Pharmacogenetics of ADRs: Warfarin Toxicity

ADR 的药物遗传学：华法林毒性

基本信息

批准号：
7531761
负责人：
Allan Edward Rettie
金额：
$ 39.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7531761
关键词：
4-Hydroxycoumarins Accident and Emergency department Active Sites Address Adherence Admission activity Adverse effects Adverse event Adverse reactions Affect American Anticoagulant therapy Anticoagulants Anticoagulation Binding Binding Sites Biological Assay CYP2C9 gene Classification Clinical Research Coagulation Factor Deficiency Complementary DNA Contracts Coumarins Cytochrome P450 DNA-Binding Proteins DNA-Protein Interaction Development Distal Dose Drops Drug Interactions Drug toxicity Elements Enzyme Inhibition Enzymes Equilibrium Etiology Event Food-Drug Interactions Funding Genes Genetic Genetic Polymorphism Genetic Variation Goals Grant Green S Haplotypes Hemorrhage Hepatic Hospitals Human Human Genetics Hydroxylation Individual Integration Host Factors International Normalized Ratio Knowledge Ligands Light Literature Liver Liver Microsomes Luciferases Medicine Membrane Membrane Proteins Metabolic Control Methodology Modeling Molecular Molecular Biology Mutation NQ-2-OH Nature Oral Outpatients Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Phase Photoaffinity Labels Preparation Price Proteins Public Health Reaction Recombinants Records Recovery Regulation Regulatory Element Reporter Reporting Research Research Personnel Research Proposals Resistance Risk Role Schedule Site Site-Directed Mutagenesis Source Structural Models Structure-Activity Relationship Techniques Therapeutic Index Time TimeLine Toxic effect Trager Psychophysical Integration Transcriptional Regulation Universities Variant Visit Vitamin K Warfarin Washington Western World Wisconsin Work alpha benzopyrone compliance behavior design enantiomer gene interaction improved indanedione medical schools membrane model mutant national surveillance novel performance site promoter prospective protein structure prediction receptor response vitamin K epoxide reductase

项目摘要

The long-term aim of this research is to understand how human genetic variation influences drug toxicity. In this renewal application, we will continue our efforts to elucidate mechanisms underlying adverse drug reactions to oral anticoagulants, specifically the coumarin drug, warfarin, which is taken daily by over 2 million Americans, and remains one of the most common causes of emergency room visits because of adverse reactions. In the previous funding period the focus was primarily on genetic variation within the cytochrome P450 enzyme, CYP2C9, because it controls metabolic clearance of the more potent (S) enantiomer of the racemic drug. However, during the previous granting period the gene for the warfarin target protein - VKORC1 - was cloned and has become the new focus of this application because it controls the pharmacodynamic response to the drug. In the present application we are attempting to understand; 1) regulatory mechanisms that influence vitamin K epoxide reductase (VKOR) hepatic expression and, 2) the fundamental nature of the warfarin binding site(s) in VKOR. To address these goals we have formulated the following aims: Specific Aim 1: Determine the functional significance of regulatory (promoter and intronic) polymorphisms at the VKORC1 locus using reporter constructs, site-directed mutagenesis and DNA/protein binding assays. Specific Aim 2: Define structure-activity relationships at the level of both the ligand and the protein for reversible and irreversible inhibition of VKOR using a set of structurally diverse vitamin K antagonists together with novel modeling of this membrane-bound enzyme. Due to the broad scope of the proposed research, this proposal brings together investigators at performance sites in Seattle and Milwaukee to work on these problems. Successful completion of these studies will add to our knowledge of the fundamental mechanisms by which; (i) polymorphisms in the VKORC1 gene affect patient dosing with warfarin and (ii) the vitamin K cycle is inhibited by warfarin.

这项研究的长期目的是了解人类遗传变异影响药物毒性。在此续签应用中，我们将继续努力阐明对口服抗凝剂的不良药物反应的基础机制，特别是香豆素药物，华法林，每天被200万人服用美国人，仍然是急诊室访问的最常见原因之一由于反应不良。在上一个资金期间，重点主要是细胞色素P450酶（CYP2C9）内的遗传变异，因为它控制外消毒药物更有效的对映异构体的代谢清除。然而，在上一个授予期间，华法林靶蛋白的基因-VKORC1- 被克隆并已成为该应用程序的新焦点，因为它控制了对药物的药效反应。在本应用中，我们正在尝试理解; 1）影响维生素K环氧还原酶的调节机制（vkor）肝表达和2）华法林结合位点的基本性质在Vkor。为了解决这些目标，我们提出了以下目的：特定目标1：确定调节性的功能意义（启动子和使用记者构造，位于现场定向的VKORC1基因座的内含子）多态性诱变和DNA/蛋白质结合测定。特定目的2：在配体的水平上定义结构活性关系以及使用一组可逆性和不可逆转抑制的蛋白质使用一组结构上多样化的维生素K拮抗剂以及新的建模膜结合酶。由于拟议的研究的广泛范围，该提案汇集了西雅图和密尔沃基表演地点的调查人员致力于解决这些问题。这些研究的成功完成将增加我们对基本的知识机制；（i）VKORC1基因中的多态性影响患者给药。华法林和（ii）华法林抑制了维生素K周期。