Alpha-Tocopherol Modulation of Xenobiotic Metabolism

描述（由申请人提供）：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，通常认为即使在相对较高的剂量（100 - 1000国际单位）下也是无毒的。具有潜在重要性的是，最近发表的干预研究报道了维生素E的不良影响，这可能与它的肝脏代谢直接相关。尽管维生素E本身可能没有不良影响，但我们的数据表明，a-生育酚上调了外源代谢，特别是细胞色素P450 3A (CYP 3A)，这是人类肝脏和肠道中的主要CYP，也是参与50%治疗药物代谢的主要酶。我们的长期目标是进一步阐明维生素E调节的途径，以便维生素E补充剂可以在维护人类健康方面发挥最佳效益。本研究的目的是确定a-生育酚分解代谢及其处置的肝脏途径，以及具体解决a-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，a-生育酚的药理学量改变了肝脏的外源分解代谢和排泄途径，同时防止肝脏“过量”维生素E积累。我们进行这些研究的基本原理是，它们的成功完成将允许利用维生素E相互作用以及与其他药物和外源药物的潜在干扰的循证知识制定公共卫生建议。我们建议：目标1。确定细胞内a-生育酚代谢途径。目标2。确定a-生育酚如何调节参与治疗药物代谢的肝细胞色素P450酶（CYPs）。目标3。测定a-生育酚调节肝脏转运蛋白的能力，这些转运蛋白已知参与a-生育酚和/或治疗药物的胆汁排泄。目标4。测定a-生育酚对其他维生素E代谢的影响。这项提议的研究具有创新性，因为它将挑战目前的范式，即a-生育酚仅作为抗氧化剂起作用。我们的研究将证明a-生育酚如何改变肝脏的异种代谢。我们相信这些研究对于我们理解a-生育酚的作用是至关重要的，特别是考虑到最近关于药物-维生素E相互作用的不良报道。我们相信，我们的发现可能会对目前数百万正在服用处方药和维生素E补充剂的美国人的自我药疗实践产生重大影响。

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.