Intestinal P450 and xenobiotic metabolism

肠道 P450 和外源代谢

• 批准号: 7660364
• 负责人: Qing-Yu Zhang
• 金额: $ 29.92万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 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/7660364
• 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 usage; Effectiveness; Enterocytes; Enzymes; Epithelial Cells; Gene Expression; Genes; Grapefruit juice; 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; public health relevance; research study; tool

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（由申请人提供）：我们的长期目标是确定肠细胞色素P450（P450）酶在药物代谢和毒性中的功能。该建议的重点是用于研究新型转基因小鼠模型的表征，用于研究药物/异种生物清除率在药物/异种生物清除率中肠道p450酶的体内功能。在初步研究中，我们产生了一个肠上皮（IE）特异性NADPH-CYTOCHROME P450还原酶（CPR）基因基因敲除小鼠模型（指定的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酶在肠道异种代谢和毒性中的综合作用。我们将使用该小鼠模型测试中心假设，即IE P450介导的药物代谢可以大大降低许多药物/异生元的口服生物利用度。在AIM 1中，我们将进一步描述新生成的IE-CPR-NULL鼠标，以确定其完整的实用程序。在AIM 2中，我们将直接确定IE CPR/P450在使用IE-CPR-NULL小鼠模型的口服药物中的第一次通量清除率中的作用。在AIM 3中，我们将检验以下假设：小肠P450介导的摄入的饮食或异种生物化学物质的第一次通用清除会影响这些化学物质调节小肠和外端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，以鉴定这些口服药物/异种生物，为此，全身生物利用性（影响药物疗效或不良药物反应的程度）受到了SI P450介导的首牌新代谢的影响。公共卫生相关性：名为IE-CPR-NULL的突变小鼠将是确定肠道p450酶在限制众多药物以及其他外国化学物质和饮食成分的全身水平中的作用的强大工具。此类知识目前很难获得，但对于优化众多临床上重要药物的有效性和安全性至关重要。