Alpha-Tocopherol Modulation of Xenobiotic Metabolism

α-生育酚对异生物质代谢的调节

基本信息

批准号：
7232624
负责人：
MARET G TRABER
金额：
$ 34.1万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232624
关键词：
ABCB1 gene Address Adverse Drug Experience Report Adverse effects American Antioxidants Biliary CYP3A4 gene Carrier Proteins Catabolism Class Clinical Clinical Research Coenzyme A Cytochrome P450 Daily Data Dose Drug Formulations Drug Metabolic Detoxication Drug Prescriptions End Point Enzymes Excretory function Fatty acid glycerol esters Food-Drug Interactions Goals Health Hepatic Human Hydroxylation Intake Intervention Studies Intestines Light Liver Messenger RNA Meta-Analysis Metabolism Oxidoreductase Pathway interactions Pharmaceutical Preparations Plasma Play Proteins Public Health Publishing Rattus Recommendation Regulation Reporting Research Risk Role Self Medication Simvastatin System Therapeutic Tissues Tocopherols Vitamin E Vitamin, Other Xenobiotic Metabolism Xenobiotics absorption alpha Tocopherol animal data base cytochrome P450 3A dietary supplements drug metabolism hypercholesterolemia in vivo inhibitor/antagonist innovation knowledge base mortality oxidation prescription document prescription procedure prevent uptake

项目摘要

DESCRIPTION (provided by applicant): Drug-nutrient interactions are of increasing concern as it has been estimated that 15 million Americans consume dietary supplements concurrently with prescription medications. Vitamin E has antioxidant benefits and is generally considered to be non-toxic even in relatively high doses (>1000 IU). Of potential importance are recently published intervention studies that have reported adverse effects of vitamin E, which may be directly related to its hepatic metabolism. Although vitamin E itself may not have adverse effects, our data suggest that a-tocopherol up-regulates xenobiotic metabolism, specifically cytochrome P450 3A (CYP 3A), the major CYP in human liver and intestine that is also the predominant enzyme involved in the metabolism of >50% of therapeutic drugs. Our long-term goal is to further elucidate the pathways involved in vitamin E regulation in order that vitamin E supplements may be used with optimal benefits in maintaining human health. The objective of this research is to define hepatic pathways for a-tocopherol catabolism and its disposition, as well as to specifically address a-tocopherol interactions with pharmacologic agents and their metabolizing systems. The central hypothesis of these studies is that pharmacologic amounts of a-tocopherol alter hepatic xenobiotic catabolism and excretion pathways that simultaneously prevent "excess" hepatic vitamin E accumulation. Our rationale for these studies is that their successful completion will allow formulation of public health recommendations using evidence-based knowledge of vitamin E interactions and potential interference with other pharmacologic agents and xenobiotics. We propose to: Aim 1. Define the intracellular pathway for a-tocopherol metabolism. Aim 2. Define how a-tocopherol modulates hepatic cytochrome P450 enzymes (CYPs) involved in the metabolism of therapeutic drugs. Aim 3. Determine the ability of a-tocopherol to modulate hepatic transport proteins known to be involved in the biliary excretion of a-tocopherol and/or therapeutic drugs. Aim 4. Determine alterations by a-tocopherol on other vitamin E's metabolism. The proposed research is innovative because it will challenge the current paradigm that a-tocopherol acts solely as an antioxidant. Our studies will demonstrate how a-tocopherol alters hepatic xenobiotic metabolism. We believe these studies are critical to our understanding of a-tocopherol actions, particularly in light of recent reports of adverse drug-vitamin E interactions. We believe that our findings may well have a significant impact on current self-medication practices of the millions of Americans currently taking prescription drugs and vitamin E supplements.

描述（由申请人提供）：毒品营养互动的相互作用越来越关注，因为据估计，有1500万美国人食用饮食补充剂与处方药同时食用。维生素E具有抗氧化剂益处，即使在相对较高的剂量（> 1000 IU）中，通常也被认为是无毒的。潜在重要性的是最近发表的干预研究，这些研究报告了维生素E的不良影响，这可能与其肝代谢直接相关。尽管维生素E本身可能不会产生不利影响，但我们的数据表明，A-Topherol上调异生物生物代谢，特别是细胞色素P450 3A（CYP 3A），人类肝脏和肠中的主要CYP，这也是涉及> 50％> 50％药物代谢的主要酶。我们的长期目标是进一步阐明维生素E调节中涉及的途径，以便可以将维生素E补充剂用于维持人类健康的最佳益处。这项研究的目的是定义A托酚分解代谢及其处置的肝途径，以及专门解决与药理学剂及其代谢系统的A托酚相互作用。这些研究的核心假设是，A-topherol的药理量改变了肝异种生物分解代谢和排泄途径，这些途径同时可以防止“过量”肝维生素E的积累。我们对这些研究的理由是，他们的成功完成将允许使用基于证据的维生素E相互作用的知识以及与其他药理剂和异种生物学的潜在干扰来制定公共卫生建议。我们建议：AIM 1。定义A-Topherol代谢的细胞内途径。 AIM 2。定义A-To-Topherol如何调节参与治疗药物代谢的肝细胞色素P450酶（CYPS）。 AIM 3。确定A托酚调节已知参与A托酚和/或治疗药物的胆汁排泄的肝运输蛋白的能力。 AIM 4。确定A-Topherol对其他维生素E代谢的改变。拟议的研究具有创新性，因为它将挑战A-Topherol仅作为抗氧化剂的当前范式。我们的研究将证明A-topherol如何改变肝异生物代谢。我们认为，这些研究对于我们对A-To-Topherol作用的理解至关重要，特别是鉴于最近关于药物 - 维生素E相互作用的报道。我们认为，我们的发现很可能会对目前服用处方药和维生素E补充剂的数百万美国人的当前自治实践产生重大影响。