Bioavailability and potency of natural-source and all-racemic alpha-tocopherol in the human: a dispute

Alpha-tocopherol occurs in nature as a single stereoisomer (RRR) while synthetic vitamin E is a mixture of eight stereoisomers (all-racemic, all-rac). The presently accepted ratio of biopotency (RRR: all-rac) is 1.36, based on the fetal resorption test in rats. This ratio has been disputed for humans. Clinical endpoint studies in humans are lacking, but plasma responses to RRR- and all-rac were measured in bioavailability studies. In nine studies comparing unlabeled forms, the ratio of plasma parameters (AUC, Cmax or steady-state concentration) concurred with the accepted ratio of biopotency within accepted bounds of equivalence. Four recent studies with simultaneous application of trideutero-RRR and hexadeutero-all-rac resulted in ratios of up to 2 for plasma, and of approximately 2.7 and approximately 3.4 for alpha-CEHC (a urinary metabolite) and umbilical cord plasma, respectively. Because these results have been widely assumed to reflect the difference in biopotency, this has prompted a proposal to the Food and Nutrition Board, National Academy of Sciences, USA to change the biopotency factor to 2 : 1. We challenge the validity of bioavailability data in lieu of clinical endpoints. Because RRR and all-rac are not chemically identical and differ in plasma and tissue kinetics and metabolism, the ratio of bioavailability parameters does not reflect the ratio of biopotency. This needs to be determined in adequately designed studies using clinical and biochemical endpoints. Until such studies have been performed it does not appear prudent to exchange the presently accepted ratio based on valid bioassays, albeit in a model animal, for another that is based on erroneous conclusions from human studies.