Incorporation of deuterated RRR- or all-rac-α-tocopherol in plasma and tissues of α-tocopherol transfer protein-null mice

Background: Most vitamin E supplements contain synthetic all-rac-alpha-tocopherol [2,5,7,8-tetramethyl-2RS-(4'RS,8'RS,12-trimethyltridecyl)-6-chromanol] with 8 stereoisomers; only I is identical to the natural stereoisomer, RRR-alpha-tocopherol [2,5,7,8-tetramethyl-2R-(4'R,8'R,12-trimethyltridecyl)-6-chromanol]. In humans, 2R-alpha-tocopherol stereoisomers are preferentially maintained in the plasma, a function that has been attributed to hepatic a-tocopherol transfer protein (alpha-TTP), but this hypothesis has not been tested. Objective: We sought to determine the functions of alpha-TTP by comparing mice that express alpha-TTP with mice that are genetically unable to express alpha-TTP. Design: Adult alpha-TTP null (Ttpa(-/-); n = 5), heterozygous (Ttpa(+/-); n = 7), and wild-type (Ttpa(+/+); n = 3) mice consumed equimolar RRR-alpha-[5,7-((CH3)-H-2)(2)]-(d(6))- and all-rac-alpha-[5-((CH3)-H-2)]-(d(3))-tocopheryl acetates (30 mg/kg diet each) for 3 mo. Subsequently, we measured labeled and unlabeled alpha-tocopherols in plasma and 17 tissues. Results: In all mice, plasma and tissue d(6)- + d(3)-alpha-tocopherols represented approximate to80-90% of total alpha-tocopherol. In the Ttpa(-/-) mice, low total alpha-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 d(6)-to d(3)-alpha-tocopherol were 1.1 +/- 0.1 and 1.8 +/- 0.2 in Ttpa(-/-) and Ttpa(+/+) mice, respectively (P < 0.0001), showing that alpha-TTP preferentially selects 2R-alpha-tocopherols for secretion into plasma. This 2:1 ratio does not support the currently defined international unit of 1.36:1 RRR-alpha-tocopherol to all-rac-alpha-tocopherol. Conclusion: Deletion of the alpha-TTP gene in mice results in an accumulation of dietary alpha-tocopherol in the liver and depletion of peripheral tissue alpha-tocopherol.