Meta-analyses studies suggest that high-dose vitamin Emay be associated with increased mortality in some populations.Vitamin E may increase the production of CYP3A4 in the liver, andthis could lead to an increase in drug metabolism, potentially loweringthe efficacy of therapeutic drugs. We hypothesized that upregulationof CYP3A4 by a-tocopherol (a-TOH) would decrease theplasma concentration of the CYP3A4 substrate midazolam. Baselinemetabolism of midazolam (1 mg intravenously) was determined in 12healthy subjects before randomization into 2 groups of 6 to receiveeither RRR-a-TOH (750 IU/d) or placebo for 3 weeks. At completion,subjects were given an additional 1 mg intravenous bolus ofmidazolam. Plasma midazolam, 1-hydroxy-midazolam, and urinarya-TOH metabolite excretion were measured using gas chromatographymass spectrometry. Serum a-TOH was measured using highperformance liquid chromatography with electrochemical detection.Serum a-TOH increased by 100% (P = 0.002) and urinary a-TOHmetabolite excretion increased 20-fold in the treatment group versusplacebo (P = 0.001). There was no effect on the area under time curveof midazolam in subjects taking a-TOH compared with placebo.These findings do not support the hypothesis that a-TOH supplementationinterferes with hepatic CYP3A4-mediated drug metabolism.