Alpha-Tocopherol Modulation of Xenobiotic Metabolism

描述(申请人提供)：与其他脂溶维生素不同，由于过量维生素E造成的毒性是极其罕见的。具有潜在重要性的是最近发表的临床研究，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。此外，在体外系统中，ct-生育酚和利福平都能激活孕烷X受体(PXR)，这是一种孤儿核受体。PXR作为与维甲酸X受体(RXR)结合的异源二聚体，与基因启动子区域的特定顺式元件结合。PXR/RXR调节肝脏异物解毒系统，包括氧化、结合和转运蛋白。重要的是，PXR调节细胞色素P450(CYP)3A，参与50%的治疗药物的代谢，生育酚作为PXR的配体可以改变这些PXR介导的途径。不幸的是，在体内，药物，甚至饮食中的α-生育酚摄入在多大程度上调节了这些途径还没有确定。因此，根据这些最新的临床发现，评估维生素E代谢以期与外源代谢系统相互作用是至关重要的。我们的长期目标是更全面地了解维生素E代谢的途径，以及维生素E如何与外源代谢相互作用。这项研究的目的是明确肝脏维生素E分解代谢的途径，以及维生素E如何影响这些途径的肝细胞调节。这些研究的中心假设是，α-生育酚通过上调肝脏异物分解代谢和排泄途径来刺激自身的分解代谢和排泄，以防止肝脏c-生育酚过量。我们进一步假设，ct-和/-生育酚有不同的代谢途径，因为-生育酚被活跃地代谢，而ct-生育酚不被代谢；此外，这些途径在男性和女性中受到不同的调节。我们的这一假说部分是基于初步数据的结果，这些数据显示，维生素E的代谢比生育酚更活跃，女性比男性更活跃地代谢“/-生育酚”。此外，我们的小鼠数据表明，细胞色素P3A与肝脏的生育酚浓度相关。我们成功完成这些研究的理由是，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剂和外源物质的潜在干扰的知识来制定公共健康建议。

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.