Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation

The metabolism of alpha-tocopherol (alpha-TOH, vitamin E) shows marked interindividual variability, which may influence the response to nutritional and therapeutic interventions with this vitamin. Recently, new metabolomics protocols have fostered the possibility to explore such variability for the different metabolites of alpha-TOH so far identified in human blood, i.e., the vitamin E metabolome, some of which have been reported to promote important biological functions. Such advances prompt the definition of reference values and degree of interindividual variability for these metabolites at different levels of alpha-TOH intake. To this end, a one-week oral administration protocol with 800 U RRR-alpha-TOH/day was performed in 17 healthy volunteers, and alpha-TOH metabolites were measured in plasma before and at the end of the intervention utilizing a recently validated LC-MS/MS procedure; the expression of two target genes of alpha-TOH with possible a role in the metabolism and function of this vitamin, namely pregnane X receptor (PXR) and the isoform 4F2 of cytochrome P450 (CYP4F2) was assessed by immunoblot in peripheral blood leukocytes. The levels of enzymatic metabolites showed marked interindividual variability that characteristically increased upon supplementation. With the exception of alpha-CEHC (carboxy-ethyl-hydroxychroman) and the long-chain metabolites M1 and alpha-13 ' OH, such variability was found to interfere with the possibility to utilize them as sensitive indicators of alpha-TOH intake. On the contrary, the free radical-derived metabolite alpha-tocopheryl quinone significantly correlated with the post-supplementation levels of alpha-TOH. The supplementation stimulated PXR, but not CYP4F2, expression of leucocytes, and significant correlations were observed between the baseline levels of alpha-TOH and both the baseline and post-supplementation levels of PXR. These findings provide original analytical and molecular information regarding the human metabolism of alpha-TOH and its intrinsic variability, which is worth considering in future nutrigenomics and interventions studies.

Automated summary

New metabolomics protocols have allowed for the exploration of individual differences in the metabolism of alpha-tocopherol, revealing marked variability in the metabolites. Enzymatic metabolites showed significant interindividual variability, while free radical-derived metabolite alpha-tocopheryl quinone demonstrated a significant correlation with post-supplementation levels of alpha-tocopherol. The study also found that the expression of certain target genes of alpha-tocopherol in leukocytes was stimulated by supplementation, highlighting the importance of considering intrinsic variability in future studies.