Cell Signaling, PXR Phosphorylation & Drug Disposition

细胞信号转导、PXR 磷酸化

基本信息

批准号：
7656908
负责人：
Jeffrey L Staudinger
金额：
$ 24.48万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656908
关键词：
7alpha hydroxylase Bile Acids Bile fluid Biochemical Biological Blood Blood Clot Blood Coagulation Factor Blood coagulation CYP3A4 gene Carrier Proteins Cell Nucleus Cell Respiration Cells Cyclic AMP-Dependent Protein Kinases Cytochrome P450 3A4 Cytochromes Cytoplasm DNA Binding Data Drug Interactions Drug Kinetics Drug Prescriptions Drug Regulations Drug Transport Excretory function Family Feces Gene Expression Gene Targeting Genes Gluconeogenesis Glucose Glycogen Goals Growth Factor Hepatic Hour Inflammation Inflammatory Inflammatory Response Interleukin-6 Interleukins Intestines Investigation Life Ligands Light Liver Liver diseases Location Mammals Mediating Methods Modeling Molecular Molecular Target Nuclear Receptors Operative Surgical Procedures Patients Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Postoperative Period Process Property Protein Kinase C Proteins RXR Repression Research Research Personnel Response Elements Signal Pathway Signal Transduction Signal Transduction Pathway Site Site-Directed Mutagenesis Steroids Testing Time Toxin Transactivation Transcription Regulatory Protein Xenobiotics activating transcription factor base citrate carrier cofactor cytochrome P-450 CYP2C subfamily cytokine human CYP2B6 protein insight member pregnane X receptor prevent programs promoter receptor receptor binding response text searching

项目摘要

DESCRIPTION (PROVIDED BY APPLICANT): Drug disposition is a highly regulated process in mammals. For example, the expression of genes encoding drug-transporting and drug-metabolizing proteins is induced by their substrates in liver and intestine. Recent research has shed new light on the molecular mechanism of this phenomenon. The pregnane X receptor (PXR) is a ligand-activated transcription factor that is expressed in liver and intestine. PXR coordinately regulates the drug-inducible expression of drug-transporting and drug-metabolizing proteins in liver and intestine. PXR binds to xenobiotic-response elements (XREs) in the promoters of its target genes as a heterodimer with the 9-cis-retinoic acid receptor (RXR). One extremely important PXR-target gene is the cytochrome P450 3A4 (CYP3A4) gene. CYP3A4 is primarily expressed in liver and intestine where it catalyzes the oxidative metabolism of nearly 60% of all clinically prescribed drugs. The hepatic expression of CYP3A4 and other PXR-target genes is rapidly suppressed in response to inflammatory cytokines, though the molecular basis of this repression is currently unknown. Repression of PXR-target gene expression occurs in people that undergo invasive surgery in response to inflammation, thereby producing altered pharmacokinetic properties of drugs in these patients. PXR is activated by a plethora of structurally diverse molecules including drugs, steroids, bile acids, and xenobiotics. Therefore, repression of PXR-target gene expression can produce potentially life-threatening drug-drug interactions. Thus, it is important to understand the molecular basis of the repression of PXR-target genes in order to predict and prevent the occurrence of drug interactions in post-operative patients. An alteration in the phosphorylation status of transcriptional regulatory proteins is a likely mechanism that mediates the repression of PXR-target gene expression following inflammation. The goals of these investigations are to (1) identify the sites of PXR phosphorylation following activation of specific cell signaling pathways, and (2) determine the effect of increased PXR phosphorylation on it's ability to (a) transactivate, (b) bind DNA, (c) translocate from the cytoplasm to the nucleus, and (d) interact with protein co-factors. Successful completion of these studies will allow us to determine the molecular basis of the repression of key drug metabolizing genes during the inflammatory response and provide increased opportunities to understand the xenobiotic response. These studies will provide additional insight into the regulation of drug disposition and drug-drug interaction.

描述（由申请人提供）：药物处置在哺乳动物中是一个受到高度监管的过程。例如，编码药物转运蛋白和药物代谢蛋白的基因的表达是由它们在肝脏和肠道中的底物诱导的。最近的研究为这种现象的分子机制提供了新的线索。孕烷 X 受体 (PXR) 是一种配体激活的转录因子，在肝脏和肠道中表达。 PXR 协调调节肝脏和肠道中药物转运和药物代谢蛋白的药物诱导表达。 PXR 作为与 9-顺式视黄酸受体 (RXR) 的异二聚体与其靶基因启动子中的异生素反应元件 (XRE) 结合。一种极其重要的 PXR 靶基因是细胞色素 P450 3A4 (CYP3A4) 基因。 CYP3A4 主要在肝脏和肠道中表达，催化近 60% 临床处方药物的氧化代谢。 CYP3A4 和其他 PXR 靶基因的肝脏表达响应炎症细胞因子而迅速受到抑制，尽管这种抑制的分子基础目前尚不清楚。 PXR 靶基因表达的抑制发生在因炎症而接受侵入性手术的患者中，从而导致这些患者的药物药代动力学特性发生改变。 PXR 被多种结构不同的分子激活，包括药物、类固醇、胆汁酸和异生素。因此，抑制 PXR 靶基因表达可能会产生潜在危及生命的药物相互作用。因此，了解 PXR 靶基因抑制的分子基础对于预测和预防术后患者药物相互作用的发生非常重要。转录调节蛋白磷酸化状态的改变可能是介导炎症后 PXR 靶基因表达抑制的机制。这些研究的目标是 (1) 确定特定细胞信号通路激活后 PXR 磷酸化的位点，以及 (2) 确定增加的 PXR 磷酸化对其以下能力的影响：(a) 反式激活，(b) 结合 DNA， (c) 从细胞质转移到细胞核，(d) 与蛋白质辅助因子相互作用。这些研究的成功完成将使我们能够确定炎症反应期间关键药物代谢基因抑制的分子基础，并为了解异生素反应提供更多机会。这些研究将为药物处置和药物相互作用的调节提供更多见解。