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）：药物处置是哺乳动物的高度调节过程。例如，编码药物转移和药物代谢蛋白的基因的表达是由其肝脏和肠中的底物诱导的。最近的研究为这种现象的分子机制提供了新的启示。妊娠X受体（PXR）是在肝脏和肠中表达的配体激活转录因子。 PXR协同调节肝脏和肠中药物转运和药物代谢蛋白的药物诱导表达。 PXR与靶基因的启动子中的异种生物反应元件（XRE）结合，作为与9- cis-反毒酸受体（RXR）的异二聚体。一个极为重要的PXR靶基因是细胞色素P450 3A4（CYP3A4）基因。 CYP3A4主要在肝脏和肠中表达，在肝脏和肠中，它催化了所有临床处方药的近60％的氧化代谢。 CYP3A4和其他PXR靶基因的肝表达迅速抑制了炎症细胞因子，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响应炎症时进行侵入性手术的人，从而在这些患者中产生药代动力学特性的改变。 PXR被多种结构多样的分子（包括药物，类固醇，胆汁酸和异种生物学）激活。因此，抑制PXR靶向基因表达可以产生潜在的威胁生命的药物相互作用。因此，重要的是要了解抑制PXR靶基因的分子基础，以预测和防止术后患者中药物相互作用的发生。转录调节蛋白的磷酸化状态改变是一种可能介导炎症后PXR靶基因表达的抑制的机制。这些研究的目标是（1）在激活特定细胞信号通路后确定PXR磷酸化的位点，（2）确定PXR磷酸化增加对（a）反式激活的能力的影响，（b）结合DNA，（b）（c）（c）（c）从细胞质转移到核与蛋白质的易位相互作用。这些研究的成功完成将使我们能够确定在炎症反应期间抑制关键药物代谢基因的分子基础，并提供更多了解异生物源反应的机会。这些研究将为药物处置和药物相互作用的调节提供更多的见解。