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.