基于Nrf2/ARE通路对γ-GCS、GST、MRP调控研究HSCT患者白消安肝脏代谢个体差异机制

造血干细胞移植(HSCT)是根治恶性血液疾病的有效手段，白消安(BU)广泛用于HSCT前大剂量预处理方案，但BU治疗范围窄，药物浓度过高或过低均易引起患者死亡率升高。BU通过肝脏谷胱甘肽转移酶(GSTs)催化和谷胱甘肽(GSH)结合代谢，γ-谷氨酰半胱氨酸合酶(γ-GCS)影响体内GSH水平，而多药耐药相关蛋白(MRPs)外排转运GSH及GSH结合物。研究提示Nrf2/ARE通路调控γ-GCS、GSTs、MRPs。我们前期研究表明BU药动学存在较大个体差异，同时γ-GCS 、GSTs、MRPs的基因多态性使其活性存在显著差异。本课题拟建立群体药动学模型定量研究中国患者γ-GCS、GST、MRP的遗传差异对BU药动学的影响。并采用HepG2细胞及Nrf2基因敲除大鼠多层次研究Nrf2/ARE通路对γ-GCS、GST、MRP的调控探讨BU肝脏代谢机制。为制定中国患者个体化给药方案提供新理论依据

Hematopoietic stem cell transplantation (HSCT) has been an effective treatment for disorders of the blood system. Busulfan (BU), widely used in high dose before HSCT, has narrow therapeutic range. High or low BU exposure is associated with increased mortality rate of patients. The hepatic metabolism of BU is conjugation with glutathione (GSH) by Glutathione transferases (GSTs). Gamma-glutamylcysteine synthetase (γ-GCS) is the rate-limiting enzyme of the synthesis of GSH. Multidrug resistance-associated proteins (MRPs) are reported to contribute for efflux of GSH and GSH-conjugates. Nrf2/ARE signaling pathway regulates expressions of γ-GCS、GSTs、MRPs. The polymorphisms of those enzymes result in significant different activities. Our previous study shows that the pharmacokinetics (PK) of BU in Chinese HSCT patients have large inter-individual differences. The aim of this study is to quantitatively study the impact of polymorphisms of γ-GCS, GST, MRP on BU PK by development of population pharmacokinetic model. HepG2 cell and Nrf2 knock-out rat are applied to study the effect of Nrf2/ARE signal pathway and its downstream γ-GCS, GST, MRP on hepatic metabolism of BU. The research will provide novel insights for BU individualized administration of Chinese HSCT patients.