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

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Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability During Supplementation antioxidants Article Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation Desirée Bartolini 1,2,*,†, Rita Marinelli 1,† , Danilo Giusepponi 3, Roberta Galarini 3 , Carolina Barola 3, Anna Maria Stabile 2, Bartolomeo Sebastiani 4, Fabiola Paoletti 3, Michele Betti 5, Mario Rende 2 and Francesco Galli 1 1 Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy; [email protected] (R.M.); [email protected] (F.G.) 2 Department of Medicine, University of Perugia, 06126 Perugia, Italy; [email protected] (A.M.S.); [email protected] (M.R.) 3 Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati”, 06126 Perugia, Italy; [email protected] (D.G.); [email protected] (R.G.); [email protected] (C.B.); [email protected] (F.P.) 4 Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 Perugia, Italy; [email protected] 5 Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61029 Urbino, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-075-585-7445 † Equal contribution. Abstract: The metabolism of α-tocopherol (α-TOH, vitamin E) shows marked interindividual variabil- ity, 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 α-TOH so far identified in human blood, i.e., the “vitamin E metabolome”, Citation: Bartolini, D.e; Marinelli, R.; Giusepponi, D.; Galarini, R.; Barola, some of which have been reported to promote important biological functions. Such advances prompt C.; Stabile, A.M.; Sebastiani, B.; the definition of reference values and degree of interindividual variability for these metabolites at Paoletti, F.; Betti, M.; Rende, M.; et al. different levels of α-TOH intake. To this end, a one-week oral administration protocol with 800 U Alpha-Tocopherol Metabolites (The RRR-α-TOH/day was performed in 17 healthy volunteers, and α-TOH metabolites were measured in Vitamin E Metabolome) and Their plasma before and at the end of the intervention utilizing a recently validated LC-MS/MS procedure; Interindividual Variability during the expression of two target genes of α-TOH with possible a role in the metabolism and function of Supplementation. Antioxidants 2021, this vitamin, namely pregnane X receptor (PXR) and the isoform 4F2 of cytochrome P450 (CYP4F2) 10, 173. https://doi.org/10.3390/ was assessed by immunoblot in peripheral blood leukocytes. The levels of enzymatic metabolites antiox10020173 showed marked interindividual variability that characteristically increased upon supplementation. With the exception of α-CEHC (carboxy-ethyl-hydroxychroman) and the long-chain metabolites M1 Received: 9 December 2020 and α-130OH, such variability was found to interfere with the possibility to utilize them as sensi- Accepted: 20 January 2021 tive indicators of α-TOH intake. On the contrary, the free radical-derived metabolite α-tocopheryl Published: 25 January 2021 quinone significantly correlated with the post-supplementation levels of α-TOH. The supplemen- Publisher’s Note: MDPI stays neutral tation stimulated PXR, but not CYP4F2, expression of leucocytes, and significant correlations were with regard to jurisdictional claims in observed between the baseline levels of α-TOH and both the baseline and post-supplementation published maps and institutional affil- levels of PXR. These findings provide original analytical and molecular information regarding the iations. human metabolism of α-TOH and its intrinsic variability, which is worth considering in future nutrigenomics and interventions studies. Keywords: α-tocopherol; vitamin E; metabolomics; nutrigenomics; pregnane X receptor; lipoxygenase- Copyright: © 2021 by the authors. 5; peroxisome proliferator-activated receptor-γ; mass spectrometry; interindividual variability Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons 1. Introduction Attribution (CC BY) license (https:// The term vitamin E refers to the essential micronutrient α-tocopherol (α-TOH) (Figure1) creativecommons.org/licenses/by/ and, at the same time, to a group of plant-derived toco-chromanols (tocopherols and to- 4.0/). Antioxidants 2021, 10, 173. https://doi.org/10.3390/antiox10020173 https://www.mdpi.com/journal/antioxidants Antioxidants 2021, 10, 173 2 of 14 Antioxidants 2021, 10, x FOR PEER REVIEW 3 of 15 cotrienols), which, despite having many biological properties, do have very poor, or rather absent, vitamin function [1]. Figure 1. Chemical structure of the vitamin E compounds included in this metabolomics investigation. These include the Figure 1. Chemical structure of the vitamin E compounds included in this metabolomics investigation. These include the vitamers α-tocopherol and γ-tocopherol, the enzymatic long-chain metabolites (LCMs) α-13’hydroxychromanol (α-130OH) vitamers α-tocopherol and γ-tocopherol, the enzymatic long-chain metabolites (LCMs) α-13’hydroxychromanol (α- and 130-carboxychromanol (α-130COOH), the middle-chain metabolite (MCM) 2,7,8-trimethyl-2-(δ-carboxymethylbutyl)-6- 13′OH) and 13′-carboxychromanol (α-13′COOH), the middle-chain metabolite (MCM) 2,7,8-trimethyl-2-(δ-carboxymethyl- α α γ hydroxychromanbutyl)-6-hydroxychroman ( -CMBHC), (α-CMBHC), the short-chain the short-chain (SCMs) carboxy-ethyl-hydroxychroman (SCMs) carboxy-ethyl-hydroxychroman metabolites ( metabolites-CEHC and (α-CEHC,-CEHC andand theγ-CEHC, free radical-derived and the free radical-derived LCM α-tocopheryl LCM quinone α-tocopheryl (α-TQ). quinone (α-TQ). α These-TOH differences is a fat-soluble in the H uptake atom donorand molecu and chainlar regulation breaker of of lipid the enzymatic peroxidation metabo- reac- α tionslism of [2 ].vitamin As a consequence, E, may also theexplain supplementation the marked variability of -TOH of has urine extensively and plasma been levels investi- of gated with the aim of combat the oxidative stress associated with age-related and inflam- carboxy-ethyl-hydroxychroman (CEHC) metabolites observed among healthy subjects matory ailments, including cancer, cardiovascular, and neurodegenerative diseases [3–5]. (Figure 1) [20–22]; these are the final products in the enzymatic catabolism of this vitamin However, nutritional and therapeutic applications of α-TOH are hardly affected by and are considered to represent good biomarkers of its intake [23]. Kelly et al. first inves- the biological heterogeneity that characterizes the metabolism and function of this vitamin tigated with a systematic approach the concentrations of α-TOH in human plasma and in humans. Marked interindividual variability is characteristically observed in the vitamin those of α-CEHC and quinone lactone (QL) metabolite in urine after α-TOH supplemen- levels of healthy subjects [6,7]. Heterogeneities have also been described in the biological tation of healthy subjects [21]; what they found, besides the expected interindividual var- response to α-TOH, including its effect of protection against lipid peroxidation [8,9], and may iability, was a high repeatability and correlation of these parameters in the study partici- help to explain the inconsistent results obtained in most of the clinical trials carried out so pants, the correspondence of which was confirmed over a period of 1 year. The stability far on this vitamin [10,11]. of this phenotype suggests that the different aspects that control the uptake and biotrans- Along with variations in the dietary intake of the vitamin, genetic background and specificformation organ of α dysfunction-TOH (reviewed (for example, elsewhere subclinical in Reference defects [24]) of are the under gastrointestinal genetic regulation. tract as- sociatedIn recent with malabsorption times, long-chain or defects metabolites of the liver(LCMs; function) Figure may 1) of help vitamin to explain E have individual come to differencesthe attention in of the the levels scientific and metabolism community. of Aα -TOH.series of studies provided the technology to synthesizeEffective and strategies determine of these nutritional metabolites assessment in biological to address systems such [23, variability25], and others are lacking. iden- Formertified their studies anti-inflammatory, [6], pointed to anti-atherogenic, the existance at theand individual detoxification level properties of different that abilities are su- inperior absorbing to those the of ingestedtheir vitamin vitamin precursors and in the(reviewed hepatic in expression Reference of [26–29]).α-TOH Because binding these pro- teins,metabolites such as have the beenα-TOH the transport last to be proteinidentified (α -TTP),and measured which are in ratherhuman difficult blood with aspects stand- to evaluateardized and in humans. validated Furthermore, procedures [23,30,31],α-TTP and their other interindividualα-TOH binding variability proteins in associated response withto α-TOH the cellular supplementation trafficking remains of the vitamin, unexplored. such as the human α-tocopherol associated proteinIn (hTAP)this study, [12 ],a presenttargeted allelic metabolomics variants associated procedure, with recently lower developed vitamin concentrations for the simul- intaneous plasma analysis at baseline of a andll the post-supplementation metabolites of α-TOH [13 ].identified
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