Farid Khallouki
email: farid_khallouki@yahoo.fr

Somayya Saber

Toufik Bouddine

Lhoussain Hajji

Bachir Elbouhali

Sandrine Silvente-Poirot

Marc Poirot
email: marc.poirot@inserm.fr

In vitro and In vivo Oxidation and Cleavage Products of Tocols : from chemical tuners to "VitaminEome" therapeutics. A Narrative Review

Keywords: AAPH: 2, 2'-azobis[2-amidinopropane]hydrochloride AMVN: 2, 2'-azobis[2, 4-dimethylvaleronitrile] α-T: α-Tocopherol α Kallikrein Related Peptidase Long chain metabolites LCMS: Liquid Chromatography, Mass Spectrometry LO,  alkoxy radical LOO vitamin E, vitamin E oxidation products, chemistry, tocopherylquinones, 5-nitro-tocopherol, vitamin E long chain Metabolites, cytotoxicity, anti-inflammatory activities. Highlights

Vitamin E components and vitamin E oxidation products (VEOP) define the "vitaminEome".

VEOP are produced through biological and chemical processes. They are found at low concentrations in vivo and may play particular biological functions linked with chemoprevention and inflammatory processes. Much data have been reported leading to more insight into VEOP. VEOP are generated through peroxy-radical generating systems and via reactive oxygen and nitrogen species as well as enzymatically by a variety of enzymes. In vivo, VEOP and their catabolites may reach the blood circulation and display physiological properties. This narrative review expands upon parent vitamin E chemistry as well as VEOP chemical concepts. The in vitro and in vivo routes by which they can be generated are exhaustively approached. Finally, we will discuss therapeutic and chemopreventive opportunities that VEOP offer with a special focus on their cytotoxic and anti-inflammatory functions.

Introduction

Vitamin E is a nutrient that is considered to be a functional food. It is the most important fat-soluble antioxidant that protects biomembranes and low density lipoproteins from oxidation. In the past decades, the chemistry of vitamin E oxidation with peroxyl radical generating systems has been systematically studied. As a result, vitamin E oxidation products (VEOP) have generated biomarkers, which may help to understand the vitamin E redox cycle and turnover. In addition, VEOP may act as physiological and/or pharmacological tuners of vitamin E in a biological environment [START_REF] Matsuo | Radical-scavenging reactions of vitamin E and its model compound, 2,2,5,7,8-pentamethylchroman-6-ol, in a tertbutylperoxyl radical generating system[END_REF][START_REF] Yamauchi | Vitamin E: mechanism of its antioxidant activity[END_REF][START_REF] Yamauchi | Chapter 13, Oxidation products of vitamin E with lipid-derived free radicals In Vitamin E Chemistry and Nutritional Benefits[END_REF]Rosenau et al. 2007a[START_REF] Rosenau | ortho-Quinone methides[END_REF][START_REF] Niki | Tocopherylquinone and tocopherylhydroquinone[END_REF][START_REF] Niki | Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence[END_REF][START_REF] Niki | Chapter 1: Vitamin E: Structure, Properties and Functions in Vitamin E. Chemistry and Nutritional Benefits[END_REF].

By preserving living organisms against oxidation processes, Vitamin E (tocols) prevents the activation and the diffusion of free radicals formed during the lipoperoxidation process. In experimental models, free radicals are produced through physical methods such as thermolysis, photolysis, radiolysis as well as sonolysis along with chemical and electrochemical methods, which are performed by electron redox transfers. Free radicals are also generated in living systems, they comprise reactive oxygen and nitrogen species. The assessment of the anti-radical capacities of tocols requires a broad range of experimental models, starting from simple tests without other lipid co-substrates, testing in biological media, in preclinical trials and finally in clinical trials. When exerting their antioxidative actions, tocols are extensively oxidized and generate VEOP. This supports further investigations as to the isolation, purification, structural identification and definition of the biological properties of these VEOP. One of the main properties of Vitamin E is to block lipid peroxidation in a lipid bulk phase, by blocking radical chain reactions. Thus, vitamin E may react with alkoxy (LO • ), alkylperoxy (LOO . ) or hydroxyl (HO • ) radicals through mechanisms that will be developed in this review to give tocopherone derivatives and other recurrent stable end products amongst which tocopherylquinone (TQ), tocored, 5methyltocolderivatives, dimers and trimers and many others (see vide infra). Therefore, vitamin E introduces a lag phase during which lipoperoxidation slows down until reaching vitamin E depletion when the rate of peroxidation increases again.

The activity of α-Tocopherol (α-T) against lipoperoxidation has gained in interest, due to the impressive development of physical chemistry approaches. The chemical mechanism is slow enough to allow a detailed characterization of the radical tocopheroxy. These studies were commonly performed by Electron Spin Resonance and Laser Flash analysis techniques [START_REF] Kohl | Electron spin resonance studies of free radicals derived from plastoquinone, αand γ-tocopherol and their relation to free radicals observed in photosynthetic materials[END_REF][START_REF] Boguth | Electron spin resonance of chromanoxy free radicals from alpha, zeta, beta, gamma, delta-tocopherol and tocol[END_REF][START_REF] Svanholm | Electrochemistry in media of intermediate acidity. VIII. Reversible oxidation products of the .alpha.-tocopherol model compound. Cation radical, cation, and dication[END_REF][START_REF] Ozawa | Electron spin resonance studies of radicals obtained by the reaction of α-tocopherol and its model compound with superoxide ion[END_REF][START_REF] Mukai | Electron spin resonance studies of chromanoxyl radicals derived from tocopherols[END_REF][START_REF] Doba | EPR spectra of some .alpha.-tocopherol model compounds. Polar and conformational effects and their relation to antioxidant activities[END_REF][START_REF] Matsuo | Electron spin resonance spectra of the chromanoxyl radicals derived from tocopherols (vitamin E) and their related compounds[END_REF][START_REF] Tsuchija | Oxidation of lipids. IV. Formation and reaction of chromanoxyl radicals as studied by electron spin resonance[END_REF].

Electrochemical models showed that vitamin E analogs are low redox-potential molecules, that reduce free radicals with a higher redox potential [START_REF] Svanholm | Electrochemistry in media of intermediate acidity. VIII. Reversible oxidation products of the .alpha.-tocopherol model compound. Cation radical, cation, and dication[END_REF][START_REF] Burton | Vitamin E: application of the principles of physical organic chemistry to the exploration of its structure and function[END_REF][START_REF] Webster | Voltammetric studies on the α-tocopherol anion and α-tocopheroxyl (Vitamin E) radical in acetonitrile[END_REF]William and Webster, 2004;[START_REF] Lee | Transformation of -tocopherol (vitamin E) and related chromanol model compounds into their phenoxonium ions by chemical oxidation with the nitrosonium cation[END_REF].

Nevertheless, current concepts of the antioxidant effects of α-T encompass some discrepancies [START_REF] Cillard | α-Tocopherol prooxidant effect in aqueous media: Increased autoxidation rate of linoleic acid[END_REF][START_REF] Terao | The peroxidizing effect of α-tocopherol on autoxidation of methyl linoleate in bulk phase[END_REF]Bowry & Stocker, 1993;[START_REF] Mukai | Kinetic study of the prooxidant effect of tocopherol. Hydrogen abstraction from lipid hydroperoxides by tocopheroxyls in solution[END_REF]. Indeed, although α-T is a well-known antioxidant agent and the main antioxidant carried by plasma lipoproteins (Herrera & Barbas, 2001), it is a pro-oxidant in vitro in strong oxidizing conditions such as high oxygen tension, in the presence of free metal ions, or at high concentrations [START_REF] Cillard | α-Tocopherol prooxidant effect in aqueous media: Increased autoxidation rate of linoleic acid[END_REF][START_REF] Inglod | Autoxidation of lipids and antioxidation by α-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size as exemplified by oxidation of human low-density lipoprotein[END_REF][START_REF] Bowry | Tocopherol-mediated peroxidation: the prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein[END_REF][START_REF] Mukai | Kinetic study of the prooxidant effect of tocopherol. Hydrogen abstraction from lipid hydroperoxides by tocopheroxyls in solution[END_REF][START_REF] Yoshida | Interaction of alpha-tocopherol with copper and its effect on lipid peroxidation[END_REF][START_REF] Witting | Inverse deuterium kinetic isotope effect for peroxidation in human low-density lipoprotein (LDL): a simple test for tocopherol-mediated peroxidation of LDL lipids[END_REF][START_REF] Bowry | Prevention of tocopherol mediated peroxidation of ubiquinol-10-free human low-density lipoprotein[END_REF][START_REF] Kontush | Antioxidant and prooxidant activity of α-tocopherol in human plasma and low-density lipoprotein[END_REF][START_REF] Upston | Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement[END_REF][START_REF] Upston | Oxidized lipid accumulates in the presence of alpha-tocopherol in atherosclerosis[END_REF][START_REF] Bernard | Quantitative studies on the peroxidation of human low-density lipoprotein initiated by superoxide and by charged and neutral alkylperoxyl radicals[END_REF]Zai-Qun, 2010). Beside its anti-oxidative potential, [START_REF] Boscoboinik | Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C[END_REF] published the first report giving evidence that α-T regulated cell signaling and gene transcription. Therefore, they showed that α-T displayed bio-potencies. However, the key functions of vitamin E, other than being a non-antioxidant, are still under debate. Vitamin E and its oxidation products have been reported to display a wide range of biochemical and pharmacological potencies. To date, many VEOP have been characterized but little is known as to their bioavailability and their exact roles in the bioactivity of α-T. The aim of this review is firstly to expose the complex chemistry of vitamin E oxidation depending on the biological model. We will next report significant in vitro and in vivo biological properties of VEOP. This review is the first comprehensive report that combines both chemical and biological aspects.

A brief survey of Vitamin E chemistry

Tocols (Vitamin E) are amphipathic and lipophilic antioxidants that are biosynthesized mostly by plants and cyanobacteria [START_REF] Dellapenna | Vitamin synthesis in plants: tocopherols and carotenoids[END_REF][START_REF] Khallouki | Chapter 3 -Vitamin E: an overview[END_REF].

Tocols are very soluble in apolar solvents and slightly soluble in alcohols. Tocols are very sensitive to light in the presence of air or other oxidants. Their phenolic group can be esterified with various acids. The resulting products can retain some of their biological activities but not their antioxidant potential. Tocols differ in the number and position of methyl groups present on the chromanol ring. Their chemical structures consist of two fused rings (6-hydroxychroman) and a long hydrocarbon side chain attached at the 2-position of the chroman ring. In Tocopherols, the side chain is saturated while in tocotrienol this side chain is a farnesyl chain with three double bonds at positions 3′, 7′ and 11′ (see figure 1). α-T is the most biologically active form amongst tocol congeners [START_REF] Pennock | A reassessment of tocopherol chemistry[END_REF]. The human body preferentially retains α-T rather than any other vitamin E analog. In 1982, the Commission on Biochemical Nomenclature (International Union of Pure and Applied Chemistry and International Union of Biochemistry and Molecular Biology Joint Commission on Biochemical Nomenclature), encompassed tocotrienols into vitamin E components. Moreover, the modern concept of "vitamin E" includes a larger group of natural as well as synthetic vitamin E derived products. The different isoforms with their exact nomenclature are shown in figure 1 and table 1 (IUPAC-IUB, 1966[START_REF] Jcbn) | Nomenclature of tocopherols and related compounds: (recommendations 1981)[END_REF][START_REF] Porter | Unified mechanism for polyunsaturated fatty acid autoxidation. Competition of peroxy radical hydrogen atom abstraction, beta-scission, and cyclization[END_REF]. α-T dietary supplements are often in esterified forms obtained by esterification of the hydroxyl group at the C6-position of the chromanol ring with an acetate, linoleate, succinate, nicotinate or phosphate group. These esterified forms are more stable and more resistant to oxidation than their parent forms but are no more antioxidant due to the blocade of the phenolic group [START_REF] Ruperez | Chromatographic analysis of αtocopherol and related compounds in various matrices[END_REF]. On the other hand, tocotrienols have only one chiral center. However the configurations of the two first existing double bonds at the position 3' and 7', allow for 4 cis/trans geometric isomers. The only natural isomer of tocotrienol that exists is the 2R, 3', trans 7'trans also known as the (2R,3′E,7′E) configuration [START_REF] Pennock | A reassessment of tocopherol chemistry[END_REF][START_REF] Drotleff | Determination of RS, E/Z-tocotrienols by HPLC[END_REF].

Other important trivial denominations of commercial and therapeutic importance are described below:

 2-epi-α-tocopherol is known as L-α-tocopherol (2S, 4'R, 8'R-α-tocopherol)
 2-ambotocopherol corresponds to a mixture of D-α-and L-α-tocopherol which is obtained using synthesis with phytyl and achiral hydroquinone, this is also know as dlalpha-tocopherol  The reduction of 5,7,8-tocotrienol in which the unsaturated 3', 7' and 11' are hydrogenated and two asymmetrical centers are created at C4' and C8' is a mixture of 2R, 4'R, 8'R ; 2R, 4'R, 8'S ; 2R, 4'S, 8'R and 2R, 4'S, 8'S, this mixture is known as 4'-ambo, 8'-ambo-α-tocopherol.

The fate of vitamin E with in vitro peroxy radical generating systems

Some known substrates of lipid peroxidation include constituents of cell membranes and plasma lipoproteins such as polyunsaturated fatty acids, cholesterol, phospholipids and lipoproteins. Lipoperoxidation occurs via reactions that by-pass the spin barrier between these lipids (the ground state is of singlet multiplicity) and oxygen (a biradical of triplet multiplicity in its fundamental state). There is consequently a need for a catalysis that will overcome this dissociation energy which will have an impact on allylic or bis allylic labile lipid protons. This leads to the formation of unstable hydroperoxides, which will break-down into toxic volatile secondary compounds (aldehydes, alcohols, ketones, epoxides). Such compounds are responsible for the oxidative deterioration of tissues. In food, the sustained oxidative damage of lipids is responsible for their changes in molecular structure and molar mass. This is associated with variations in the physical properties of lipids and a degradation in the quality of food. This causes organoleptic changes and loss of microbiological and nutritional properties. In vivo, if defensive systems are overwhelmed, these compounds could contribute to the development of certain cancers, neurodegenerative diseases and atherosclerosis. Several reviews have been published on this topic but much more mechanistic insight is required to improve our knowledge and our understanding of these processes (Frankel, 1980[START_REF] Frankel | Photooxidation of unsaturated fats[END_REF][START_REF] Frankel | Lipid Oxidation[END_REF][START_REF] Poisson | Corps gras alimentaires : aspects chimiques, biochimiques et nutritionnels. Lipides et corps gras alimentaires[END_REF][START_REF] Niki | Lipid peroxidation: physiological levels and dual biological effects[END_REF][START_REF] Bochkov | Generation and biological activities of oxidized phospholipids[END_REF][START_REF] Yin | Free radical lipid peroxidation: mechanisms and analysis[END_REF][START_REF] Niki | Lipid oxidation that is, and is not, inhibited by vitamin E: Consideration about physiological functions of vitamin E[END_REF].

Lipoperoxidation proceeds in three steps: the initiation step, the propagation step and the termination step. The alkyl radical generated from an unsaturated lipid after hydrogen radical abstraction (carbon-centered radicals, L . ) is named the initiation step. There are many factors that influence the reaction at this stage. These include on the one hand, intrinsic factors such as the physical state of the system, the presence or not of pro-oxidants such as transition metal ions, the presence of biological heme or non-heme irons as well as initiating agents amongst many others. On the other hand, extrinsic factors include temperature, light, pH, oxygen partial pressure, and the presence of water [START_REF] Hsieh | Oxidation of polyunsaturated fatty acids: mechanisms, products, and ininhibtion with emphasis on fish[END_REF]. Lipid peroxidation can be triggered by photosentitizers such as pigments. This involves the formation of an excited singlet state of oxygen as observed with hydrophobic porphyrin derivatives [START_REF] Jeong | Design and properties of porphyrin-based singlet oxygen generator[END_REF].

While the antioxidant power of vitamin E family members are well studied in vitro in various solvents and lipid suspensions, in vivo, lipid oxidation can occur through enzymatic reactions performed by oxidoreductases, lipooxygenases and cyclooxygenases [START_REF] Yin | Free radical lipid peroxidation: mechanisms and analysis[END_REF][START_REF] Hajeyah | The biosynthesis of enzymatically oxidized lipids[END_REF]. Auto-oxidation of lipids may also take place in the presence of free radicals that may already be present in the medium. As illustrated for linoleate (figure 2), a vulnerable bis allylic carbon atom forms a radical with a low rate constant reaction between two cis double bonds of the fatty acid) (-CH=CH-CH2-CH=CH-). The radical formed at C-11 (highlighted in bold), is delocalized over the five carbons from C-9 to C-13 [START_REF] Porter | Autoxidation of polyunsaturated lipids. Factors controlling the stereochemistry of product hydroperoxides[END_REF][START_REF] Porter | Unified mechanism for polyunsaturated fatty acid autoxidation. Competition of peroxy radical hydrogen atom abstraction, beta-scission, and cyclization[END_REF][START_REF] Porter | Autoxidation of polyunsaturated fatty acids, an expanded mechanistic study[END_REF](Porter et al., , 1986[START_REF] Kenar | Identification and quantification of the regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein[END_REF][START_REF] Davis | In vivo and in vitro lipid peroxidation of arachidonate esters: the effect of fish oil ω-3 lipids on product distribution[END_REF][START_REF] Xu | Rate constants for peroxidation of polyunsaturated fatty acids and sterols in solution and in liposomes[END_REF]. The radical formed is then stabilized by intramolecular rearrangements leading to a conjugated diene, which can subsequently react with dioxygen to form a lipid peroxyl radical (LOO • ). Because of its constant high rate, the lipid peroxy-radical will attack another polyunsaturated lipid molecule in a continuous process, causing the formation of a new lipid radical (L . ). This is associated with the formation of an unstable primary lipid hydroperoxide (LOOH), and this is termed the propagation step. In the termination step, lipoperoxidation occurs when radicals combine and stop the propagation step. In vivo, lipid hydroperoxides can either be metabolized through a selenoperoxidase-mediated two electron reduction to give rise to the corresponding less toxic alcohols, or may entail a one electron reduction to generate a free radical-mediated chain peroxidation, hence decomposing into low reactive peroxyl radicals (LOO . ) as afore mentioned. However, depending on whether they react with specific transition metals, redox cycles with Iron and Copper being the most reactive, these hydroperoxides may then produce extremely reactive alkoxyl radicals (LO . ) (Halliwell and Gatteridje, 1984;[START_REF] Sevanian | Mechanisms and consequences of lipid peroxidation in biological systems[END_REF]. The decomposition of hydroperoxides may also generate hydroxyl radicals (HO • ) via the well-known reactions of "Fenton and Haber Weiss", through the "Beckman-Radi-Freeman pathway" or the "Cadenas-Poderoso shunt" during a nitrative stress (reviewed in [START_REF] Boveris | The concept of oxidative stress in pathology In[END_REF].

Antioxidants may stop lipid peroxidation through different mechanisms. They can directly interrupt the propagation of the radical chain reaction, they can act as metal chelators, inhibiting the catalysis of the production of free radicals, or they can act as quenchers in the case of photo-oxidation by active singlet-oxygen. They may also act as "synergists": molecules that help to increase the antioxidant activity such as phospholipids [START_REF] Frankel | Photooxidation of unsaturated fats[END_REF][START_REF] Bandarra | Antioxidant synergy of α-tocopherol and phospholipids[END_REF]. As shown by -T in various in vivo or in vitro systems, the energy of dissociation of its phenolic moiety is weak and therefore facilitates the radical reactions via a dehydrogenating oxidation. Moreover, with any other co-substrate lipid (unsaturated fatty acid, phospholipid, or cholesterol) in homogeneous solutions, in aqueous dispersions such as micelles or liposomes (used as a model to mimic the in vivo lipid oxidations), and in biological fluids such as plasma, vitamin E reacts with peroxy radicals to form different oxidation products (VEOP). The antioxidant activity of vitamin E is deep-rooted by its chemical structure, and is also adapted to its level, its mobility, and its solubility either in a dispersed system or in a homogeneous phase. Its antioxidant potential will also depend on the physical state of a given microenvironment of the system (Huang et al., 1996). Vitamin E is more powerful as an antioxidant in polar emulsified media such as oil-water emulsions, plasma membrane and phospholipids with a high surface/volume (HSV) ratio, than in a continuous lipid phase such as oils due to its hydrophobic nature [START_REF] Frankel | Interfacial phenomena in the evaluation of antioxidants: bulk oils vs emulsions[END_REF]. This behavior is known as Porter's polar paradox [START_REF] Porter | Paradoxical behavior of antioxidants in food and biological systems[END_REF] which unfortunately disregards the influence of many other factors.

In homogeneous solutions as well as in heterogeneous lipid bilayers, α-T inhibits lipid peroxidation either by trapping the chain-carrying LOO • or by scavenging the initiator (the initial oxidant ROO • ). α-T acts as a radical proton donor to a peroxyl radical, and transforms itself into a tocopheroxy radical of weak reactivity. This reaction is fast and is even faster than the reaction of lipids with other lipid peroxy radicals [START_REF] Niki | Inhibition of oxidation of methyl linoleate in solution by vitamin E and vitamin C[END_REF]. In vitro, kinetic studies indicated that the rate constant for -T + ROO •  -TO • + ROOH is greater than l0 6 M -1 s -l [START_REF] Winterle | Products of stoichiometry of reaction of vitamin E with alkylperoxy radicals[END_REF][START_REF] Min | Chemistry and reaction of singlet oxygen in foods[END_REF][START_REF] Naumov | Antioxidant and prooxidant effects of tocopherol[END_REF][START_REF] Choe | Chemistry and Reactions of Reactive Oxygen Species in Foods[END_REF]. The speed with which tocols react with a peroxy radical reflects their direct respective antioxidant properties (Burton and Inglod, Kamal-eldin & Appelqvist, 1996). One molecule of α-T can scavenge two molecules of radicals such as LOO • . The mechanisms involved in this effect take place in a stepwise fashion. 1) α-T deactivates free radicals through a Hydrogen Atom Transfer (HAT), which acts via a homolytic breaking of the O-H bond of the chromanol backbone, giving rise to a more stable α-tocopheroxyl radical (α-TO • ), also called the α-tocopheryl-semiquinone radical. 2) α-TO • may also be formed via a Single Electron Transfer (SET) in which an electron is first transferred from α-T to the radical, and the tocophenoxy radical cation is then deprotonated. 3) Another proposed mechanism relies on a Sequential Proton Loss and Electron Transfer (SPLET). SPLET proceeds first by a deprotonation of -T's phenolic group, forming a -tocopheroxy anion, which in turn transfers an electron to the radical, giving rise to the -tocopheroxy radical. In addition, tocols may also undergo another SPLET to form a relatively less reactive chromanoxylium cation, which is stable for a few hours in dry lipophilic solvents at low temperatures [START_REF] Wilson | Significant differences in the electrochemical behavior of the alpha-, beta-, gamma-, and delta-tocopherols (vitamin E)[END_REF]. Subsequent electron and proton transfers may lead to the formation of tocopherylquinone methide (oQM) from either the tocopheroxy radical or the tocopheroxy cation. Moreover, experimental systems often lead to an unusual reactivity of the 5a-methyl group of -T in both apolar and polar media (Goodhue and Risley, 1964;[START_REF] Skinner | Reaction products of tocopherols[END_REF][START_REF] Suarna | Effect of alcohols on the oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol[END_REF]. The 5a-methyl group of the chromanol backbone (see structure figure 1 above) is also critically involved in the formation of oQM. This is not observed with other tocol congeners, which are partially methylated, such as and -T. These tocols show other oxidation behaviors (see vide infra). The HAT mechanism predominates in apolar solvents, SET and SPLET are more prevalent in polar solvents, whereas all three mechanisms may coexist in micellar or heterogeneous systems [START_REF] Najafi | DFT/B3LYP Study of the Substituent Effect on the Reaction Enthalpies of the Individual Steps of Single Electron Transfer-Proton Transfer and Sequential Proton Loss Electron Transfer Mechanisms of Chroman Derivatives Antioxidant Action[END_REF][START_REF] Wang | Effects of nitro-and amino-group on the antioxidant activity of genistein: a theoretical study[END_REF]. Figure 3 depicts the three main possible intermediates obtained that will lead to α-T oxidation products.

Generation of oQM is governed by the type of oxidant used, solvent polarity and its hydration state (Rosenau et al., 2007a). oQM contains an , -ethylenic ketone which may be converted via a 1,4-addition with nucleophiles, into covalent quinone-Nucleophile residues. In addition, hetero-Diels-Alder reactions may also occur and usually give rise to α-T dimers and trimers (Nilsson et al., 1968a,b;Schröder and Netscher, 2001;[START_REF] Rosenau | Stabilisation and First Direct Spectroscopic Evidence of the Quinone Methide Derived from Vitamin E[END_REF].

-TO • forms resonance-stabilized tocopherol radicals, and amongst these forms the position 8 is predominant (this is depicted in the figure 4). -TO • are stable enough to inhibit the formation of another radical and to stop the propagation of a chain reaction. -TO • may give rise to different metabolites. The major metabolites are 8a-lipiddioxy-α-tocopherone (I), 8a-alkoxy-α-tocopherone (II), their hydrolysis products 8a-hydroxy-α-tocopherone (III) and 8a-hydroxyperoxy-α-tocopherone (IV), and the end product α-tocopherylquinone (α-TQ, V).

When the amount of dioxygen (O2) is limiting, -T can react directly with the alkyl radicals in position C-6 instead of position C-8a to give 6-O-α-tocopheryl ethers (VI) in appreciable amounts. Another group of -TO • metabolites are C-4a/C-5-epoxy-8a-hydroperoxy-αtocopherone (VII), C7/C8-epoxy-8a-hydroperoxy-α-tocopherones (VIII) and their respective hydrolyzable products α-tocopherolquinone-2,3-oxide (α-TQE1, IX) and αtocopherolquinone-5,6-oxide (α-TQE2, X). Furthermore, α-T may also undergo a self-coupling reaction to form α-tocopheryl spiro-dimers (XI), α-tocopheryl ethano-dimers (XII) and α-tocopheryl spiro-trimers (XIII) (Kamal-Eldin & Appelqvist, 1996;[START_REF] Liebler | Gas chromatography-mass spectrometry analysis of vitamin E and its oxidation products[END_REF][START_REF] Rosenau | Stabilisation and First Direct Spectroscopic Evidence of the Quinone Methide Derived from Vitamin E[END_REF][START_REF] Rosenau | From a theoretical concept to biochemical reactions: strain induced bond localization (SIBL) in oxidation of vitamin E[END_REF]Rosenau et al., , 2007aRosenau et al., ,b, 2009;;Kamal-Eldin et al., 2008). Compounds X-XII display antioxidant activities [START_REF] Csallany | Oxidation products of α-tocopherol formed in autoxidizing methyl linoleate[END_REF]Yamauchi et al., 1988). The formation of 5alkyloxy-7,8-dimethyltocol (XIV) is also observed. The manifold of vitamin E oxidation products described in this review is depicted in Figure 5.

From a mechanistic point of view, some interesting features can be reported: Two α-TO • s may combine either to form a non-radical product (recombination) or may also lead through a disproportionation reaction to the parent α-T and oQM. α-T can give hydroxy-and peroxyketal tocopherones [START_REF] Winterle | Products of stoichiometry of reaction of vitamin E with alkylperoxy radicals[END_REF][START_REF] Rosenau | Chemical composition of alpha-tocopherol, in Encyclopedia of Vitamin E[END_REF], spiro-dimers (XI) and spiro-trimers (XIII) with good yields via o-QM and the respective Diels Alder reaction, mainly in inert and aprotic solvents [START_REF] Suarna | Oxidations of vitamin E (.alpha.-tocopherol) and its model compound 2,2,5,7,8-pentamethyl-6-hydroxychroman. A new dimer[END_REF][START_REF] Krol | Mechanisms of dimer and trimer formation from ultraviolet-irradiated alpha-tocopherol[END_REF]Schröder and Netscher, 2001;Rosenau et al., 2007a,b). A revisited mechanism involved in the formation of these dimers and trimers as well as in the formation of the 5-alkyloxy-dimethyltocol has been solved by [START_REF] Rosenau | Chemical composition of alpha-tocopherol, in Encyclopedia of Vitamin E[END_REF]. This reaction proceeded via a heterolytic reaction with oQM as an intermediate, ruling out the occurrence of 5a-C-centered radical intermediates as earlier proposed (Goodhue and Risley, 1964;Nilsson et al., 1968a;[START_REF] Suarna | Oxidations of vitamin E (.alpha.-tocopherol) and its model compound 2,2,5,7,8-pentamethyl-6-hydroxychroman. A new dimer[END_REF].

Furthermore, several other reactions may also be in competition hence limiting the antioxidant capacities of tocols. Solvolysis is a crucial contributor in tocol oxidation processes. Indeed, protic solvents may interact with phenols, hence preventing the interaction of phenolic OH with radicals [START_REF] Iwatsuki | Effects of solvents and media on the antioxidant activity of alpha-tocopherol[END_REF]. As an example, with ethanol as a solvent, α-T gives rise to 8a-ethoxy-tocopherone (XV) [START_REF] Svanholm | Electrochemistry in media of intermediate acidity. VIII. Reversible oxidation products of the .alpha.-tocopherol model compound. Cation radical, cation, and dication[END_REF][START_REF] Jore | Radiolytic study of -tocopherol oxidation in ethanolic solution[END_REF][START_REF] Sumarno | Solvent influence on model oxidations of α-tocopherol[END_REF][START_REF] Suarna | Effect of alcohols on the oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol[END_REF][START_REF] Litwinienko | Solvent effects on the rates and mechanisms of reaction of phenols with free radicals[END_REF][START_REF] Reichardt | Solvents and Solvent Effects in Organic Chemistry[END_REF][START_REF] Losada-Barreiro | Transfer of antioxidants at the interfaces of model food emulsions: distributions and thermodynamic parameters[END_REF].

The regeneration of α-TO • is often done by reducing agents such as vitamin C [START_REF] Scarpa | Formation of αtocopherol radical and recycling of α-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes: An electron paramagnetic resonance study[END_REF][START_REF] Liebler | Antioxidant protection of phospholipid bilayers by α-tocopherol. Control of α-tocopherol status and lipid peroxidation by ascorbic acid and glutathione[END_REF][START_REF] Liebler | Oxidation of vitamin E during iron-catalyzed lipid peroxidation: evidence for electron-transfer reactions of the tocopheroxyl radical[END_REF]. Vitamin C itself is either regenerated by reduced glutathione, cysteine or dihydrolipoic acid as intermediates [START_REF] Niki | Regeneration of vitamin E from tocopheroxyl radical by glutathione and vitamin C[END_REF][START_REF] Constantinescu | Vitamin E recycling in human erythrocyte membranes[END_REF][START_REF] Traber | Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-alpha-tocopherol[END_REF]. α-TO • can either be regenerated by nordehydroguaiaretic acid (NDGA) [START_REF] Liebler | Oxidation of vitamin E during iron-catalyzed lipid peroxidation: evidence for electron-transfer reactions of the tocopheroxyl radical[END_REF], ubiquinols [START_REF] Niki | Mechanisms and dynamics of antioxidant action of ubiquinol[END_REF][START_REF] Stoyanovsky | Ubiquinone-dependent recycling of vitamin E radicals by superoxide[END_REF] and bilirubin [START_REF] Neuzil | Free and albumin-bound bilirubin is an efficient co-antioxidant for α-tocopherol, inhibiting plasma and low-density lipoprotein lipid peroxidation[END_REF][START_REF] Bowry | Prevention of tocopherol mediated peroxidation of ubiquinol-10-free human low-density lipoprotein[END_REF], but at a slower rate than vitamin C.

Moreover, in vivo, Vitamin E may also be regenerated via a continuous supply of food antioxidants such as polyphenolic compounds. If -T is not regenerated, kinetic evidence shows that it reacts with peroxy radical generating systems. This can be seen in vitro with a homodimeric thermolabile azometabolites, containing an N = N double bond, that may undergo a temperature-dependent homolysis through first-order kinetics in the presence of α-TO • , thereby generating nitrogen and peroxyl radicals in aerobic systems. The most widely used azo compounds include 2,2'-azobis[2,4-dimethylvaleronitrile] (AMVN), 2,2'-azobis[2amidinopropane]hydrochloride (AAPH) [START_REF] Yamauchi | Vitamin E: mechanism of its antioxidant activity[END_REF]), 2,2-diphenyl-1picrylhydrazyl (DPPH) [START_REF] Tsuchija | Oxidation of lipids. IV. Formation and reaction of chromanoxyl radicals as studied by electron spin resonance[END_REF][START_REF] Musialik | Scavenging of dpph• radicals by vitamin E is accelerated by its partial ionization: the role of sequential proton loss electron transfer[END_REF] and 2,2'azobis(isobutyronitrile) (AIBN) [START_REF] Skinner | Reaction products of tocopherols[END_REF][START_REF] Mill | Comprehensive Chemical Kinetics[END_REF]. Unlike dialkylperoxides (ROOR') or alkylhydroperoxides (ROOH), these azometabolites do not react with themselves or with the solvent [START_REF] Mill | Comprehensive Chemical Kinetics[END_REF][START_REF] Winterle | Products of stoichiometry of reaction of vitamin E with alkylperoxy radicals[END_REF]. On the other hand, thermolysis or photolysis dissociation of dialkylperoxides or alkylhydroperoxides are also used as initiators and immediately lead to the formation of two oxyradicals with a very high affinity for hydrogens. This is often illustrated by di-t-butyl hydroperoxide (DTBP) and t-butyl hydroperoxide (TBHP). TBHP decomposed more readily in polar than in apolar solvents [START_REF] Stannett | The Kinetics of the Decomposition of Tertiary Hydroperoxides in Solvents[END_REF]. In apolar solvents, polytocopherols such as dimers and trimers have been characterized in appreciable amounts in the autoxidation of -T with unsaturated lipids [START_REF] Csallany | Oxidation products of α-tocopherol formed in autoxidizing methyl linoleate[END_REF]Yamauchi et al., 1988). In polar protic solvents, TBHP could immediately oxidize -T and solvolysis via a chromanoxylium cation led to the formation of 5a-ethoxymethyl-7,8dimethyltocol (XVI), α-TQ (V) as well as 5-formyl-7,8dimethyltocol (XVII). In addition, -tocopherol spiro-dimers (XI) and trimers (XIII) were also observed but not as much as in apolar solvents [START_REF] Suarna | Effect of alcohols on the oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol[END_REF][START_REF] Suarna | Oxidation of the α-tocopherol model compound 2,2,5,7,8-pentamethyl-6-chromanol in the presence of alcohols[END_REF].

Furthermore, the reaction of -T with less reactive peroxides such as ditertbutyl peroxy radicals leads mostly to a mixture of epoxytocopherones [START_REF] Matsumoto | Oxidation of a vitamin E model compound, 2,2,5,7,8-pentamethylchroman-6-ol, with the t-butylperoxyl radical[END_REF][START_REF] Matsuo | Radical-scavenging reactions of vitamin E and its model compound, 2,2,5,7,8-pentamethylchroman-6-ol, in a tertbutylperoxyl radical generating system[END_REF][START_REF] Liebler | Oxidation of vitamin E: Evidence for competing autoxidation and peroxyl radical trapping reactions of the tocopheroxyl radical[END_REF][START_REF] Liebler | Oxidation of vitamin E during iron-catalyzed lipid peroxidation: evidence for electron-transfer reactions of the tocopheroxyl radical[END_REF]. Under aerobic conditions, Oxygen-centered peroxyl radicals (LOO . ) derived from AMVN in hexane, acetonitrile or in liposomes, react respectively with α-TO • at the C-8a position, to give 8a-(lipid-dioxy)--tocopherone (I), 8a-(hydroxy)--tocopherone (III), and their hydrolysis product α-TQ (V). Interestingly, the three systems also provide epoxytocopherones (VII and VIII) and their respective hydrolysis products 2,3-epoxy-α-tocopherolquinone (IX) and 5,6-epoxy-α-tocopherolquinone (X) along with a small amount of 8a-(1-cyano-1,3-dimethyl)butylperoxy-α-tocopherone diastereoisomers (XVIII). The content of tocopherones compared to epoxytocopherones is dependent on the microenvironment of the medium although the yield of the α-TQ end product appears to be similar in the three different systems [START_REF] Liebler | Oxidation of vitamin E: Evidence for competing autoxidation and peroxyl radical trapping reactions of the tocopheroxyl radical[END_REF](Liebler et al., , 1994[START_REF] Liebler | Antioxidant stoichiometry and the oxidative fate of vitamin E in peroxyl radical scavenging reactions[END_REF][START_REF] Liebler | Gas chromatography-mass spectrometry analysis of vitamin E and its oxidation products[END_REF]. The reaction performed in hexane gave 8a-substituted tocopherone adducts in appreciable amounts compared to the reaction performed on liposome systems which were found to give higher amounts in epoxytocopherones [START_REF] Liebler | Antioxidant stoichiometry and the oxidative fate of vitamin E in peroxyl radical scavenging reactions[END_REF]. In another report, α-T is oxidized in the presence of AMVN in polar protic solvents such as ethanol, and led to other epoxytocopherone stereoisomers such as 4a,5-epoxy-8a-ethoxy-α-tocopherone (XIX), 7,8-epoxy-8a-ethoxytocopherone (XX) and 8a-(1-cyano-1,3-dimethyl)butylperoxy-αtocopherone (XVIII) [START_REF] Yamauchi | Reaction products of αtocopherol with a free radical initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)[END_REF]. [START_REF] Liebler | Oxidation of vitamin E: Evidence for competing autoxidation and peroxyl radical trapping reactions of the tocopheroxyl radical[END_REF][START_REF] Liebler | Oxidation of vitamin E during iron-catalyzed lipid peroxidation: evidence for electron-transfer reactions of the tocopheroxyl radical[END_REF] demonstrated two distinct pathways of different origins respectively for the formation of 8a-(lipidioxy)-α-tocopherone derivatives compared to the epoxytocopherone systems either in homogeneous systems or with liposomes. These two systems resulted from two competing reactions between α-TO • and peroxy radicals. Moreover, unlike the formation of tocopherone diastereomers which were directly involved in the antioxidant activity of α-T, epoxytocopherones were not and may occur only by autoxidation of α-T probably by a four-electron oxidation.

In other reports, the oxidation of -T by methyl linoleate hydroperoxide generating systems, entails the formation of stable products such as -TQ, as well as the formation of dimers and trimers [START_REF] Csallany | Oxidation products of α-tocopherol formed in autoxidizing methyl linoleate[END_REF]Yamauchi et al, 1988). In addition, with methyl linoleate-AMVN-derived peroxyl radicals, the primary products formed include 8a-(lipiddioxy)--tocopherones, four stereoisomers of methyl-13-(8a-peroxy--tocopherone)-9(Z),11(E)-octadienoate and four others of methyl-9-(8a-peroxy--tocopherone)-10(E),12(Z)octadienoate (an example of structure (XXI) is depicted in fig. 5) [START_REF] Yamauchi | Reaction products of α-tocopherol with methyl linoleate-peroxyl radicals[END_REF].

The thermolytic incubation at 37 °C of liposomes containing -T with AMVN as an initiator, led to the formation of 8a-(1-cyano-1,3-dimethyl)butylperoxy-α-tocopherone (Fig. 5, XVIII), 8a-(hydroperoxy)tocopherone (Fig. 5, IV), -TQ (Fig. 5, V), 4a,5-epoxy-8ahydroperoxytocopherone (Fig. 5, VII), 2,3-epoxy--tocopherol quinone (Fig. 5, IX), and 5,6epoxy-a-tocopherol quinone (Fig. 5, X) [START_REF] Liebler | Peroxyl radical trapping and autoxidation reactions of α-tocopherol in lipid bilayers[END_REF]. [START_REF] Yamauchi | Isolation and characterization of addition products of α-tocopherol with peroxyl radicals of dilinoleoylphosphatidylcholine in liposomes[END_REF][START_REF] Yamauchi | Oxidation of alpha-tocopherol during the peroxidation of dilinoleoylphosphatidylcholine in liposomes[END_REF][START_REF] Yamauchi | Preparation and characterization of 8a-(phosphatidylcholine-dioxy)-alpha-tocopherones and their formation during the peroxidation of phosphatidylcholine in liposomes[END_REF], showed that α-T suppressed the formation of different hydroperoxides formed in liposomes using the lipophilic AMVN or the hydrophilic AAPH radicals as initiators. For example, multilamellar liposomes of dilinoleoyl phosphatidylcholine (DLPC) liposomes containing small amounts of -T (0.1 mol %) incubated with AMVN as an initiator, led to the production of a mixture of 8a-alkyldioxy-α-tocopherones as major products.

Epoxytocopherones and their respective stable end-products were also detected. Amongst these products, α-TQ, epoxytocopherones 2,3 oxide and tocopherone 5,6 oxide, and DLPCderived 8a-(lipid-dioxy)-α-tocopherones were formed with the mechanism described above for the methyl linoleate model. Indeed, peroxyl radical liposomes react with the αtocopheroxy radical in position C8a. The central Sn-2-position of phospholipids was more subject to oxidation compared to the external Sn-1,3 positions of the glycerol moiety (Neff and ElAgaimy, 1996). In addition, the most labile allylic proton at C-11, in the Sn-2 position, generated a carbon-centered radical by transfer of a hydrogen in C-9 or C-13 respectively. As an example, one isomer formed is the 1-linoleoyl-2-[13-(8a-dioxy-(α-tocopherone)-9(Z),11(E)-octadecadienoyl]-3-sn-phosphatidylcholine (DLPC-derived 8a-(lipid-dioxy)-αtocopherones (XXII)) (figure 5). No evidence for the formation of such a compound has been found in vivo. The 8a-(phospholipid-dioxy)-α-tocopherones were indeed deemed degraded to produce α-tocopherylquinone [START_REF] Yamauchi | Isolation and characterization of addition products of α-tocopherol with peroxyl radicals of dilinoleoylphosphatidylcholine in liposomes[END_REF][START_REF] Yamauchi | Oxidation of alpha-tocopherol during the peroxidation of dilinoleoylphosphatidylcholine in liposomes[END_REF][START_REF] Yamauchi | Preparation and characterization of 8a-(phosphatidylcholine-dioxy)-alpha-tocopherones and their formation during the peroxidation of phosphatidylcholine in liposomes[END_REF].

Lipid hydroperoxides may be decomposed into free radicals through a transition metal catalysis (Halliwell and Gatteridje, 1984;[START_REF] Sevanian | Mechanisms and consequences of lipid peroxidation in biological systems[END_REF]. Iron III complexcatalyzed decomposition of methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate with α-T in aerobic homogeneous solutions has been studied by [START_REF] Yamauchi | Iron-catalyzed reaction products of αtocopherol with methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate[END_REF]. They report that the lipid alkoxyl radicals that are generated tend to rearrange into carbon-centered epoxyallylic radicals, which are then added to the 8a-carbon radical of α-T. The 5) [START_REF] Yamauchi | Iron-catalyzed reaction products of αtocopherol with methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate[END_REF].

Although in human LDL, α-T does not provide any protection against oxidation of the cholesterol-esterified linoleate [START_REF] Kim | Lipid-soluble 3pyridinol antioxidants spare alpha-tocopherol and do not efficiently mediate peroxidation of cholesterol esters in human low-density lipoprotein[END_REF], the in vitro peroxidation of LDL lipids generates hydroperoxides mainly from cholesteryl linoleate (Ch18:2). 9-and 13hydroperoxides with trans, cis conjugated diene were formed as the major oxidation products if endogenous α-T was present in the LDL [START_REF] Horton | Lipid peroxidation and mechanisms of toxicity[END_REF][START_REF] Frei | Antioxidant defenses and lipid peroxidation in human blood plasma[END_REF][START_REF] Kenar | Identification and quantification of the regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein[END_REF]. Oxidation products of α-T with peroxyl radicals generated by ironcatalyzed decomposition of Ch18:2 hydroperoxides (Ch18:2-OOH) in homogeneous systems, have been investigated [START_REF] Yamauchi | Preparation of the addition products of alpha-tocopherol with cholesteryl linoleate-peroxyl radicals[END_REF]. The results indicated that the peroxyl radicals from CH18:2-OOH react with the 8a-carbon radical of α-T to form addition products such as cholesteryl (8a-dioxy-α-tocopherone)-epoxyoctadecenoates (4 isomers) along with cholesteryl (8a-dioxy-α-tocopherone) octadecadienoates (2 isomers), these are illustrated by structures XXIV and XXV, depicted in figure 5 [START_REF] Yamauchi | Preparation of the addition products of alpha-tocopherol with cholesteryl linoleate-peroxyl radicals[END_REF].

During lipoperoxidation, research on other congeners (γ-and -), which were not fully methylated gave somewhat other insights into their oxidation products as well as their antioxidant potentials. Similar tocopherones were formed, albeit in smaller amounts than for the α-form, including 8a-(alkyl-dioxy)-γ-tocopherones (XXVI) and 8a-(alkyl-dioxy)-tocopherones. Self recombinations of γand tocopheroxy radicals led to the formation of other dimer types that still have potent antioxidant activities by means of their free hydroxy protons. More specifically, the emerging products from the γ-form include, in addition to 8a-(lipid-dioxy)-5-(γ-tocopheroxy)-γ-tocopherone (XXVII), the γ-tocopherol diphenylether dimer (γ-TED, XXVIII), 5-(γ-tocopheroxy-5-yl)-γ-tocopherol (γ-TBD, XXIX) along with γtocored (XXX) and γ-tocopherylquinone (γ-TQ, XXXII) [START_REF] Komoda | A dimeric oxidation product of gamma-tocopherol in soybean oil[END_REF]Fujitani & Yukagaku, 1984 ;[START_REF] Yamauchi | Vitamin E: mechanism of its antioxidant activity[END_REF]. Tocored (XXX) is an intense bright orange-red metabolite, which may also be formed from the fully methylated chroman moiety of α-T due to the unusual cleavage at the 5a-methyl group site of α-T [START_REF] John | Über einige oxydationsprodukte der tokopherole und analoger einfacher modellkörper. 6. Mitteilung über antisterilitätsfaktoren (Vitamin E)[END_REF][START_REF] Komoda | Interaction of tocored with unsaturated fatty esters[END_REF]. The exact mechanism responsible for its formation was elegantly deciphered by [START_REF] Rosenau | Novel tocopherol compounds VIII. Reaction mechanism of the formation of α-tocored[END_REF]. Compared to the γ-form, similar results have been reported with δ-T, however, no evidence on the formation of δ-TBD compared to γ-TBD, has been reported in the autoxidation of methyl linoleate with the AMVN peroxyl radical generating system [START_REF] Yamauchi | Vitamin E: mechanism of its antioxidant activity[END_REF].

Vitamin E oxidation products with other radicals and oxidants

At a first glance, in the absence of other lipid co-substrates, tocol oxidometric assays have been achieved in strong acid media or using conventional reagents based on transition metals (3d) and lanthanides (4f) which may form colored compounds. Indeed, the oxidizability of the 6-hydroxychroman ring of α-T and δ-T with metal ions generates the corresponding 1,4-Benzoquinones [START_REF] John | Über einige oxydationsprodukte der tokopherole und analoger einfacher modellkörper. 6. Mitteilung über antisterilitätsfaktoren (Vitamin E)[END_REF][START_REF] Frampton | The Production of Tocored upon the Oxidation of dl α-Tocopherol with Ferric Chloride[END_REF][START_REF] Frampton | -Tocopurple, an oxidation product of -tocopherol[END_REF][START_REF] Skinner | Reaction products of tocopherols[END_REF][START_REF] Khallouki | Molecular and biochemical analysis of the estrogenic and proliferative properties of vitamin E compounds[END_REF]. When the oxidation was carried out in boiling alcohol, it gave tocored, amongst other minor metabolites including hydroxy-p-quinone (tocopurple, XXXI). The oxidation of α-T with ferric chloride, was earlier the basis for precise and simple reactions to carry out in clinical routine assays to help characterize tocopherols colorimetrically [START_REF] Emmerie | Colorimetric determination of α-tocopherol (vitamin E)[END_REF][START_REF] Martinek | Method for the determination of vitamin E (total tocopherols) in serum[END_REF]. More interestingly, a mild oxidation of α-T with alkaline ferricyanide K3Fe(CN)6, a red crystalline and hydrophilic solid oxidant of α-T, caught the attention of several biochemists due to its probable resemblance with in vivo vitamin E oxidation, which generates α-T dimers and trimers [START_REF] Nelan | The oxidation product from α-tocopherol and potassium ferricyanide and its reaction with ascorbic and hydrochloric acid[END_REF][START_REF] Schudel | Über die chemie des vitamins E. 2. Mitteilung. Die struktur des kaliumferricyanid-oxydations produktes von α-Tocopherol[END_REF][START_REF] Skinner | Oxidation products of vitamin E and its model, 6hydroxy-2,2,5,7,8-pentamethyl-chroman. V. Studies of the products of alkaline ferricyanide oxidation[END_REF]and Nilsson et al., 1968b).

A metastable state of oxygen such as singlet oxygen confers it dienophilic properties.

It can be either quenched physically or chemically by other species to return to its ground state, or react via 1,3-addition, as well as [4/2] cycloaddition in a similar manner to the Diels/Alder reaction. From a kinetic point of view, α-T reacts favorably with singlet oxygen, but to a lesser extent with oxygen superoxide. Singlet oxygen may also originate from multiple substrates including anion superoxide, ozone, hydrogen peroxide, enzymes and sensitizers amongst many others [START_REF] Krinsky | Antioxidant functions of carotenoids[END_REF]. When it reacts with α-T, it yields α-TQ and TQE [START_REF] Grams | Dye-sensitized photooxidation of .alpha.tocopherol[END_REF][START_REF] Clough | Chemistry of singlet oxygen. 30. The unstable primary product of tocopherol photooxidation[END_REF][START_REF] Neely | Products and relative reaction rates of the oxidation of tocopherols with singlet molecular oxygen[END_REF][START_REF] Sies | Strategies of antioxidant defense[END_REF]. The reaction of α-T with superoxide ion (O2 -. ) in aprotic solvents was different from that observed under protic conditions [START_REF] Kaiser | Physical and chemical scavenging of singlet molecular oxygen by tocopherols[END_REF][START_REF] Ha | α-Tocopherol oxidation mediated by superoxide anion. II. Identification of the stable α-Tocopherol oxidation products[END_REF]. In line with this, it may act either as a nucleophile [START_REF] Dietz | Nucleophilic reactions of electrogenerated superoxide ion[END_REF] or as an electrogenerated base (EGB) [START_REF] Sugawara | Electrogenerated bases. VI. II. Reaction of electrogenerated anion superoxides with some carbon acids[END_REF]. The reaction of α-T with superoxide anion O2 .-in a protic solvent is very slow [START_REF] Nishikimi | Oxidation of alpha-tocopherol model compound by superoxide anion[END_REF]. In aprotic solvents, it produced two unique tocopherone isomers, hydroxylated at the position C7, both were stereoisomers of 7-hydroxy-8,8a-epoxyα-tocopherone (XXXIII). However, under protic conditions (10% water in acetonitrile), the reaction with α-T produced compounds such as α-TQ, α-tocopherol dimer, and α-tocopherylquinone-2,3-epoxide (Ha and Cssalany, 1992). In addition, [START_REF] Matsumoto | The reaction of a α-tocopherol model compound with KO2, a new oxidation product of 6-hydroxy-2,2,5,7,8-pentamethylchroman[END_REF], used a rare oxidizing and drying salt of superoxide anion O2 -. in a reaction with an analog of α-T (6-hydroxy-2,2,5,7,8-pentamethylchroman) in aprotic polar tetrahydrofuran. With this system, they were able to hydroxylate the C-5 of the chroman ring. The same behavior was described by oxidation with bromine of α-T inducing the formation of 5-bromomethyl--tocopherol (XXXIV) [START_REF] Rosenau | Novel tocopherol compounds I. Bromination of αtocopherol reaction mechanism and synthetic applications[END_REF]. The oxidation of α-T with organic oxidants such as N-bromosuccinimide or with quinone reagents, led to the formation of 8ahydroxy-α-tocopherone (IV) [START_REF] Durckheimer | The chemistry of 9-hydroxy-α-tocopherone, a quinone hemiacetal[END_REF]. The same compound has been detected as the main product in a micellar system, in which α-T was dispersed in an aqueous media with deoxycholate as an emulsifier and oxidized by xanthine-xanthine oxidase, a system that mostly generated superoxide anion and hydroxyl radicals [START_REF] Nishikimi | Oxidation by superoxide of tocopherols dispersed in aqueous media with deoxycholate[END_REF].

All tocols except the fully methylated α-T and α-tocotrienol (α-T3) react with nitrous acid. γ-T forms 5-nitro-γ-tocopherol (tocoyellow) which is a yellow nitro compound [START_REF] Brigelius-Flohé | Vitamin E: function and metabolism[END_REF][START_REF] Cooney | Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alphatocopherol[END_REF]. Dimers -TED and -TBD have also been formed with 2% triethylamine oxide (TMAO) in a methyl linoleate system [START_REF] Ishikawa | The mechanism of synergism between tocopherols and trimethyl amine oxide in the inhibition of the autoxidation of methyl linoleate[END_REF].

Thermal oxidation of α-T in hexane may readily lead to α-TQ, 5-formyl-γ-tocopherol

(5-F-γ-T), as well as spirodimers and spirotrimers and the formation of -T was also observed [START_REF] Büsing | Separation of α-tocotrienol oxidation products and eight tocochromanols by HPLC with DAD and fluorescence detection and identification of unknown peaks by DAD, PBI-EIMS, FTIR, and NMR[END_REF][START_REF] Kreps | Synthesis and analysis of tocopheryl quinone and tocopherol esters with fatty acids in heated sunflower oil[END_REF]. The thermal decomposition of other forms of tocols such as α-T3, which is the least thermostable Tocotrienol vitamin, with the highest rate of degradation [START_REF] Piironen | Stability of tocopherols and tocotrienols during storage of foods[END_REF][START_REF] Ko | Effects of tocopherols and tocotrienols on the inhibition of autoxidation of conjugated linoleic acid[END_REF], led to the formation of oxidation products similar to the α-T congener. These include 7-formyl-β-tocotrienol (XXXV) and 5-formyl-γtocotrienol (XXXVI) as well as α-tocotrienol dihydroxydimers (XXXVII) as major products alongside α-tocotrienol quinone (XXXIX), α-tocotrienol spiro-dimers (XXXVIII) and αtocotrienol spiro-trimers (XL) (Busing and Ternes, 2011). More recent insights into the oxidation products of the eight forms of tocols thermally stressed in an apolar solvent such as hexane, have also been performed and comprehensively reported by [START_REF] Drotleff | HPLC separation of vitamin E and its oxidation products and effects of oxidized tocotrienols on the viability of MCF-7 breast cancer cells in vitro[END_REF].

Vitamin E oxidation products in oils

Different findings as to the decomposition of tocols at high temperature in oils have been reported both in natural oils and in tocopherol-stripped oils.

The formation of TQ, Epoxy-tocopherylquinone and α-Tocotrienylquinone epoxides as well as tocored rather than Tocopherones, have often been detected [START_REF] Murkovic | Formation of α-tocopherolquinone and α-tocopherolquinone epoxides in plant oil[END_REF][START_REF] Verleyen | Modeling of alphatocopherol loss and oxidation products formed during thermoxidation in triolein and tripalmitin mixtures[END_REF][START_REF] Nagy | Comprehensive analysis of vitamin E constituents in human plasma by liquid chromatography-mass spectrometry[END_REF]Büsing and Drotleff, 2012;Niki, 2019), whereas photoirradiation of extra virgin Olive Oil entailed the formation of tocopherone stereoisomers with no TQ observed [START_REF] Tanno | Analysis of oxidation products of αtocopherol in extra virgin olive oil using liquid chromatography-tandem mass spectrometry[END_REF]. Tocored was also reported to be a strong natural antioxidant useful for oil preservation and especially suitable for lipid based food substrates [START_REF] Komoda | A dimeric oxidation product of gamma-tocopherol in soybean oil[END_REF][START_REF] Zheng | Highpurity tocored improves the stability of stripped corn oil under accelerated conditions[END_REF]. Tocored was reported to be present for the first time in cottonseed oil [START_REF] Golumbic | Antioxidants and Autoxidation of Fats. XIV. The isolation of new antioxidants from vegetable fats[END_REF], in germ oil [START_REF] Swift | Gamma-tocopherol as a precursor of a red quinoid substance developed in cottonseed oil during oxidation[END_REF][START_REF] Komoda | A dimeric oxidation product of gamma-tocopherol in soybean oil[END_REF] as well as in soybean oil [START_REF] Komoda | Studies on cause of color reversion of edible soybean oil and its prevention: part II tocored as a precursor of color reversion of soybean oil[END_REF]. The concentration of tocored in soybean was found to be moisture-dependent, and could reach 102.2 mg kg -1 [START_REF] Komoda | Studies on cause of color reversion of edible soybean oil and its prevention: part II tocored as a precursor of color reversion of soybean oil[END_REF]. Tocopherylquinone is a major oxidation metabolite present in oils. It may accumulate as the plant's response to biotic as well as abiotic stress including drought, thermal stress, and leaf age [START_REF] Kruk | Occurrence and function of α-tocopherol quinone in plants[END_REF][START_REF] Kruk | Tocopherol as singlet oxygen scavenger in photosystem II[END_REF]Munne-Bosch, 2005). At high thermal oxidation or cooking, -TO • undergoes a self-coupling to produce dimers and trimers in corn oil, and mixed dimers with two different tocopherols and tocotrienols have also been reported (Nilsson et al., 1968b). However, these products were not subsequently observed and this was probably due to the different dimerization kinetics observed for each tocol analog [START_REF] Gutfinger | Studies of tocopherols dimers from soybean oil by reaction gas chromatography[END_REF]Niki, 2019).

Vitamin E oxidation products in biological samples

Oxidation products of vitamin E have also been detected in the urine and plasma of animals and humans, in cell cultures, in human atherosclerotic lesions amongst many other biological samples, and some are reported here [START_REF] Csallany | Conversion of d-α-tocopherol-C14 to tocopheryl-p-quinone in vivo[END_REF][START_REF] Hughes | Synthesis of alpha-tocopherolquinone by the rat and its reduction by mitochondria[END_REF][START_REF] Vatassery | A liquid chromatographic method for the simultaneous determination of alpha-tocopherol and tocopherolquinone in human red blood cells and other biological samples where tocopherol is easily oxidized during sample treatment[END_REF][START_REF] Wurzel | Oxidative damage and antioxidant status in the lungs and bronchoalveolar lavage fluid of rats exposed chronically to cigarette smoke[END_REF][START_REF] Jain | Vitamin E and vitamin E-quinone levels in red blood cells and plasma of newborn infants and their mothers[END_REF][START_REF] Yanagawa | Age-related change in the alpha-tocopherolquinone/alpha-tocopherol ratio in the rat erythrocyte membrane[END_REF][START_REF] Terentis | Vitamin E oxidation in human atherosclerotic lesions[END_REF]Mangialasche 2013a;[START_REF] Torquato | Analytical strategies to assess the functional metabolome of vitamin E[END_REF]. It is worth noting that numerous biological systems are able to reduce tocopherylQuinone to tocopherylhydroQuinone (TQH2) and this reaction may occur normally in vivo [START_REF] Kohar | Is alphatocopherol a reservoir for alpha-tocopherol hydroquinone[END_REF]. Moreover, α-T is not the sole precursor of α-TQ, there is also a proof of concept that α-TQ can also be biosynthesized even in the absence of α-T, in normal human plasma, and in animal tissues. The concentration of α-TQ remains smaller compared to the parent compound due, in part, to the recycling of -TO • into α-T. In vivo studies have shown that α-TQ and its epoxide derivatives did not alter the antioxidant status in rat liver tissues. This clearly indicates the presence of an efficient reductase that catalyzes α-TQ into α-TQH2 via the epoxide forms. The reductase was identified as the NAD(P)H:quinone oxidoreductase 1 (NQO1) [START_REF] Siegel | The reduction of alphatocopherolquinone by human NAD(P)H: quinone oxidoreductase: The role of alphatocopherol hydroquinone as a cellular antioxidant[END_REF][START_REF] Leray | Simultaneous determination of homologues of vitamin E and coenzyme Q and products of αtocopherol oxidation[END_REF][START_REF] Mayhoub | Optimization of thiazole analogues of resveratrol for induction of NAD (P) H:quinone reductase 1 (QR1)[END_REF], or as thioredoxin reductase with varying potencies [START_REF] Fang | Ebselen: a thioredoxin reductasedependent catalyst for alpha-tocopherol quinone reduction[END_REF][START_REF] Gregor | Distribution of tocopheryl quinone in mitochondrial membranes and interference with ubiquinone-mediated electron transfer[END_REF]). α-TQ behaves like a redox-cycling agent. It may act as an antioxidant after its conversion in biological systems to its reduced form α-TQH2. α-TQH2 acts as a potent radical-scavenging agent and is more active than ubiquinol (a reduced form of coenzyme Q), or its parent molecule α-T [START_REF] Kruk | Fluorescence properties of plastoquinol, ubiquinol and α-tocopherol quinol in solution and liposome membranes[END_REF][START_REF] Kohar | Is alphatocopherol a reservoir for alpha-tocopherol hydroquinone[END_REF][START_REF] Neuzil | α-Tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low density lipoprotein lipids[END_REF][START_REF] Shi | Comparative study on dynamics of antioxidative action of alpha-tocopheryl hydroquinone, ubiquinol, and alpha-tocopherol against lipid peroxidation[END_REF][START_REF] Niki | Tocopherylquinone and tocopherylhydroquinone[END_REF][START_REF] Shrader | Towards a modern definition of vitamin E-evidence for a quinone hypothesis[END_REF]).

α-TQH2 can be re-oxidized into α-TQ, hence constituting a quinone/hydroquinone antioxidant redox system as illustrated in figure 6 [START_REF] Niki | Inhibition of oxidation of methyl linoleate in solution by vitamin E and vitamin C[END_REF][START_REF] Mukai | Kinetic study of the prooxidant effect of tocopherol. Hydrogen abstraction from lipid hydroperoxides by tocopheroxyls in solution[END_REF][START_REF] Shi | Comparative study on dynamics of antioxidative action of alpha-tocopheryl hydroquinone, ubiquinol, and alpha-tocopherol against lipid peroxidation[END_REF][START_REF] Itoh | Advantages and limitation of BODIPY as a probe for the evaluation of lipid peroxidation and its inhibition by antioxidants in plasma[END_REF].

In experimental models of isolated rat liver mitochondria as well as in perfused rat liver, the reaction of α-T with AAPH or with tertbutylhydroperoxide, generated α-TQ, α-TQH2 and epoxyquinones, with no evidence of the formation of 8a-(lipid-dioxy)-αtocopherones) (Ham & Liebler, 1992, 1997). In lipid bilayers, 8a-hydroperoxytocopherones were detected as very minor products throughout peroxyl radical-mediated oxidations [START_REF] Matsuo | Radical-scavenging reactions of vitamin E and its model compound, 2,2,5,7,8-pentamethylchroman-6-ol, in a tertbutylperoxyl radical generating system[END_REF]. It has also been reported that in rat, chick and earthworm tissues, a rare 2,5,6-trimethyl-3-(farnesylfarnesylgeranyl-geranyl)1,4-benzoquinone was formed following α-T side-chain oxidation and elongation (Martius and Purer (1963)). In bovine muscle microsome systems, as well as in chilled and frozen fish muscle, the presence of α-TQ along with epoxytocopherones as the main α-T oxidation products respectively was reported [START_REF] Faustman | α-Tocopherol oxidation in beef and in bovine muscle microsomes[END_REF][START_REF] Pazos | α-Tocopherol oxidation in fish muscle during chilling and frozen storage[END_REF]. In isolated LDL, the main oxidation product of α-T was α-TQ alongside 5,6-epoxy-α-tocopherylquinone (α-TQE1) and its hydrolytic product 2,3-epoxy-α-tocopherylquinone (α-TQE2) [START_REF] Terentis | Vitamin E oxidation in human atherosclerotic lesions[END_REF]. The presence of a phosphorylated form of α-T, although present in small quantities in various biological samples (plasma, tissues), suggested the existence of an α-tocopherol kinase/phosphatase, which remains to be identified [START_REF] Zingg | alpha-Tocopheryl phosphate an active lipid mediator[END_REF].

Furthermore, from a nitrative stress point of view, in mammals, large quantities of Nitric Oxide (NO . ), are generated through the oxidative deamination of arginine by iNos synthase catalysis [START_REF] Marietta | Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate[END_REF]Nathann 1992;[START_REF] Chiueh | Neuroprotective properties of nitric oxide[END_REF]. NO . is a mixed hydrosoluble/liposoluble gas highly diffusible in cell membranes from the vascular system. At high concentrations, NO . quickly interacts with the superoxide anion radical to produce the toxic peroxynitrite (ONOO ─ ) anion, which is a powerful oxidant of biological tissues [START_REF] Radi | Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide[END_REF][START_REF] Ischiropoulos | Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase[END_REF]. This entails the formation of two radicals: a hydroxyl radical and a nitro radical, at physiological pH. Unlike the full methylated α-tocopherol, the 5th position in the -T is unoccupied on the chromanol ring, and may undergo facile electrophilic or nucleophilic susbtitution reactions, which explains why 5-nitro--tocopherol

(5-NO2--T, XLII, fig. 5) is produced [START_REF] Cooney | Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alphatocopherol[END_REF][START_REF] Hoglen | Reactions of peroxynitrite with gamma-tocopherol[END_REF][START_REF] Christen | Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol, physiological implications[END_REF][START_REF] Hensley | HPLC-electrochemical detection of tocopherol products as indicators of reactive nitrogen intermediates[END_REF]. 5-NO2--T was not detected in human LDL possibly due to the regeneration of -T by -T [START_REF] Beckman | Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly[END_REF][START_REF] Umeno | Isomer distribution of hydroxyoctadecadienoates (HODE) and hydroxyeicosatetraenoates (HETE) produced in the plasma oxidation mediated by peroxyl radical, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen[END_REF][START_REF] Morita | Comparative study on the plasma lipid oxidation induced by peroxynitrite and peroxyl radicals and its inhibition by antioxidants[END_REF],

although it has been observed in vitro by the treatment of lipoproteins with peroxynitrite and in lipopolysaccharide-stimulated rat astrocytes [START_REF] Christen | Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol, physiological implications[END_REF][START_REF] Christen | Analysis of plasma tocopherols α, γ, and 5nitro-γ in rats with inflammation by HPLC coulometric detection[END_REF]. In vivo, 5-NO2--T and its probable metabolites are possible biomarkers of the formation of reactive nitrogen species. Indeed a number of studies have reported increasing levels of 5-NO2--T in smokers and sick individuals with metabolic syndromes associated with elevated nitrative stress [START_REF] Christen | Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol, physiological implications[END_REF][START_REF] Morton | Evidence for the nitration of gamma-tocopherol in vivo: 5-nitro-gamma-tocopherol is elevated in the plasma of subjects with coronary heart disease[END_REF][START_REF] Williamson | The nitration product 5-nitro-gamma-tocopherol is increased in the Alzheimer brain[END_REF][START_REF] Leonard | Studies in humans using deuterium-labeled alpha-and gamma-tocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production[END_REF][START_REF] Devaraj | Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome[END_REF]. In addition, 5-chloro--tocopherol may also be formed due to the action of Hypochlorous acid (HOCl), both products are considered as specific biomarkers of nitrative and oxidative stress respectively. In vivo, HOCl, which is generated by stimulated neutrophils during inflammation and infection, may also react with -T as well as -T to produce -TQ and -TQ respectively [START_REF] Eiserich | Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification[END_REF][START_REF] Nguyen | Reaction of gamma-tocopherol with hypochlorous acid[END_REF].

Although some studies showed no evidence of the formation of dimers or trimers [START_REF] Plack | Metabolic products of α-tocopherol in the liver of rats given intraperitoneal injections of [14C]-alpha-tocopherol[END_REF]Bieri (1963, 1964)), other researchers succeeded in their isolation from mammalian livers and spleens (Csallany et al, 1963a,b;[START_REF] Mellors | The distribution and metabolism of alpha-tocopherol in the rat[END_REF][START_REF] Draper | Isolation of a trimer of α-tocopherol from mammalian liver[END_REF][START_REF] Strauch | Dimers and trimers of alphatocopherol: metabolic and synthetic studies[END_REF]. In mouse skin irradiated by UV, the topical application of α-T induced the formation of α-T dimers as major photoproducts [START_REF] Kramer-Stickland | UV-B-induced photooxidation of vitamin E in mouse skin[END_REF].

In vivo Vitamin E Catabolites

If tocols are oxidized at the level of their chroman cycles in vitro (see vide supra), their phytyl side chains still remain stable against chemical attacks (Rosenau et al., 2007a[START_REF] Rosenau | ortho-Quinone methides[END_REF].

However, in vivo vitamin E isoforms are catabolized at different rates in the liver to produce α-, β-, γ-, and δ-carboxyethylhydroxychromanol (CEHC). The formation of various tocol metabolites through the side chain oxidation pathway, has also been detected in plasma and cell cultures [START_REF] Sontag | Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism: novel mechanism of regulation of vitamin E status[END_REF][START_REF] Jiang | Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats[END_REF][START_REF] Jiang | Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using liquid chromatography tandem mass spectrometry[END_REF]. This biotransformation is catalyzed by phase I enzymes, much like tocopherol ω-hydroxylase activity, which is associated with microsomal cytochrome CYP4F2 and CYP3A4. These enzymes catalyze the -hydroxylation of the methyl terminal, and susbsequently, a microsomal dehydrogenase oxidation step led to 13'-hydroxychromanol (13'-OH) and 13'-carboxychromanol (13'-COOH) production [START_REF] Birringer | Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation[END_REF]. The oxidative chain-shortening reactions leading to these products consists in five cycles of β-oxidation. Two steps occur in peroxisomes and three occur in mitochondria. Each β-oxidation cycle cleaves a two carbon moiety from the main side chain to give 3′-COOHs as end products, and mid or shorter-chain carboxychromanols such 11′-, 9′-, 7′-and 5′-COOHs [START_REF] Birringer | Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation[END_REF][START_REF] Birringer | Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells[END_REF][START_REF] Sontag | Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism: novel mechanism of regulation of vitamin E status[END_REF]Mustacich et al., 2010;[START_REF] Jiang | Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using liquid chromatography tandem mass spectrometry[END_REF][START_REF] Bartolini | alpha-Tocopherol metabolites (the vitamin E metabolome) and their interindividual variability during supplementation[END_REF]. These metabolites have intact ring structures illustrating their non participation in the antioxidant activity of tocols [START_REF] Schultz | Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply[END_REF][START_REF] Galli | Gas chromatography mass spectrometry analysis of carboxyethyl-hydroxychroman metabolites of alpha-and gamma-tocopherol in human plasma[END_REF][START_REF] Galli | The effect of αand γ-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation[END_REF][START_REF] Freiser | Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman and sulfated long-chain carboxychromanols in rats[END_REF]). Long chains of -T metabolites are depicted in figure 7.

The enzyme kinetics necessary to form carboxy chromanol derivatives depend on the presence of their other isoforms as well as their respective concentrations [START_REF] Devaraj | Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome[END_REF]. α-T is metabolized by Cyp3A4 [START_REF] Birringer | Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation[END_REF], while Cyp4F2 preferentially oxidizes γ-T and -T [START_REF] Sontag | Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism: novel mechanism of regulation of vitamin E status[END_REF][START_REF] Leonard | Studies in humans using deuterium-labeled alpha-and gamma-tocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production[END_REF]. CEHC (3'-COOH)

predominates in human plasma and stems essentially from γ-T oxidation (up to 10 µM) [START_REF] Burbank | A short course of gamma-tocopherol mitigates LPS-induced inflammatory responses in human's ex vivo[END_REF]. Long chain carboxychromanol 11′-COOHs from -T and γ-T forms were found in the plasma of rodents [START_REF] Jiang | Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using liquid chromatography tandem mass spectrometry[END_REF], while and γ-13'COOH were found in mice feces [START_REF] Jiang | Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice[END_REF]. In parallel, these compounds can be found in bioconjugated forms in plasma, bile, feces or urine. Sulfated, glucuronidated forms were found in animal and human urine [START_REF] Chiku | Novel urinary metabolite of d-deltatocopherol in rats[END_REF][START_REF] Swanson | Urinary excretion of 2,7,8trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman is a major route of elimination of gamma-tocopherol in humans[END_REF][START_REF] Schultz | Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply[END_REF][START_REF] Zhao | Analysis of multiple metabolites of tocopherols and tocotrienols in mice and humans[END_REF][START_REF] Li | Isolation and identification of alpha CEHC sulfate in rat urine and an improved method for the determination of conjugated alpha-CEHC[END_REF] as well as in human plasma [START_REF] Jiang | Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats[END_REF][START_REF] Freiser | Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman and sulfated long-chain carboxychromanols in rats[END_REF].

Glucosidated forms were reported to be present in mouse urine [START_REF] Cho | Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation[END_REF] and unconjugated forms were detected in feces [START_REF] Zhao | Analysis of multiple metabolites of tocopherols and tocotrienols in mice and humans[END_REF][START_REF] Pein | Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase[END_REF].

Studies in humans using deuterium-labeled αand γ-T demonstrated faster plasma γ-T disappearance and greater γ-metabolite production [START_REF] Leonard | Studies in humans using deuterium-labeled alpha-and gamma-tocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production[END_REF]. γ-T is indeed rapidly converted by the liver in a cytochrome P450-dependent manner to its water-soluble metabolite γ-carboxyethyl hydroxychroman (γ-CEHC) in a free or bioconjugated form. These forms have been proposed to be those expected to exert beneficial biopotencies in vivo as well as at the cellular level.

Large dose α-T dietary supplementation in humans and animals gives rise to the production of sulfated or glucuronide derivatives that can be found in urine. These are known as "Simon" metabolites. These are yellow oils, considerably more polar than α-T or any of its known oxidation products and are slightly soluble both in water and in lipophilic solvents.

These metabolites were identified as α-Tocopheronic acid, α-tocopheronolactone and γtocopheronolactone [START_REF] Simon | The metabolism of vitamin E. I. The absorbtion and excretion of d-α-tocopheryl-5-methyl-C 14 -succinate[END_REF][START_REF] Pan | Analysis of primary metabolites of alphatocopherol in human urine by liquid chromatography-mass spectrometry[END_REF]. These metabolites were first thought to be artefacts formed under high dietary supplementation and only side-products under physiological conditions [START_REF] Krishnamurthy | The absorption, storage, and metabolism of alphatocopherol-Cu in the rat and chicken[END_REF][START_REF] Schultz | Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply[END_REF]. Interestingly, their is a certain analogy in the degradation of tocol side chains with the bile acid catabolism of cholesterol which leads to the formation of cholic acid [START_REF] Bloch | The biological conversion of cholesterol to cholic acid[END_REF]. Recent studies reported that α-TQ undergoes a similar ω-oxidation to that of α-T, catalyzed by the same Cyp enzymes [START_REF] Shrader | Towards a modern definition of vitamin E-evidence for a quinone hypothesis[END_REF][START_REF] Taylor | ω-Hydroxylation of α-tocopheryl quinone reveals a dual function for cytochrome P450-4F2 in vitamin E metabolism[END_REF]. The catabolism of α-TQ is correlated with the human urine content of conjugated α-tocopheronolactone [START_REF] Pope | Synthesis and analysis of conjugates of the major vitamin E metabolite, alpha-CEHC[END_REF][START_REF] Sharma | Urinary conjugated α-tocopheronolactone-a biomarker of oxidative stress in children with type 1 diabetes[END_REF]. α-tocopheronolactone is the final metabolite from the αTQ-ω-oxidation pathway. The proposed pathway depicting the fate of α-TQ is shown in the figure 8.

In humans and mice, α-carboxyethylhydroxychroman (α-CEHC) glycine and its glucoronide form as well as α-CEHC taurine have also been characterized as urinary metabolites and α-CEHC glutamine has been detected in the urine of mice [START_REF] Johnson | Novel metabolites and roles for α-tocopherol in humans and mice discovered by mass spectrometry-based metabolomics[END_REF]. 5-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-2-methyl-pentanoic acid (α-CMBHC, XLI, fig. 5) was also characterized in human urine as a minor metabolite [START_REF] Pope | New synthesis of (+/-)-alpha-CMBHC and its confirmation as a metabolite of alpha-tocopherol (vitamin E)[END_REF].

Biological and Medical Significance of Vitamin E oxidation Metabolites

Vitamin E is proposed to act through a non-specific antioxidant mechanism via its catabolites. Studies on the biological significance of tocol catabolites have been reviewed in several reports. This includes anti-inflammatory, anti-atherogenic and chemopreventive activities as well as cytotoxicity, apoptosis and activation of several signaling pathways at the cellular and molecular level. These effects were found to be more potent with vitamin E catabolites than their unmetabolized precursors [START_REF] Jiang | Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy[END_REF][START_REF] Galli | Vitamin E emerging aspects and new directions[END_REF][START_REF] Schubert | Long-chain metabolites of vitamin E: metabolic activation as a general concept for lipid-soluble vitamins[END_REF][START_REF] Jiang | Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms[END_REF].

In biological systems, the best surrogate indicators associated with oxidative and nitrative stress are α-TQ and 5-NO2--T (tocoyellow) as well as their ratios α-TQ/α-T and 5-NO2--T/-T which are also used as biomarkers and were found to be associated with some debilitating conditions such as ischemia/reperfusion [START_REF] Murphy | Antioxidant depletion in aortic crossclamping ischemia: increase of the plasma alpha-tocopheryl quinone/alpha-tocopherol ratio[END_REF]), Alzheimer's disease [START_REF] Radi | Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide[END_REF]Mangialasch et al., 2012Mangialasch et al., , 2013a,b;,b;[START_REF] Casati | Vitamin E and Alzheimer's disease: the mediating role of cellular aging[END_REF], hypercholesterolemia [START_REF] Ballard | Single low-density lipoprotein apheresis does not improve vascular endothelial function in chronically treated hypercholesterolemic patients[END_REF], coronary diseases [START_REF] Morton | Evidence for the nitration of gamma-tocopherol in vivo: 5-nitro-gamma-tocopherol is elevated in the plasma of subjects with coronary heart disease[END_REF] and paraphysiological states [START_REF] Mottier | Comparison of gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry methods to quantify α-tocopherol and α-tocopherolquinone levels in human plasma[END_REF]. Other data showed that bioprenylquinones may monitor changes in the physical properties of the lipid bilayer [START_REF] Cain | Molecular motion in membranes as indicated by X-ray diffraction[END_REF][START_REF] Spisni | Interactions between ubiquinones and phospholipid bilayers, A spin-label study[END_REF][START_REF] Fato | Determination of partition and lateral diffusion coefficient of ubiquinones by fluorescence quenching of n-(9anthroyloxy) stearic acid in phospholipid vesicles and mitiochondrial membranes[END_REF]. Bioprenylquinones are produced by mitochondria and peroxysomes, which could mediate their effects since they are known to control cell cycle regulation, apoptosis, inflammation as well as cytotoxicity or cytoprotection.

α-TQ was found to be the major tocopherylquinone in vivo compared to γ-TQ [START_REF] Kiyose | Simultaneous determination of alpha-, gamma-tocopherol and their quinones in rats plasma and tissues using reversed-phase highperformance liquid chromatography[END_REF]. This may be explained, as proposed by Cornwell's team, by an evolutionary approach.

Indeed poor cellular uptake of γ-T allowed the generation of only a small amount of its mutagenic metabolite γ-TQ [START_REF] Cornwell | Mutagenicity of tocopheryl quinones: evolutionary advantage of the selective accumulation of dietary alpha-tocopherol[END_REF].

The exact biological roles of these bioprenylquinones have not yet been fully explored, although in plants, a number of studies have shown evidence that -TQ participates in the photosynthetic electron transport and metabolism [START_REF] Itoh | Modification of photosystem I reaction center by the extraction and exchange of chlorophylls and quinones[END_REF]. -TQ has been identified as a major oxidation product of -T in atherosclerotic plaques [START_REF] Terentis | Vitamin E oxidation in human atherosclerotic lesions[END_REF].

In addition, different plasma concentrations of VEOP are observed in Alzheimer's disease (AD) and were related to cognitively healthy subjects. Humans exhibited a broad inter-individual fluctuation in leukocyte telomere length (LTL) that is strongly correlated with age, sex, heredity, as well as with lifespan. The levels of α-TQ/α-T and 5-NO2--T/-T ratio, were significantly associated with AD in patients with small Leucocyte Telomers [START_REF] Casati | Vitamin E and Alzheimer's disease: the mediating role of cellular aging[END_REF]. Moreover, in vitro, α-TQ targets multiple pathogenic factors involved in Alzheimer's disease (AD). α-TQ inhibits α-amyloid aggregation, disaggregating preformed fibrils and decreases reactive oxygen species, NO and inflammatory cytokines levels (Yang et al., 2010;[START_REF] Mangialasche | Tocopherols and tocotrienols plasma levels are associated with cognitive impairment[END_REF]Mangialasche et al., , 2013a)).

The cytotoxicity of Vitamin E metabolites has been broadly studied in vitro.

Tocopherylquinone cytotoxicity can be explained either by their redox cycling properties or by their interactions with specific protein targets. Indeed, due to its electrophilic character, -TQ can undergo "Michael" addition with amines and thiol residues present in proteins and nucleic acids. This leads to the formation of quinone-Nucleophile residues, which are considered to be involved in -TQ cytotoxicity. These properties are not shared with the fully methylated non-arylating quinone α-TQ [START_REF] Cornwell | Electrophile tocopheryl quinones in apoptosis and mutagenesis: thermochemolysis of thiol adducts with proteins and in cells[END_REF][START_REF] Niki | Tocopherylquinone and tocopherylhydroquinone[END_REF]. Both γ-TQ and δ-TQ are highly cytotoxic arylating electrophiles. Both compounds were reported to be highly cytotoxic in leukemic cells independently of their P glycoprotein status and were more potent than anthracyclines [START_REF] Thornton | Antioxidant and cytotoxic tocopheryl quinones in normal and cancer cells[END_REF][START_REF] Cornwell | Cytotoxicity of tocopherols and their quinones in drug sensitive and multidrug-resistant leukemia cells[END_REF][START_REF] Jones | γ-Tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells[END_REF][START_REF] Cornwell | Mutagenicity of tocopheryl quinones: evolutionary advantage of the selective accumulation of dietary alpha-tocopherol[END_REF][START_REF] Cornwell | Electrophile tocopheryl quinones in apoptosis and mutagenesis: thermochemolysis of thiol adducts with proteins and in cells[END_REF][START_REF] Sachdeva | Tocopherol metabolism using thermochemolysis: chemical and biological properties of gammatocopherol, gamma-carboxyethyl-hydroxychroman, and their quinones[END_REF]. α-TQ is cytotoxic against human breast adenocarcinoma cells ZR-75-1 [START_REF] Thornton | Antioxidant and cytotoxic tocopheryl quinones in normal and cancer cells[END_REF][START_REF] Cornwell | Cytotoxicity of tocopherols and their quinones in drug sensitive and multidrug-resistant leukemia cells[END_REF][START_REF] Jones | γ-Tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells[END_REF]. In another report, [START_REF] Wang | Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress[END_REF] studied TQ cytotoxicity in neuroblastoma cell lines. They reported that unlike α-TQ or its precursor α-T, -TQ (10 mM) induced endoplasmic reticulum (ER) stress by activating the pancreatic ER kinase (PERK) signaling pathway. This pathway involves elF2α, ATF4, and C/EBP homologous protein (CHOP).

CHOP mediated the apoptosis signaling network which is involved in several human diseases such as diabetes, cancer and neurodegenerative disorders.

Androgen Receptors (AR) are members of the nuclear steroid receptor superfamily, which act as ligand-activated transcription factors. AR control the expression of genes involved in the growth, survival, and differentiation of prostate cells [START_REF] Zhu | Androgen receptor and growth factor signaling cross-talk in prostate cancer cells[END_REF]. α-TQ was reported to induce anti-androgenic effects on prostate cancer cells. α-TQ induces a down-regulation of the AR at the protein and at the mRNA level in LAPC4 and LNCaP cells. This effect was associated with a decrease of androgen-induced PSA release in LNCaP cells. In contrast, α-TQ was inefficient on the androgen-independent cell lines Du145 and PC3 (Thompson and MacKenzie 2008). Furthermore, [START_REF] Fajardo | Antioxidants abrogate alpha-tocopherylquinone-mediated down-regulation of the androgen receptor in androgen-responsive prostate cancer cells[END_REF] reported a reduced prostate cancer incidence amongst male smokers, primarily associated with Vitamin E supplementation. This bioactivity of Vit E might also be related to the formation of α-TQ during chronic oxidative stress. Indeed, α-TQ but not α-T decreased the overexpression by 5fold of human prostate gland genes such as TM4SF1, KLK2, and PSA.

γ-TQ (20-50 mM) was reported to induce apoptosis in other cell lines such as human leukemia HL-60, colon adenocarcinoma WiDr cells and murine thymoma cells in a dose-and time-dependent manner [START_REF] Calviello | Gamma-tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release[END_REF]. Such a pro-apoptotic effect was associated with a modification of the mitochondrial transmembrane potential, the release of mitochondrial cytochrome c and the activation of caspase-9. In contrast α-T and α-TQ are weakly cytotoxic on Human colon cancer HCT-116 and HT-29 cells, whilst these cells are sensitive to γ-TQ and δ-TQ [START_REF] Dolfi | Inhibitory effects of different forms of tocopherols, tocopherol phosphates, and tocopherol quinones on growth of colon cancer cells[END_REF].

More recently TQ and its reduced forms were reported to control ferroptosis in cancer cells. Ferroptosis is an iron-dependant programmed cell death acting via the redox control of 15-lipoxygenase (15-LO) [START_REF] Hinman | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15lipoxygenase[END_REF], but the fine mechanism involved in this effect deserves further investigations. This effect may be controlled by multiple pathways that integrate both intra-and extracellular signals. Ferroptosis seems to play a role in critical adaptations to the redox metabolism in a wide array of diseases (Do [START_REF] Van | Ferroptosis a newly characterized form of cell death in Parkinson's disease that is regulated by PKC[END_REF][START_REF] Stockwell | Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[END_REF][START_REF] Wenzel | PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals[END_REF][START_REF] Li | Ferroptosis A trigger of proinflammatory state progression to immunogenicity in neuroinflammatory disease[END_REF]. α-TQ is a more dynamic inhibitor of ferroptosis than its precursor α-T. α-TQ inhibits 15-LO through the reduction of its active non-heme Fe 3+ center into the inactive Fe 2+ state; hence inhibiting ferroptosis signals by blocking the formation of lipid peroxidation products [START_REF] Hinman | Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15lipoxygenase[END_REF].

A janus facet have also been ascribed to γ-TQ. Indeed, γ-TQ was cytoprotective in PC12 cells and immature primary cortical cells, whilst pre-treatment of these cells at sublethal concentrations resulted in an increase in the levels of γ-TQH2 and glutathione. This effect was due to an increase of cysteine availability in an ATF4-dependent manner [START_REF] Ogawa | Gammatocopheryl quinone, not alpha-tocopheryl quinone, induces adaptive response through upregulation of cellular glutathione and cysteine availability via activation of ATF4[END_REF].

Altogether these effects highlight that the efficacy of TQ metabolites to kill cells depends on the TQ types, the concentrations used during treatments as well as the cellular context.

Apart from TQ metabolites, some studies have focused on the cytotoxicity of long chain metabolites of vitamin E. α-13′-COOH and δ-13′-COOH or δ-13′-OH at 20µM were found to be more cytotoxic than their tocopherol precursors or their short and mid-chain carboxychromanol oxidation products when tested on liver hepatoma Hep-G2 cells. These compounds induced both caspase-3 and caspase-9 activation, PARP-1 cleavage, a reduction of the mitochondrial membrane potential, and an increase in the intracellular and intramitochondrial reactive oxygen species levels [START_REF] Birringer | Proapoptotic effects of long-chain vitamin E metabolites in HepG2 cells are mediated by oxidative stress[END_REF]. δ-Tocotrienol-13'-COOH (Garcinoic acid), first isolated from an African bitter nut Garcinia kola [START_REF] Mazzini | Configuration of the vitamin E analogue garcinoic acid extracted from Garcinia Kola seeds[END_REF], significantly suppressed the growth of human colon cancers (HCT-116, HT-29, Caco-2 and normal epithelial cells (CCD841CoN), and appeared to induce apoptosis and autophagy in human cancer cells. These effects were associated with a modulation of the sphingolipid metabolism. δ-Tocotrienol-13'-COOH induced an increase in intracellular dihydrosphingosin, dihydroceramide and ceramide levels and a decrease in sphingomyelins. This modulation of the lipid metabolism is associated with a rapid induction of apoptosis [START_REF] Jang | Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice[END_REF].

Moreover, [START_REF] Drotleff | HPLC separation of vitamin E and its oxidation products and effects of oxidized tocotrienols on the viability of MCF-7 breast cancer cells in vitro[END_REF] reported that an oxidized γ-tocotrienol was cytotoxic in the human estrogen receptor positive breast cancer cell line MCF-7. In the human colon adenocarcinoma cell line LS180, α-CEHC, γ-CEHC and α-13'-COOH were found to stimulate the expression of P glycoprotein [START_REF] Podszun | The long chain αtocopherol metabolite α-13'-COOH and γ-tocotrienol induce P-glycoprotein expression and activity by activation of the pregnane X receptor in the intestinal cell line LS 180[END_REF]. The cytotoxicity expressed as the percentage of growth inhibition of different cell lines leading to the IC50 values of vitamin E in vivo metabolites in previously studied cancer cell lines are summarized in table 2.

It is well established that the production of pro-inflammatory compounds are catalyzed by cyclooxygenases (COXs)-or 5-lipoxygenases, and several cytokines/chemokines and are associated with chronic inflammation in tumorigenesis [START_REF] Wang | Eicosanoids and cancer[END_REF][START_REF] C1424 Ben-Neriah | Inflammation meets cancer, with NF-κB as the matchmaker[END_REF][START_REF] Grivennikov | Immunity, inflammation, and cancer[END_REF]. 5-lipoxygenase (5-LOX)-catalyzed leukotriene and cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoids are key regulators of inflammation and both play a key role in inflammation-associated diseases. Theses enzymes are potent targets for vitamin E metabolites. Metabolites of vitamin E in their free or sulfated forms were detected in the plasma and urine of both animals and humans. Long chain metabolites (LCMs) are excreted via the bile into the intestine and are mainly found in the feces (Bardowell et al., 2012a, b;[START_REF] Jiang | Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice[END_REF][START_REF] Jiang | Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy[END_REF]. Importantly, LCMs are found in human plasma at nanomolar concentrations albeit with some substantial fluctuations [START_REF] Wallert | Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro[END_REF][START_REF] Galli | Vitamin E emerging aspects and new directions[END_REF][START_REF] Pein | Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase[END_REF]. Short chain metabolites (SCMs) are mainly found in glucoronidated forms in human urine [START_REF] Swanson | Urinary excretion of 2,7,8trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman is a major route of elimination of gamma-tocopherol in humans[END_REF]. Such compounds (LCMs) mediate immune functions and have been examined for their anti-inflammatory potentials.

This field of research is a very dynamic one and deserves further investigations. Docking experiments suggested that 13'-carboxychromanol metabolites from all tocols bind to COX-2 and HMG-CoA reductase yielding specific biological activities [START_REF] Sarkisyan | Vitamin and antioxidant properties of tocopherols: characteristic of the molecular mechanisms of action[END_REF]. In COX-preinduced cells with 5 µM arachidonic acid as a substrate, long-chain carboxychromanols, but not their vitamin E sulfated analogs, reduced COX-2 activity. 9'-and 13'-carboxychromanol, both inhibited purified COX-2 with an IC50 of 6 or 4 μM, respectively. 13'-carboxychromanol was reported to be a competitive inhibitor of arachidonate on both COX-1 and COX-2. These compounds were found to be more potent than analogs with shorter side-chains and their tocopherol precursors [START_REF] Jiang | Long-chain carboxychromanols metabolites of vitamin E are potent inhibitors of cyclooxygenases[END_REF].

In human blood neutrophils or differentiated HL-60 cells, the long-chain metabolites of vitamin E derived from δ-tocopherol and δ-tocotrienol were both shown to be potent dual inhibitors of cyclooxygenase COX-2 and 5-Lipooxygenase. In these studies, δ-Tocotrienol-13'-COOH (Garcinoic acid) appeared to be slightly stronger than δ-Tocopherol-13'-COOH in inhibiting 5-LOX with an IC50 of 2 and 0.5-1 µM respectively, but less potent in inhibiting COX-2 with an IC50 of 9.8 μM and 4 μM respectively [START_REF] Jiang | Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively[END_REF][START_REF] Jiang | Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy[END_REF][START_REF] Jiang | Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms[END_REF].

Furthermore, δ-Tocopherol-13'-COOH decreased the cellular production of ionophorestimulated LTB4 in HL-60 cells (a leukotriene involved in inflammation) regardless of the different stimuli with an IC50 of 4-7 μM [START_REF] Jiang | Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively[END_REF]. In another study, δT-13'-COOH was found to display an anti-inflammatory activity close to that of ibuprofen. δT-13'-COOH was found to be more potent than all other tested tocol analog metabolites [START_REF] Grammas | Anti-inflammatory effects of tocopherol metabolites[END_REF][START_REF] Jiang | Long-chain carboxychromanols metabolites of vitamin E are potent inhibitors of cyclooxygenases[END_REF][START_REF] Jiang | Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy[END_REF].

More data have reported direct interactions of such vitamin E metabolites with 5lipoxygenase (5-LO) [START_REF] Pein | Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase[END_REF]. The mechanism of α-T-13'-COOH anti-inflammatory potential was also revealed by [START_REF] Pein | Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase[END_REF]. They showed both by library screening (liver-on-chip) and in vitro and in vivo testing, that this compound was a potent allosteric inhibitor of 5-lipoxygenase in human leukocytes. α-T-13'-COOH efficiently suppressed inflammation within immune cells in mouse models of peritonitis and asthma.

5-LOX is involved in the biosynthesis of lipoxins, and resolvins [START_REF] Serhan | Pro-resolving lipid mediators are leads for resolution physiology[END_REF].

Unlike zileuton, a synthetic leucotriene inhibitor (a 5-LOX inhibitor clinically used against asthma), α-T-13′-COOH was found to strongly increase systemic resolvin E3 levels in mice with less toxicity [START_REF] Pein | Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase[END_REF].

Apart from these bioactivities, LCMs appear to regulate lipid homeostasis and Longchain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro which might strongly alter atherogenic processes [START_REF] Wallert | Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro[END_REF].

In a more recent report, α-13′-COOH revealed possible antiatherogenic effects via the modulation of the lipoprotein lipase system which reduced VLDL-induced foam cell formation in THP-1 macrophages [START_REF] Kluge | The vitamin E long-chain metabolite α-13′-COOH affects macrophage foam cell formation via modulation of the lipoprotein lipase system[END_REF]. These metabolites, including Garcinoic acid (δ-T3-13′-COOH), were also inhibitors of lipopolysaccharide-stimulated inducible nitric oxide synthase (iNos) expression and Cox 2 in murine RAW264.7 macrophages (Wallert et al., 2015;[START_REF] Ciffolilli | Human serum determination and in vitro anti-inflammatory activity of the vitamin E metabolite alpha-(13′-hydroxy)-6hydroxychroman[END_REF][START_REF] Schmölz | Optimized incubation regime for nitric oxide measurements in murine macrophages using the Griess assay[END_REF][START_REF] Wallert | The vitamin E derivative garcinoic acid from Garcinia kola nut seeds attenuates the inflammatory response[END_REF].

α-13'-COOH and -13'-COOH analogs activated all three PPARs in a dose-dependent manner, exhibiting remarkable activity [START_REF] Willems | Endogenous vitamin E metabolites mediate allosteric pargamma activation with unprecedented co-regulatory interactions[END_REF]. δ-T3-13′-COOH (Garcinoic acid)

along with other LCMs were found to be peroxisome proliferator-activated receptor PPARγ and pregnan X receptor (PXR) antagonists [START_REF] Willems | Endogenous vitamin E metabolites mediate allosteric pargamma activation with unprecedented co-regulatory interactions[END_REF]. δ-T3-13′-COOH is also a modulator of nuclear receptors involved in the β-amyloid metabolism and progression of Alzheimer's disease [START_REF] Marinelli | Garcinoic acid prevents βamyloid (Aβ) deposition in the mouse brain[END_REF].

In vitro and animal (but not yet human) studies, identified -CEHC as a mild endogenous natriuretic factor distinct from α-CEHC. This observation may be of physiological importance in the regulation of the water-sodium balance by inhibiting the potassium channel and increasing the secretion of urinary sodium. In contrast, -T and -T

did not exhibit such properties [START_REF] Wechter | A new endogenous natriuretic factor: LLU-alpha[END_REF][START_REF] Murphy | Antioxidant depletion in aortic crossclamping ischemia: increase of the plasma alpha-tocopheryl quinone/alpha-tocopherol ratio[END_REF][START_REF] Saito | Tocotrienol, a vitamin E homolog, is a natriuretic hormone precursor[END_REF]. In animal studies, -CEHC was shown to protect against metal-induced nephrotoxicity through various mechanisms such as an antioxidant-based mechanism [START_REF] Appenroth | LLU-alpha, an endogenous metabolite of -tocopherol, is more effective against metal nephrotoxicity in rats than -tocopherol[END_REF], the down-regulation of COX-2 and the inhibition of the anti-apoptosis protein NF-κB (Hensley et al., 2004;[START_REF] Jiang | Long-chain carboxychromanols metabolites of vitamin E are potent inhibitors of cyclooxygenases[END_REF]. -CEHC inhibited the expression of cyclin D1 which induced a cell cycle arrest in the G1 phase in prostate cancer cells [START_REF] Galli | The effect of αand γ-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation[END_REF]. Moreover, -CEHC may also control the neutrophil oxidative burst through the negative modulation of PKC-related signaling [START_REF] Varga | Effects of tocopherols and 2,2'-carboxyethyl hydroxychromans on phorbolester-stimulated neutrophils[END_REF]. [START_REF] Li | γ-Carboxyethyl hydroxychroman, a metabolite of γ-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose[END_REF] showed that -CEHC also exerts vasoprotective effects which may preserve eNOS signaling in human aortic endothelial cells (HAECs) subjected to hyperglycemia-like conditions by decreasing the expression of VCAM, E-Selectin, and IL-8.

Along with these observations, Simon metabolites with open chroman rings were considered as biomarkers of the antioxidant potential of vitamin E [START_REF] Simon | The metabolism of vitamin E. II. Purification and characterization of urinary metabolites of alpha-tocopherol[END_REF]).

Although, they were first considered as artefacts formed by simple oxidation [START_REF] Schultz | Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply[END_REF], other reports illustrated by [START_REF] Pope | Synthesis and analysis of conjugates of the major vitamin E metabolite, alpha-CEHC[END_REF] provided evidence that Simon metabolites may be native metabolites. More recent studies underlined the importance of the content of α-tocopheronolactone conjugates in the urine of children with type 1 diabetes compared to healthy children, the contents were fifteen times greater in diabetic individuals [START_REF] Sharma | Urinary conjugated α-tocopheronolactone-a biomarker of oxidative stress in children with type 1 diabetes[END_REF].

Conclusion and future directions

Overall, this complex study created a scientific perspective on tocochromanol oxidation products which may be much more diverse. There remains a growing interest to fully clarify the physiological functions of vitamin E as well as its janus faced effects. We have attempted to cover the research available to date. Evidence suggests that VEOP are good candidates to exert different biological properties according to their chemical structures and are more active than their metabolized precursors, which suggests that the physiological functions of vitamin E are still not yet fully understood.

The effect of TQ against cancer cell proliferation and the anti-inflammatory effects of tocol LCMs may be generated through several molecular mechanisms that deserve to be further investigated. Furthermore, the concentrations used for in vitro studies are far more elevated than those found in animal plasma and biological tissues. In addition, very little is known about the absorption, distribution and transport of VEOP and their putative receptors and other targets. The future challenge could also focus on studies of their specific bioavailabilities in rodents and humans and the eventual increase of their cellular uptake to try and improve their pharmacological properties. Furthermore, the toxicities of TQ must be taken into account as some compounds are electrophilic and alkylating. On the other hand, in vivo, if Tocopherones are formed, they might be reduced into tocopherols and thus neutralized through enzymatic systems that are not yet identified. Although the catabolism of tocopherylquinones has been analyzed in vivo and a cross-talk has been established with the long chains of -tocopherol and Simon products, the human catabolites of 5-NO2--T do warrant further investigations.

More research is therefore needed to study the other tocopherol congeners, their respective metabolites formed in humans and the determination of their potentially beneficial role in health. Indeed, tocotrienol congeners are quite different from tocopherols. They differ in their chemical structures, their stereochemistry, their metabolisms and their biological activities. Tocotrienols have indeed the same reactivity in vitro towards free radicals as tocopherols, but may disseminate faster than tocopherols in biomembranes and cultured cells due to their unsaturated nature, their plasma levels in humans however have been much less studied compared to tocopherols [START_REF] Hayes | Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: observations in humans and hamsters[END_REF].

The "vitaminEome" (figure 9) includes a large diversity of products of transformation of vitamin E components, including oxidative self-condensation products, Simon metabolites, side-chain and chromanol oxidation products as well as conjugation products with lipids, phosphate and sulfate.

The limitation of this study is that the "vitaminEome" was mainly characterized through in vitro using and requires validation studies in human.

A precise knowledge of the "vitaminEome" is thus important. The identification of actors controlling this metabolism will give pharmacogenomic data that will predict the impact of these dietary components on human health. Therefore, exploring and determining the "vitaminEome" in humans will be crucial not only in future randomized trials but also if we consider that vitamin E is widely used in dietary supplements.

Figure captions

  8a-(epoxylipid-dioxy)-α-tocopherone products that are formed include 4a,5-epoxy8ahydroperoxy--tocopherone and an -tocopherol dimer along with two stereoisomers of methyl (13S)-(8a-dioxy--tocopherone)-(9Z,11E)-octadecadienoate, four stereoisomers of methyl-9-(8a-dioxy--tocopherone)-(12,13)-epoxy-(10E)-octadecenoate and four stereoisomers of methyl-11-(8a-dioxy--tocopherone)-(12,13)-epoxy-(9Z)-octadecenoate (an example of structure (12S, 13S, XXIII) is depicted in figure

Figure 1 :

 1 Figure 1: structural features of Tocols (Tocopherols and Tocotrienols). The natural α-T has a 2R, 4'R and 8'R configuration. Therefore, its systematic name is (2R, 4'R, 8'R)-α-tocopherol, formerly known as d-α-tocopherol, the abbreviation RRR-α-T is also used. It can be obtained by condensation of trimethylhydroquinone with phytol (DellaPenna and Pogson, 2006). A total racemic tocopherol mixture is then obtained, with 8 different stereoisomers, due to 3 chiral centers at C-2, C-4 ' and C-8. Each of the four tocopherols may be represented by the configurations RRR, RSR, RRS, RSS, SRR, SSR, SRS and SSS. Therefore 32 stereoisomers may be produced. The commercial forms of vitamin E are RRR-α-tocopherol which is the natural stereoisomer or a synthetic form, called all-racemic-α-tocopherol or all-rac-αtocopherol, which is a mixture in approximately equal amounts of the 8 stereoisomers in the case of α-tocopherol[START_REF] Lodge | Vitamin E bioavailability in humans[END_REF].

Figure 2 :Figure 3 :

 23 Figure 2: Possible initiation of bis allylic carbons and mechanism of formation of 9-Hydroperoxide and 13-Hydroperoxide in the autoxidation of linoleic acid

Figure 4 :Figure 5 :

 45 Figure 4: α-tocopheroxyl radical and its resonance-stabilized forms

Figure 5bis :

 5bis Figure 5bis: Investigated structures referred to in the text (continued).

Figure 6 :Figure 7 :Figure 8 :

 678 Figure 6: Illustration using α-tocopherylquinone as an example of one and two electron reductions generating semiquinone and tocopherylhydroquinone. NQO1 : NADPH Quinone Oxidoreductase

Figure 9 :

 9 Figure 9: Scheme showing the "VitaminEome"

Table 1 : Designation of different Vitamin E structures

 1

	R1 R2 R3 DESIGNATIONS
	tocopherols H	H	H	2-methyl-2-(4',8',12'-trimethyltridecyl) chroman-6-ol
	α-tocopherol CH3 CH3 CH3 5,7,8-trimethyltocol.
	β-tocopherol CH3 H	CH3 5,8-dimethyl-tocol
	γ-tocopherol H	CH3 CH3 7,8-dimethyltocol
	-tocopherol H	H	CH3 8-methyl-tocol.
	tocotrienols H	H	H	2-methyl-2-(4',8',12'-trimethyltrideca-3',7',11' trienyl)chroman -6
				-ol,
	α-tocotrienol CH3 CH3 CH3 5,7,8-trimethyltocotrienol,
	β-tocotrienol CH3 H	CH3 5,8-dimethyltocotrienol,
	γ-tocotrienol H	CH3 CH3 7,8-dimethyltocotrienol,
	-tocotrienol H	H	CH3 8-methyltocotrienol,