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. ? ?
| Farley, Sherry M; Leonard, Scott W; Taylor, Alan W et al. (2013) ?-Hydroxylation of phylloquinone by CYP4F2 is not increased by ?-tocopherol. Mol Nutr Food Res 57:1785-93 |
| Traber, Maret G; Stevens, Jan F (2011) Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med 51:1000-13 |
| Kuiper, Heather C; Bruno, Richard S; Traber, Maret G et al. (2011) Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radic Biol Med 50:848-53 |
| Traber, Maret G; Labut, Edwin M; Leonard, Scott W et al. (2011) ýý-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes. Free Radic Biol Med 51:2031-40 |
| Traber, Maret G; Mustacich, Debbie J; Sullivan, Laura C et al. (2010) Vitamin E status and metabolism in adult and aged aryl hydrocarbon receptor null mice. J Nutr Biochem 21:1193-9 |
| Mustacich, Debbie J; Leonard, Scott W; Patel, Neha K et al. (2010) Alpha-tocopherol beta-oxidation localized to rat liver mitochondria. Free Radic Biol Med 48:73-81 |
| Traber, Maret G; Leonard, Scott W; Traber, Daniel L et al. (2010) ?-Tocopherol adipose tissue stores are depleted after burn injury in pediatric patients. Am J Clin Nutr 92:1378-84 |
| Mustacich, Debbie J; Gohil, Kishorchandra; Bruno, Richard S et al. (2009) Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J Nutr Biochem 20:469-76 |
| Frank, Jan; Lee, Sangeun; Leonard, Scott W et al. (2008) Sex differences in the inhibition of gamma-tocopherol metabolism by a single dose of dietary sesame oil in healthy subjects. Am J Clin Nutr 87:1723-9 |
| Taylor, Alan W; Bruno, Richard S; Traber, Maret G (2008) Women and smokers have elevated urinary F(2)-isoprostane metabolites: a novel extraction and LC-MS methodology. Lipids 43:925-36 |
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