Interactions between teratogens and genetic factors in the mechanismsof malformations in the offspring of epileptic mothers.

本项目的目的是评估抗癫痫药物（AED）和母亲及其后代遗传因素对先天性畸形发生的相对影响，并获得以下结果：1.确定了AED因素对癫痫母亲后代畸形发生的主导作用。 AED因素包括高药物剂量、高血清药物浓度、使用具有高致畸潜力的AED（扑米酮>丙戊酸>苯妥英>卡马西平>苯巴比妥）和AED多药治疗（特别是丙戊酸加卡马西平）。2.AED致畸机制仍在研究中，但推测AED的环氧化物中间体和其他有毒代谢物（例如， 4-en丙戊酸）与母体化合物本身一起参与。由药物遗传变异性以及药物间相互作用决定的代谢激活和解毒之间的平衡与致畸活性相关。 AEDs引起的叶酸缺乏和叶酸代谢受损可能会导致药物的致畸性。3.对于安全治疗的个体预测测试，需要建立停药标准和指示药物解毒途径缺陷的标志物。

The purpose of this project is to assess the relative contributions of antiepileptic drugs (AED) and genetic factors of mothers and their offspring to occurrence of congenital malformations, and the following results were obtained :1.The predominant contribution of AED factors to the occurrence of malformation in the offspring of epileptic mothers has been established. The AED factors include a high drug dose, a high serum drug concentration, the use of AEDs with a high potential for teratogenicity (primidone>valproate>phenytion>carbamazepine>phenobarbital) and AED polytherapy (especially valproate plus carbamazepine).2.The mechanisms of teratogenicity of AED is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AED (ex, 4-en valproate) together with maternal compound itself are invloved. The balance between metabolic activation and detoxification determined by pharmacogenetic variability as well as drug-drug interaction is the relevant to the teratogenic activity. Folate deficiency and impaired folate matabolism caused by AEDs may contribute to the teratogenicity of the drugs.3.For individual predictive testing for safe therapy, the establishment of criteria of the drug withdrawal and markers indicative of the defects in the drug detoxification pathway is needed.