A feasibility study quantifying in vivo human alpha-tocopherol metabolism

Authors: CLIFFORD, ANDREW - UCD, NUTR. DEPT.; DE MOURA, FABIANA - UCD, NUTR. DEPT.; HO, CHARLENE - UCD, NUTR. DEPT.; CHUANG, JENNIFER - UCD, NUTR. DEPT.; Follett, Jennifer; FADEL, JAMES - UCD, NUTR. DEPT.; VOGEL, JOHN - UCD, NUTR. DEPT.; NOVOTNY, JANET - UCD, NUTR. DEPT.; COHN, WILLIAM - UCD, NUTR. DEPT.

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2006
Publication Date: 8/1/2006
Citation: Clifford, A.J., De Moura, F.F., Ho, C.C., Chuang, J.C., Follett, J.R., Fadel, J.G., Vogel, J.S., Novotny, J.A., Cohn, W. 2006. A feasibility study quantifying in vivo human alpha-tocopherol metabolism. American Journal of Clinical Nutrition 84:1430-1441, 2006.

Interpretive Summary: The term vitamin E includes 4 tocopherols and 4 tocotrienols. Among the 4 tocopherols, '-tocopherol ('-TOC) has the highest vitamin E activity. Natural '-TOC is a single stereoisomer commonly called RRR-'-tocopherol (RRR-'-TOC). Chemically synthesized '-TOC is an equal mix of 8 stereoisomers and is commonly called all-rac-'-tocopherol (all-rac-'-TOC). Quantitation of human vitamin E metabolism is incomplete despite its nutritional importance and effects of different '-TOC stereoisomers are well known, but gaps exist about quantitative aspects of their metabolism We aimed to quantify and interpret natural RRR- versus synthetic all-rac-'-TOC metabolism in an adult using kinetic modeling to analyze and interpret the data. Use of 14-C radiolabeled '-TOC enabled key features of metabolism of this important vitamin to be quantified through use of Accelerator Mass Spectrometry (AMS). The use of AMS allowed us to better determine the fate of a true tracer dose of 14C-RRR-'-TAc over a 63 d period, then after a 3 month long washout period, we did same for 14C-all-rac-'-TAc in a crossover design in a healthy man. Both isomers were well absorbed; all-rac-alpha-tocopherol was preferentially degraded and eliminated in urine, the major route. RRR-alpha-tocopherol had a longer residence time and larger distribution than did all-rac-alpha-tocopherol. Liver had 2 distinct alpha-tocopherol pools. The model is a hypothesis, its estimates are model-dependent, and it encourages further testing.

Technical Abstract: BACKGROUND: Quantitation of human vitamin E metabolism is incomplete, so we quantified RRR- and all-rac-alpha-tocopherol metabolism in an adult. OBJECTIVE: The objective of the study was to quantify and interpret in vivo human vitamin E metabolism. DESIGN: A man was given an oral dose of 0.001821 micromol [5-14CH3]RRR-alpha-tocopheryl acetate (with 101.5 nCi 14C), and its fate in plasma, plasma lipoproteins, urine, and feces was measured over time. Data were analyzed and interpreted by using kinetic modeling. The protocol was repeated later with 0.001667 micromol [5-14CH3]all-rac-alpha-tocopheryl acetate (with 99.98 nCi 14C). RESULTS: RRR-alpha-tocopheryl acetate and all-rac-alpha-tocopheryl acetate were absorbed equally well (fractional absorption: approximately 0.775). The main route of elimination was urine, and approximately 90% of the absorbed dose was alpha-2(2'-carboxyethyl)-6-hydroxychroman. Whereas 93.8% of RRR-alpha-tocopherol flow to liver kinetic pool B from plasma was returned to plasma, only 80% of the flow of all-rac-alpha-tocopherol returned to plasma; the difference (14%) was degraded and eliminated. Thus, for newly digested alpha-tocopherol, the all-rac form is preferentially degraded and eliminated over the RRR form. Respective residence times in liver kinetic pool A and plasma for RRR-alpha-tocopherol were 1.16 and 2.19 times as long as those for all-rac-alpha-tocopherol. Model-estimated distributions of plasma alpha-tocopherol, extrahepatic tissue alpha-tocopherol, and liver kinetic pool B for RRR-alpha-tocopherol were, respectively, 6.77, 2.71, and 3.91 times as great as those for all-rac-alpha-tocopherol. Of the lipoproteins, HDL had the lowest 14C enrichment. Liver had 2 kinetically distinct alpha-tocopherol pools. CONCLUSIONS: Both isomers were well absorbed; all-rac-alpha-tocopherol was preferentially degraded and eliminated in urine, the major route. RRR-alpha-tocopherol had a longer residence time and larger distribution than did all-rac-alpha-tocopherol. Liver had 2 distinct alpha-tocopherol pools. The model is a hypothesis, its estimates are model-dependent, and it encourages further testing.