Izsum.it (C.B.); [email protected] (F.P.) Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 Perugia,

Izsum.it (C.B.); [email protected] (F.P.) Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 Perugia, Italy; [email protected] Division of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61029 Urbino, Italy; [email protected] Correspondence: [email protected]; Tel.: +39-075-585-7445 Equal contribution.Citation: Bartolini, D.e; Marinelli, R.; Giusepponi, D.; Galarini, R.; Barola, C.; Stabile, A.M.; Sebastiani, B.; Paoletti, F.; Betti, M.; Rende, M.; et al. Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability through Supplementation. Antioxidants 2021, 10, 173. https://doi.org/10.3390/ antiox10020173 Received: 9 December 2020 Accepted: 20 January 2021 Published: 25 JanuaryPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Abstract: The metabolism of -tocopherol (-TOH, vitamin E) shows marked interindividual variability, which could influence the response to nutritional and therapeutic interventions with this vitamin. Not too long ago, new metabolomics protocols have fostered the possibility to discover such variability for the various metabolites of -TOH so far identified in human blood, i.e., the “vitamin E metabolome”, some of which have been reported to market crucial biological functions. Such advances prompt the definition of reference values and degree of interindividual variability for these metabolites at distinctive levels of -TOH intake. To this finish, a one-week oral administration protocol with 800 U RRR–TOH/day was performed in 17 healthful volunteers, and -TOH metabolites were measured in plasma ahead of and at the end of your intervention utilizing a lately validated LC-MS/MS procedure; the expression of two target genes of -TOH with possible a part inside the metabolism and function of this vitamin, namely pregnane X NPY Y2 receptor Activator Formulation receptor (PXR) and also 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 improved upon supplementation. Together with the exception of -CEHC (carboxy-ethyl-hydroxychroman) and also the long-chain metabolites M1 and -13 OH, such variability was identified to interfere using the possibility to use them as sensitive indicators of -TOH intake. On the contrary, the free of charge radical-derived metabolite -tocopheryl quinone significantly correlated with the PDE10 Inhibitor Synonyms post-supplementation levels of -TOH. The supplementation stimulated PXR, but not CYP4F2, expression of leucocytes, and important correlations were observed in between the baseline levels of -TOH and each the baseline and post-supplementation levels of PXR. These findings supply original analytical and molecular data relating to the human metabolism of -TOH and its intrinsic variability, that is worth thinking of in future nutrigenomics and interventions studies. Keywords: -tocopherol; vitamin E; metabolomics; nutrigenomics; pregnane X receptor; lipoxygenase5; peroxisome proliferator-activated receptor-; mass spectrometry; interindividual variabilityCopyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This short article is definitely an open access short article distributed under the terms and situations in the Inventive Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).1. Introduction The term vitamin E refers towards the critical micronutrient -tocophe.