OXIDATIVE DAMAGE IN HUMAN FETAL LIVER

描述 许多药物，其还原代谢物能够进行氧化还原 循环，也具有显著的致畸特性。 已经 假设活性氧（ROS）的产生是一种 化学致畸作用重要机制。 这项建议旨在 利用胎肝切片作为体外模型系统， 抗癫痫药物暴露后的氧化损伤机制 苯妥英是一种致畸的促氧化剂 主要研究者将 在一系列的表达上建立剂量-反应关系， 氧化应激的生物标志物和诱导细胞凋亡。 这些 包括：氧化剂应答转录因子（c-fos，核 因子-κ B），生长停滞和DNA损伤基因（Bcl-2，GADD 45），组织 谷胱甘肽状态、脂质膜损伤和诱导细胞凋亡。 在确定苯妥英暴露与 生物标志物表达，先前暴露于膳食抗氧化剂的影响 （BHA-丁基羟基茴香醚）在防止生化和细胞 苯妥英治疗诱导的氧化应激的后果将是 考察

DESCRIPTION A number of drugs, whose reduced metabolites are capable of undergoing redox cycling, also possess significant teratogenic properties. It has been postulated that the production of reactive oxygen species (ROS) is an important mechanism in chemical teratogenesis. This proposal is designed to utilize fetal liver slices as an in vitro model system to evaluate mechanisms of oxidative damage subsequent to exposure to the anti-epileptic drug, phenytoin, a teratogenic pro-oxidant. The principal investigator will establish dose-response relationships on the expression of a series of biomarkers of oxidative stress and on the induction of apoptosis. These include: oxidant-responsive transcription factors (c-fos, nuclear factor-kappa B), growth arrest and DNA damage genes (Bcl-2, GADD45), tissue glutathione status, lipid membrane damage and the induction of apoptosis. Subsequent to establishment of a relationship between phenytoin exposure and biomarker expression, the impact of prior exposure to a dietary antioxidant (BHA-butylated hydroxyanisole) in preventing the biochemical and cellular consequences of the oxidative stress induced by phenytoin treatment will be examined.