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Incorporation of deuterated RRR- or all-rac--tocopherol in plasma and tissues of -tocopherol transfer protein–null mice^1,2,3

¹ From the Linus Pauling Institute, Oregon State University, Corvallis (SWL and MGT); the Department of Nutrition, the University of California, Berkeley (YT); the Gladstone Institute of Cardiovascular Disease, San Francisco (YT and RVF); the Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco (RVF); and the Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento (MGT).

Background: Most vitamin E supplements contain synthetic all-rac--tocopherol [2,5,7,8-tetramethyl-2RS-(4'RS,8'RS,12-trimethyltridecyl)-6-chromanol] with 8 stereoisomers; only 1 is identical to the natural stereoisomer, RRR--tocopherol [2,5,7,8-tetramethyl-2R-(4'R,8'R,12-trimethyltridecyl)-6-chromanol]. In humans, 2R--tocopherol stereoisomers are preferentially maintained in the plasma, a function that has been attributed to hepatic -tocopherol transfer protein (-TTP), but this hypothesis has not been tested.

Objective: We sought to determine the functions of -TTP by comparing mice that express -TTP with mice that are genetically unable to express -TTP.

Design: Adult -TTP null (Ttpa^-/-; n = 5), heterozygous (Ttpa^+/-; n = 7), and wild-type (Ttpa^+/+; n = 3) mice consumed equimolar RRR--[5,7-(C²H₃)₂]-(d₆)- and all-rac--[5-(C²H₃)]-(d₃)-tocopheryl acetates (30 mg/kg diet each) for 3 mo. Subsequently, we measured labeled and unlabeled -tocopherols in plasma and 17 tissues.

Results: In all mice, plasma and tissue d₆- + d₃--tocopherols represented 80–90% of total -tocopherol. In the Ttpa^-/- mice, low total -tocopherol concentrations were found in plasma (5.4%) and most other tissues (2–20%), but liver concentrations were 39% of those of Ttpa^+/+ mice. Peripheral tissue ratios of d₆- to d₃--tocopherol were 1.1 ± 0.1 and 1.8 ± 0.2 in Ttpa^-/- and Ttpa^+/+ mice, respectively (P < 0.0001), showing that -TTP preferentially selects 2R--tocopherols for secretion into plasma. This 2:1 ratio does not support the currently defined international unit of 1.36:1 RRR--tocopherol to all-rac--tocopherol.

Conclusion: Deletion of the -TTP gene in mice results in an accumulation of dietary -tocopherol in the liver and depletion of peripheral tissue -tocopherol.

Key Words: Vitamin E • deuterium-labeled -tocopherol • -TTP knockout mice • mass spectrometry • vitamin E requirement • liver • brain

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