Alpha-Tocopherol Modulation of Xenobiotic Metabolism

α-生育酚对异生物质代谢的调节

• 批准号: 7030595
• 负责人: MARET G TRABER
• 金额: $ 27.47万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7030595
• 关键词: biotransformation; clearance rate; cytochrome P450; dietary supplements; drug metabolism; enzyme activity; enzyme inhibitors; gene expression; hydroxylation; laboratory rat; liver metabolism; messenger RNA; nucleic acid quantitation /detection; nutrient drug interaction; nutrition related tag; oxidation; protein quantitation /detection; simvastatin; tocopherols; toxin; toxin metabolism; transport proteins; vitamin metabolism

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.

药物-营养素相互作用越来越受到关注，因为据估计，有1500万美国人在服用处方药的同时服用膳食补充剂。维生素E具有抗氧化作用，通常被认为是无毒的，即使在相对高的剂量（>1000 IU）。具有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的不良反应，这可能与其肝脏代谢直接相关。虽然维生素E本身可能没有副作用，但我们的数据表明α-生育酚上调异生物质代谢，特别是细胞色素P450 3A（CYP 450 3A），其是人类肝脏和肠道中的主要酶，也是参与>50%的治疗药物代谢的主要酶。我们的长期目标是进一步阐明参与维生素E调节的途径，以使维生素E补充剂在维持人类健康方面具有最佳益处。本研究的目的是确定α-生育酚催化剂的肝脏途径及其处置，以及专门解决α-生育酚与药物及其代谢系统的相互作用。这些研究的中心假设是药理学量的α-生育酚改变肝脏异生物质代谢和排泄途径，同时防止“过量”肝脏维生素E蓄积。我们进行这些研究的理由是，这些研究的成功完成将允许使用基于证据的维生素E相互作用和与其他药物和外源性物质的潜在干扰的知识来制定公共卫生建议。我们建议：目标1。定义α-生育酚代谢的细胞内途径。目标2.定义α-生育酚如何调节参与治疗药物代谢的肝细胞色素P450酶（CYP）。目标3.确定α-生育酚调节已知参与α-生育酚和/或治疗药物胆汁排泄的肝转运蛋白的能力。目标4。确定α-生育酚对其他维生素E代谢的改变。拟议的研究是创新的，因为它将挑战目前的范式，a-生育酚仅作为一种抗氧化剂。我们的研究将证明α-生育酚如何改变肝脏异生物质代谢。我们相信这些研究对于我们理解α-生育酚的作用至关重要，特别是考虑到最近关于药物-维生素E不良相互作用的报道。我们相信，我们的研究结果可能会对目前正在服用处方药和维生素E补充剂的数百万美国人的自我药疗实践产生重大影响。