Dietary Cysteine:Conceptal Response to Oxidative Stress

膳食半胱氨酸：对氧化应激的概念反应

• 批准号: 6524838
• 负责人: CRAIG HARRIS
• 金额: $ 6.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524838
• 关键词: chemoprevention; cysteine; cytoprotection; dietary aminoacid; embryo /fetus culture; embryo /fetus tissue /cell culture; embryo /fetus toxicology; glutathione; laboratory rabbit; laboratory rat; nutrient interaction; nutrition related tag; oxidative stress; species difference; teratogens; toxicant interaction

DESCRIPTION (provided by applicant) Adequate dietary intake of thiol amino acids has been implicated as an important factor in the ability to withstand chemical and environmental insults that elicit oxidative stress. Without adequate free cysteine, the ability to restore glutathione that is lost due to oxidation is compromised by inadequate glutathione synthesis where sensitive target cells and tissues are damaged or killed due to the consequences of unresolved oxidative stress. The mechanisms of some important human diseases and adverse health conditions (e.g., HIV, malnutrition, inflammation) have been directly linked to low systemic glutathione, secondary to decreases in cysteine availability. Similar consequences of depleted and/or oxidized glutathione, leading to exacerbation of embryotoxicity and increased frequency and severity of teratogenic lesions, have been reported. Several human teratogens are known to elicit oxidative stress, although relatively little is known about the mechanisms that regulate antioxidant activity in the conceptus. Demonstrated differences in the rates of new glutathione synthesis in the developing embryo and its extra-embryonic membranes suggest that the availability of free cysteine, as the rate-limiting precursor for new glutathione synthesis, might be important for the determination of selectivity or resistance to chemical embryotoxicants. The investigators hypothesize that the availability of free cysteine in the embryo and visceral yolk sac of the post-implantation embryo determines the extent to which the embryo is able to maintain adequate glutathione concentrations and respond to chemically-induced oxidative stress by synthesizing new glutathione for restoration of normal redox status. Preliminary experiments with chemical embryotoxins, such as the pesticides lindane and aminocarb, show selective decreases in free cysteine concentrations prior to observed depletion of glutathione and onset of toxicity. Interspecies comparisons between the rat and rabbit show significant reductions in tissue glutathione and cysteine in the rabbit that may help explain the greater sensitivity of the rabbit to teratogens that produce oxidative stress such as thalidomide. The investigators propose to compare glutathione/glutathione disulfide/cysteine status and rates of new glutathione synthesis between rat and rabbit conceptual tissues. They will assess the effects of lindane and aminocarb on these endpoints and determine whether mechanistic relationships exist between a species' or tissue's ability to obtain cysteine and synthesize new glutathione and specific cell sensitivity or resistance to toxic chemicals. Whole animal, whole embryo culture and cell cultures (micromass limb/midbrain and spinal neural crest) will used to assess the role of cysteine in embryoprotection. In vitro and in vivo experiments will determine whether dietary restriction of cysteine differentially exacerbates toxicity in the two species and/or whether dietary or direct supplementation of cysteine is adequate to protect the embryo from chemical insult.

描述（由申请人提供） 足够的硫醇氨基酸饮食摄入已被认为是 承受化学和环境的能力的重要因素 侮辱引起氧化应激。 没有足够的自由半胱氨酸， 恢复因氧化而丢失的谷胱甘肽的能力会受到损害 谷胱甘肽合成不足，其中敏感的靶细胞和组织是 由于未解决的氧化应激的后果而受损或杀死。 这 某些重要人类疾病和不良健康状况的机制 （例如，艾滋病毒，营养不良，炎症）已直接与低 全身性谷胱甘肽，继发性半胱氨酸的可用性降低。 耗尽和/或氧化的谷胱甘肽的类似后果，导致 胚胎毒性加剧，频率和严重程度的增加 据报道，致畸性病变。 几种人类畸胎系是已知的 引起氧化应激，尽管对 调节概念中抗氧化活性的机制。 证明 发育中的胚胎中新谷胱甘肽合成速率的差异 它的外毛膜膜表明免费的 半胱氨酸作为新谷胱甘肽合成的限速前体，可能 对于确定对化学的选择性或抗性很重要 胚胎毒剂。 调查人员假设免费的可用性 植入后胚胎的胚胎和内脏蛋黄囊中的半胱氨酸 确定胚胎能够保持足够的程度 谷胱甘肽浓度并响应化学诱导的氧化应激 通过合成新的谷胱甘肽以恢复正常的氧化还原状态。 化学胚胎毒素的初步实验，例如农药 Lindane和Aminocarb，在自由半胱氨酸中显示出选择性降低 观察到谷胱甘肽耗尽和发作之前的浓度 毒性。 大鼠和兔子之间的种间比较 兔子中组织谷胱甘肽和半胱氨酸的显着减少 可能有助于解释兔子对teratogen的更大敏感性 产生氧化应激，例如沙利度胺。 调查人员建议 比较谷胱甘肽/谷胱甘肽二硫化物/半胱氨酸状态和新的速率 大鼠和兔子概念组织之间的谷胱甘肽合成。 他们会的 评估Lindane和Aminocarb对这些终点的影响，并确定 物种或组织能力之间是否存在机械关系 获得半胱氨酸并合成新的谷胱甘肽和特定细胞 对有毒化学物质的敏感性或抗性。 全动物，整个胚胎 培养和细胞培养物（微肢肢/中脑和脊髓神经波峰） 将用于评估半胱氨酸在胚胎保护中的作用。 体外和 体内实验将确定半胱氨酸的饮食限制 差异加剧这两个物种的毒性和/或是否饮食 或直接补充半胱氨酸足以保护胚胎免受 化学侮辱。