Pippenger C E
Department of Biomedical and Health Sciences, Grand Valley State University, Allendale, Michigan, USA.
Epilepsia. 2003;44 Suppl 3:24-32. doi: 10.1046/j.1528-1157.44.s3.3.x.
The pharmacology of neural tube defects (NTDs) is a complex issue. Several theories regarding the etiology of NTDs emphasize the importance of interactions between genetic, environmental, and biochemical factors at a key point in time. One such factor is chronic drug therapy, a potential consequence of which is the formation of toxic drug metabolites, including free radicals (FRs), which have been implicated in the etiology of NTDs. Under normal physiological conditions, FRs are quickly destroyed by antioxidant defense systems. However, FR-mediated cellular damage can occur if these defense systems fail or are overburdened, such as in patients who are genetically deficient in FR scavenging enzyme activity (FRSEA) or who are receiving chronic drug therapy. Congenital defects, including NTDs, resulting from FR-induced damage have been reported in both experimental animals and humans. For example, the use of antiepileptic drugs (AEDs) during pregnancy that have the propensity to form FRs during their metabolism are associated with an increased risk of the development of congenital malformations, including NTDs. This article reviews the biochemistry of FRs, the factors regulating FR scavenging capacity, and the theories regarding the etiology of NTDs; presents a hypothesis of a unified mechanism for AED-induced NTDs and other congenital defects; and briefly discusses the roles of folate and selenium in the prevention of NTDs.
神经管缺陷（NTDs）的药理学是一个复杂的问题。关于NTDs病因的几种理论强调了遗传、环境和生化因素在关键时间点相互作用的重要性。其中一个因素是长期药物治疗，其潜在后果是形成有毒的药物代谢产物，包括自由基（FRs），这些自由基被认为与NTDs的病因有关。在正常生理条件下，FRs会被抗氧化防御系统迅速破坏。然而，如果这些防御系统失效或负担过重，例如在FR清除酶活性（FRSEA）基因缺陷的患者或接受长期药物治疗的患者中，就会发生FR介导的细胞损伤。实验动物和人类中都报道了由FR诱导损伤导致的先天性缺陷，包括NTDs。例如，孕期使用在代谢过程中容易形成FRs的抗癫痫药物（AEDs）与包括NTDs在内的先天性畸形发生风险增加有关。本文综述了FRs的生物化学、调节FR清除能力的因素以及关于NTDs病因的理论；提出了AEDs诱导NTDs和其他先天性缺陷的统一机制假说；并简要讨论了叶酸和硒在预防NTDs中的作用。
