Intestinal P450 and xenobiotic metabolism

肠道 P450 和外源代谢

基本信息

批准号：
8319914
负责人：
Qing-Yu Zhang
金额：
$ 10.48万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319914
关键词：
Adult Adverse reactions Affect Animal Feed Animal Model Antihypertensive Agents Aryl Hydrocarbon Hydroxylases Benzo(a)pyrene Biological Availability CYP1A1 gene CYP3A4 gene Cells Chemicals Colon Communities Cyclosporine Cytochrome P450 Data Diet Dose Drug Controls Drug Interactions Drug Kinetics Drug toxicity Drug usage Effectiveness Enterocytes Enzymes Epithelial Cells Gene Expression Genes Grapefruit juice Health Hyperlipidemia Immunosuppressive Agents In Vitro Intestines Intravenous Kidney Knockout Mice Knowledge Light Liver Lovastatin Lung Mediating Metabolic Metabolic Biotransformation Metabolism Microarray Analysis Microsomes Midazolam Mus Mutant Strains Mice NADPH-Ferrihemoprotein Reductase Names Nifedipine Oral Organ Pathway interactions Permeability Pharmaceutical Preparations Physiology Play Pravastatin Proteins Reaction Relative (related person)Research Role Safety Site Small Intestines Study models Synthetic Diet Testing Therapeutic Agents Toxic Environmental Substances Toxic effect Transgenic Mice Xenobiotic Metabolism Xenobiotics base chemical carcinogenesis drug efficacy drug metabolism electron donor in vivo insight intestinal epithelium metabolic abnormality assessment mouse model neonate novel research study tool

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to determine the function of intestinal cytochrome P450 (P450) enzymes in drug metabolism and toxicity. The focus of this proposal is on the characterization of a novel transgenic mouse model for studying the in vivo function of intestinal P450 enzymes in drug/xenobiotic clearance. In preliminary studies, we have generated an intestinal epithelium (IE)-specific NADPH-cytochrome P450 reductase (Cpr) gene knockout mouse model (designated IE-Cpr-null). The gene product of Cpr is the obligatory electron donor to all microsomal P450s. Thus, using the IE-Cpr-null mouse model, we can study the combined roles of IE microsomal P450 enzymes in intestinal xenobiotic metabolism and toxicity. We will use this mouse model to test the central hypothesis that IE P450-mediated drug metabolism can substantially lower the oral bioavailability of numerous drugs/xenobiotics. In Aim 1, we will further characterize the newly generated IE-Cpr-null mouse, in order to identify its full utility. In Aim 2, we will directly determine the role of IE CPR/P450s in the first-pass clearance of oral drugs using the IE-Cpr-null mouse model. In Aim 3, we will test the hypothesis that small intestinal P450-mediated first-pass clearance of ingested dietary or xenobiotic chemicals influences the ability of these chemicals to regulate gene expression in the small intestine and extra-gut organs. Through the proposed studies, we hope to establish the utility of the novel IE-Cpr-null mouse model for identifying those oral drugs/xenobiotics, for which systemic bioavailability (which affects drug efficacy or, alternatively, extent of adverse drug reactions) is substantially influenced by SI P450-mediated first-pass metabolism. PUBLIC HEALTH RELEVANCE: The mutant mouse named IE-Cpr-null will be a powerful tool for determination of the role of intestinal P450 enzymes in limiting the systemic levels of numerous drugs and other foreign chemicals and dietary ingredients. Such knowledge is currently difficult to obtain, and yet is critical for optimizing the effectiveness and safety of numerous clinically important drugs.

描述（申请人提供）：我们的长期目标是确定肠道细胞色素P450（P450）酶在药物代谢和毒性中的功能。该提案的重点是表征一种新型转基因小鼠模型，用于研究肠道 P450 酶在药物/异生素清除中的体内功能。在初步研究中，我们建立了肠上皮（IE）特异性NADPH-细胞色素P450还原酶（Cpr）基因敲除小鼠模型（命名为IE-Cpr-null）。 Cpr 的基因产物是所有微粒体 P450 的强制性电子供体。因此，使用 IE-Cpr-null 小鼠模型，我们可以研究 IE 微粒体 P450 酶在肠道异生物质代谢和毒性中的综合作用。我们将使用该小鼠模型来测试中心假设，即 IE P450 介导的药物代谢可以显着降低多种药物/异生素的口服生物利用度。在目标 1 中，我们将进一步表征新生成的 IE-Cpr-null 鼠标，以确定其完整实用性。在目标 2 中，我们将使用 IE-Cpr-null 小鼠模型直接确定 IE CPR/P450 在口服药物首过清除中的作用。在目标 3 中，我们将检验以下假设：小肠 P450 介导的摄入膳食或外源化学物质的首过清除会影响这些化学物质调节小肠和肠外器官中基因表达的能力。通过拟议的研究，我们希望建立新型 IE-Cpr-null 小鼠模型的实用性，用于识别那些口服药物/外源性药物，这些药物/外源性药物的全身生物利用度（影响药物疗效或药物不良反应的程度）基本上是受 SI P450 介导的首过代谢的影响。公共健康相关性：名为 IE-Cpr-null 的突变小鼠将成为确定肠道 P450 酶在限制多种药物和其他外来化学物质和膳食成分的全身水平方面的作用的有力工具。这些知识目前很难获得，但对于优化众多临床重要药物的有效性和安全性至关重要。