围内，胚体（EB）分化区域的大小几乎相同，直到MET浓度达到400μg/mL时，EB分化区域才出现显著差异。在800μg/mL MET浓度下，EB生长的大小显著减小。相同的试验表明GLIM、RSG和NIM为弱胚胎毒性物质。
基于EST，MET可被归类为弱胚胎毒性物质，这表明对于患有妊娠期糖尿病的孕妇应谨慎开具该药物。
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