Alpha-Tocopherol Modulation of Xenobiotic Metabolism

描述（由申请人提供）：与其他脂溶性维生素不同，过量维生素E引起的毒性极为罕见。潜在的重要性是最近发表的临床研究报告了维生素E的副作用，这可能与它的肝脏代谢直接相关。此外，在体外系统中，ct-生育酚和利福平（一种已知的异种代谢刺激剂）都激活了妊娠X受体（PXR），这是一种孤儿核受体。PXR作为异源二聚体与类视黄醇X受体（RXR）结合到基因启动子区域的特定顺式元件上。PXR/RXR调节肝脏外源性解毒系统，包括氧化、偶联和转运体。重要的是，PXR调节细胞色素P450 (CYP)3A， CYP参与bb50 50%的治疗药物的代谢，ct-生育酚作为PXR配体可以改变这些PXR介导的途径。不幸的是，药物，甚至饮食，a-生育酚摄入调节这些途径在体内的程度还没有确定。因此，基于这些最近的临床发现，从与异种代谢系统相互作用的角度来评估维生素E代谢是至关重要的。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如何与异种代谢相互作用。本研究的目的是确定维生素E分解代谢的肝脏途径，以及维生素E如何影响肝细胞对这些途径的调节。这些研究的中心假设是，a-生育酚通过上调肝脏外源分解代谢和排泄途径来刺激其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-生育酚被积极代谢，而ct-生育酚则不是；此外，这些途径在男性和女性中受到不同的调节。我们的这一假设部分基于初步数据的结果，这些数据显示，“-”比“-”生育酚代谢更活跃，而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CYP3A与肝脏ct-生育酚浓度相关。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。

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.