Glutathione homeostasis in Sickle Cell Disease

纯合子镰状细胞病(HbSS)的特征是溶血增加 “镰刀形”红细胞比率。此外，患有糖化血红蛋白综合征的人还 体内产生的抗氧化剂的红细胞浓度较低 谷胱甘肽(GSH)，表明它们的抗氧化能力受损。它 已经提出，超氧自由基的产生是由 半铬，铁原子和释放的血红素基团，导致过氧化 红细胞膜，这有助于镰刀过程。然而， 抗氧化能力实际受损的程度和机制(S) 潜在的这种损害，以及与氧化剂损害和 HbSS在体内的镰刀程度尚未确定。这项研究 提出的建议解决了以下假设：i)HbSS受试者 红细胞GSH浓度高于对照组，因为它们合成 GSH以较慢的速度下降。Ii)谷胱甘肽合成速度较慢是由于 甘氨酸和半胱氨酸的可用性是因为从头合成较慢 这两种氨基酸。三)补充HbSS受试者的饮食 半胱氨酸、甘氨酸或半胱氨酸加甘氨酸都会刺激GSH的合成。 达到高于其消耗率的水平，从而补充GSH池 尺码。四)HbSS受试者的较高氧化负荷直接与 谷胱甘肽的合成和可利用性降低，从而刺激谷胱甘肽 合成速度会导致氧化应激降低。使用生物化学 和稳定同位素示踪方法，这些假说将在32 患有HbSS的受试者和8名对照受试者在年龄、性别和日常生活方面匹配 饮食摄入量。实验方案将确定1)中的差异 红细胞GSH、半胱氨酸和甘氨酸的合成速率，2)全身 蛋白质分解率，3)血浆过氧化脂质浓度， 4)红细胞对氧化应激的抵抗力 几周的饮食补充。所获得的数据将提供对 氧化能力与镰刀和饮食的关系 干预可改善HbSS患者的代谢状态。

Homozygous sickle cell disease (HbSS) is characterized by increased hemolytic rate of "sickle shaped" erythrocytes. In addition, individuals with HbSS also have lower erythrocyte concentrations of the endogenously produced antioxidant glutathione (GSH), suggesting that they have impaired antioxidant capacity. It has been proposed that the generation of superoxide free radical by hemichromes, iron atoms and released haem groups, leads to peroxidation of the erythrocyte lipid membrane, which contributes to the sickling process. However, the extent to which antioxidant capacity is actually impaired, the mechanism(s) underlying such an impairment, and the relationships to oxidant damage and to the degree of in vivo sickling in HbSS have not been determined. The research proposed addresses the following hypotheses: i) HbSS subjects have lower erythrocyte GSH concentrations than control subjects because they synthesize GSH at a slower rate. ii) The slower rate of GSH synthesis is due to reduced availability of glycine and cysteine because of slower de novo synthesis of these two amino acids. iii) Supplementing the diets of the HbSS subjects with either cysteine, glycine, or cysteine plus glycine will stimulate GSH synthesis to a higher rate than its rate of consumption thereby replenishing the GSH pool size. iv) The higher oxidative load of the HbSS subject is directly related to the decreased synthesis and availability of GSH, hence stimulation of GSH synthesis rate will result in a decreased oxidative stress. Using biochemical and stable isotope tracer methods, these hypotheses will be tested in 32 subjects with HbSS and 8 control subjects matched for age, gender and usual dietary intakes. The experimental protocol will determine differences in 1) the rates of synthesis of erythrocyte GSH, cysteine and glycine, 2) whole body protein breakdown rate, 3) the plasma concentrations of lipid hydroperoxides, 4) the resistance of erythrocyte to oxidative stress at baseline and after a 4 weeks of dietary supplementation. The data obtained will provide insight into the relationship between oxidant capacity and sickling and whether dietary intervention can improve the metabolic status of subjects with HbSS.