Alpha-Tocopherol Modulation of Xenobiotic Metabolism

α-生育酚对异生物质代谢的调节

• 批准号: 7247037
• 负责人: MARET G TRABER
• 金额: $ 7.08万
• 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/7247037
• 关键词: Alpha; Tocopherol; Modulation; Xenobiotic; Metabolism

DESCRIPTION (provided by applicant): Toxicity due to excess vitamin E, unlike other fat-soluble vitamins, is extremely rare. Of potential importance are recently published clinical studies that have reported adverse effects of vitamin E, which may be directly related to its hepatic metabolism. Additionally, in an in vitro system both ct-tocopherol and rifampicin, a known stimulator of xenobiotic metabolism, activated the pregnane X receptor (PXR), an orphan nuclear receptor. PXR as a heterodimer with the retinoid X receptor (RXR) binds to specific ciselements in the promoter regions of genes. PXR/RXR regulates hepatic xenobiotic detoxification systems, including oxidation, conjugation and transporters. Importantly, PXR regulates cytochrome P450 (CYP)3A which is involved in the metabolism of >50% of therapeutic drugs, ct-Tocopherol acting as a PXR ligand could alter these PXR-mediated pathways. Unfortunately, the extent to which pharmacologic, or even dietary, a-tocopherol intakes modulate these pathways in vivo has not been determined. As a consequence, and based upon these recent clinical findings, it is of critical importance to evaluate vitamin E metabolism with a view towards interactions with xenobiotic-metabolizing systems. Our long-term goal is to more completely understand the pathways of vitamin E metabolism and how vitamin E interacts with xenobiotic metabolism. The objective of this research is to define hepatic pathways for vitamin E catabolism and how vitamin E impacts hepatic cellular regulation of these pathways. The central hypothesis of these studies is that a-tocopherol stimulates its own catabolism and excretion by up-regulating hepatic xenobiotic catabolism and excretion pathways in order to prevent hepatic c_-tocopherol excess. We further hypothesize that there are different pathways for ct- and /-tocopherols because,-tocopherol is actively metabolized while ct-tocopherol is not; moreover, these pathways are regulated differently in males and females. We have based this hypothesis, in part, on the results of preliminary data showing that ¿- is more actively metabolized than is txtocopherol, and that women more actively metabolize "/-tocopherol than do men. Additionally, our mouse data demonstrate that CYP3A is correlated with hepatic ct-tocopherol concentrations. 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.

描述（适用提供）：与其他脂溶性维生素不同，由于超过维生素E引起的毒性极为罕见。最近发表了潜在重要性的临床研究，这些临床研究报告了维生素E的不良影响，这可能与其肝素代谢直接相关。此外，在体外系统中，已知的异种生物代谢的刺激剂CT托酚和利福平，激活了孤儿核受体的怀孕X受体（PXR）。 PXR作为与视乙他X受体（RXR）的异二聚体与基因启动子区域的特定培养物结合。 PXR/RXR调节肝脏异种解毒系统，包括氧化，结合和转运蛋白。重要的是，PXR调节与> 50％的治疗药物的代谢有关的细胞色素P450（CYP）3A，用作PXR配体的CT托酚可以改变这些PXR介导的途径。不幸的是，尚未确定在体内调节这些途径的药理学或什至饮食中的A-Topherol摄入的程度。结果，基于这些最新的临床发现，评估维生素E代谢并观察与异生物生物 - 代谢系统相互作用至关重要。我们的长期目标是更完全了解维生素E代谢的途径以及维生素E如何与异种生物代谢相互作用。这项研究的目的是定义维生素E分解代谢的肝途径以及维生素E如何影响这些途径的肝细胞调节。这些研究的核心假设是，抗翅酚醇通过上调肝异种生物分解代谢和极端途径来刺激其自身的分解代谢，并极端刺激其分解代谢，以防止肝C_-Tophophorol超过。我们进一步假设CT-和 / - 托酚有不同的途径，因为 - 生育酚是积极代谢的，而CT-生育酚则不代谢。此外，在男性和女性中，这些途径的调节不同。我们基于此假设的一部分是基于初步数据的结果表明，与txtocopherol相比，`````````````''''/tocopherol更为积极地代谢，并且女性更积极地代谢“/ - 托酚酚”。此外，与hepatitic CT型肝脏的群体相关的是，我们的鼠标数据允许这些研究的启动型。利用基于证据的维生素E相互作用知识以及与其他药物和异种生物的潜在干扰。