Vitamin E: Emerging aspects and new directions

Galli F, Azzi A, Birringer M, Cook-Mills JM, Eggersdorfer M, Frank J, Cruciani G, Lorkowski S, Özer NK.

Free Radic Biol Med. 2017 Jan;102:16-36. doi: 10.1016/j.freeradbiomed.2016.09.017. Epub 2016 Nov 2.

Abstract

The discovery of vitamin E will have its 100th anniversary in 2022, but we still have more questions than answers regarding the biological functions and the essentiality of vitamin E for human health. Discovered as a factor essential for rat fertility and soon after characterized for its properties of fat-soluble antioxidant, vitamin E was identified to have signaling and gene regulation effects in the 1980s. In the same years the cytochrome P-450 dependent metabolism of vitamin E was characterized and a first series of studies on short-chain carboxyethyl metabolites in the 1990s paved the way to the hypothesis of a biological role for this metabolism alternative to vitamin E catabolism. In the last decade other physiological metabolites of vitamin E have been identified, such as α-tocopheryl phosphate and the long-chain metabolites formed by the ω-hydroxylase activity of cytochrome P-450. Recent findings are consistent with gene regulation and homeostatic roles of these metabolites in different experimental models, such as inflammatory, neuronal and hepatic cells, and in vivo in animal models of acute inflammation. Molecular mechanisms underlying these responses are under investigation in several laboratories and side-glances to research on other fat soluble vitamins may help to move faster in this direction. Other emerging aspects presented in this review paper include novel insights on the mechanisms of reduction of the cardiovascular risk, immunomodulation and antiallergic effects, neuroprotection properties in models of glutamate excitotoxicity and spino-cerebellar damage, hepatoprotection and prevention of liver toxicity by different causes and even therapeutic applications in non-alcoholic steatohepatitis. We here discuss these topics with the aim of stimulating the interest of the scientific community and further research activities that may help to celebrate this anniversary of vitamin E with an in-depth knowledge of its action as vitamin.

Sahari MA, Moghimi HR, Hadian Z, Barzegar M, Mohammadi A.

Food Chem. 2017 Jan 15;215:157-64. doi: 10.1016/j.foodchem.2016.07.139. Epub 2016 Jul 28.

Abstract

The aim of this study was to prepare α-tocopherol loaded nanoliposomes as carriers of DHA and EPA and to investigate their physicochemical properties, such as peroxide value (PV), volatile compounds (VOCs), particle size, size distribution, zeta potential and morphology of the liposomes. The particle size of liposomes was in the range of 82.4-107.2nm. The highest extent of lipid oxidation was observed at 40°C for 90days, with the lowest PV and propanal levels for a nanoliposome formulation in comparison with the control sample. The zeta potential of the nanoliposomes was decreased during storage. No significant change in the PV and zeta potential of the liposome formulations with α-tocopherol was observed at 4°C after 90days (0.14meq/kg and -43.5mV, respectively). This study demonstrated that incorporation of α-tocopherol into liposomes contributes a significant antioxidant effect on DHA and EPA.

Abu-Fayyad A, Nazzal S.

Int J Pharm. 2017 Jan 16;519(1-2):145-156. doi: 10.1016/j.ijpharm.2017.01.020. [Epub ahead of print]

Abstract

Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T₃) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T₃. Yield and the identity of the synthesized products were confirmed by ¹H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T₃ isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T₃PGS 1000 and δ-T₃PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T₃PGS 1000 and δ-T₃PGS 1000 conjugate.

Santolim LV, Amaral ME, Fachi JL, Mendes MF, Oliveira CA.

J Nutr Biochem. 2017 Jan;39:86-92. doi: 10.1016/j.jnutbio.2016.09.011. Epub 2016 Oct 11.

Abstract

Connexins (Cx) and cadherins are responsible for cell homeostasis. The Cx activity is directly related to cholesterol. The present work investigates whether vitamin E, with or without caloric restriction (CR), alters the mRNA expression of Cx26, Cx32, Cx43, N-cadherins (N-cads), E-cadherins (E-cads) and alpha-smooth muscle actin (α-SMA), and evaluates their relation to cholesterol metabolism in rat liver. Animals were divided into different groups: control with ad libitum diet (C), control+vitamin E (CV), aloric restriction with intake to 60% of group C (CR), and the intake of group CR+vitamin E (RV). There were increases of manganese superoxide dismutase (Mn-SOD) and glutathione S-transferase mu 1, indicating antioxidant effects of CR and vitamin E. An increase of nitric oxide in the CR group was in agreement with the Mn-SOD data. Supplementation with vitamin E, with or without CR, upregulated the expression of Cx26 mRNA and increased low-density lipoprotein cholesterol (LDL-c) in the CV group. Reductions of Cx32 and Cx43 were associated with lower LDL-c. Increases in Hmgcr and low-density lipoprotein receptor (LDLr) in the CV and RV groups could be explained by the effect of vitamin E. A reduction of LDLr in the CR group was due to the reduced dietary intake. Increases in cadherins in the CV, CR and RV groups were indicative of tissue maintenance, which was also supported by increases of α-SMA in groups CV and RV. Finally, vitamin E, with or without CR, increased Cx26, probably modulated by expression of the Hmgcr and LDLr genes. This suggests important relationship of Cxs and cholesterol metabolism genes.

Bacci C, Vanzo V, Frigo AC, Stellini E, Sbricoli L, Valente M.

Oral Dis. 2017 Jan;23(1):62-68. doi: 10.1111/odi.12573. Epub 2016 Sep 15.

Abstract

This randomized, double-blind, placebo-controlled crossover study assessed the efficacy of topical tocopherol acetate compared with placebo in easing oral discomfort in patients with reticular oral lichen planus (ROLP). Thirty-four patients with clinically diagnosed and histologically confirmed ROLP were randomly assigned to two groups, which received first one of two treatments (treatment 1 or 2) for a month, then the other (treatment 2 or 1) for another month, with a two-week washout between them. One treatment contained tocopherol acetate and the other only liquid paraffin. The primary outcome was less discomfort, measured on a visual analog scale (VAS). Secondary outcomes were as follows: length of striae measured and photographed at each follow-up; surface area of lesions; and a modified Thongprasom score. No statistically significant differences emerged between the two treatments (1 vs 2) in terms of VAS scores (P > 0.05; 0.8624) or length of striae (P = 0.0883). Significant differences were seen for surface area of lesions (P < 0.05, P = 0.0045) and modified Thongprasom scores (P = 0.0052). The two treatments differed only in terms of the surface area of the lesions and Thongprasom scores, not in VAS scores for discomfort or the length of patients’ striae. Topical tocopherol proved effective in the treatment of ROLP.

Traber MG, Mah E, Leonard SW, Bobe G, Bruno RS.

Am J Clin Nutr. 2017 Jan 11. pii: ajcn138495. doi: 10.3945/ajcn.116.138495. [Epub ahead of print]

Abstract

Vitamin E supplementation improves liver histology in patients with nonalcoholic steatohepatitis, which is a manifestation of the metabolic syndrome (MetS). We reported previously that α-tocopherol bioavailability in healthy adults is higher than in those with MetS, thereby suggesting that the latter group has increased requirements. We hypothesized that α-tocopherol catabolites α-carboxyethyl hydroxychromanol (α-CEHC) and α-carboxymethylbutyl hydroxychromanol (α-CMBHC) are useful biomarkers of α-tocopherol status. Adults (healthy or with MetS; n = 10/group) completed a double-blind, crossover clinical trial with four 72-h interventions during which they co-ingested 15 mg hexadeuterium-labeled RRR-α-tocopherol (d₆-α-T) with nonfat, reduced-fat, whole, or soy milk. During each intervention, we measured α-CEHC and α-CMBHC excretions in three 8-h urine collections (0-24 h) and plasma α-tocopherol, α-CEHC, and α-CMBHC concentrations at various times ≤72 h. Conclusion, urinary α-CEHC and α-CMBHC are useful biomarkers to noninvasively assess α-tocopherol adequacy, especially in populations with MetS-associated hepatic dysfunction that likely impairs α-tocopherol trafficking.

Alias D, Ruiz-Tovar J, Moreno A, Manso B, Diaz G, Duran M, Garcia-Olmo D.

Surg Infect (Larchmt). 2017 Jan 6. doi: 10.1089/sur.2016.199. [Epub ahead of print]

Abstract

Despite several interventions having been adopted to reduce the incidence of incisional surgical site infection (SSI), it still remains a challenge for surgeons, because incisional SSI is a common cause of health-care-associated infection, leading to increased morbidity, prolonged hospital stay, patient discomfort, and increased sanitary costs. The aim of this study was to evaluate the effect on incisional SSI of vitamin E ointment in the subcutaneous tissue of patients undergoing a laparoscopic colorectal surgical procedure. A randomized study was performed. Patients with colorectal neoplasms undergoing an elective laparoscopic surgical procedure were included. The patients were randomized into two groups: Those patients undergoing a subcutaneous vitamin E ointment application (Group 1) and those patients who did not receive it (Group 2). Incisional SSI, post-operative pain, and analytical acute phase reactants were analyzed. There were 108 patients who were assessed for eligibility, and 101 patients were analyzed. The incisional SSI rate was 4% in Group 1 and 17.6% in Group 2 (p = 0.03). Mean post-operative pain, 24 hours after operation, was 17.3 ± 10.5 mm in Group 1 and 31.9 ± 18.9 mm in Group 2 (p < 0.001). Median hospital stay was six days in Group 1 and eight days in Group 2 (p < 0.001). White blood cell count was significantly lower in Group 1 (p < 0.001). Conclusion, the subcutaneous application of sterile vitamin E acetate ointment leads to a reduction in the incisional SSI rate, lower post-operative pain, and decrease in C-reactive protein and white blood cell count.

Georgousopoulou EN, Panagiotakos DB, Mellor DD, Naumovski N.

Maturitas. 2017 Jan;95:55-60. doi: 10.1016/j.maturitas.2016.11.003. Epub 2016 Nov 9.

Abstract

A systematic review of studies was undertaken to evaluate the potential effect of intake of tocotrienols or circulating levels of tocotrienols on parameters associated with successful ageing, specifically in relation to cognitive function, osteoporosis and DNA damage. Following PRISMA guidelines a systematic review of epidemiological observational studies and clinical trials was undertaken. Inclusion criteria included all English language publications in the databases PubMed and Scopus, through to the end of July 2016. Evidence from prospective and case-control studies suggested that increased blood levels of tocotrienols were associated with favorable cognitive function outcomes. A clinical trial of tocotrienol supplementation for 6 months suggested a beneficial effect of intake on DNA damage rates, but only in elderly people. Regarding osteoporosis, only in vitro studies with cultures of human bone cells were identified, and these demonstrated significant inhibition of osteoclast activity and promotion of osteoblast activity. In conclusion, research in middle-aged and elderly humans suggests that tocotrienols have a potential beneficial anti-ageing action with respect to cognitive impairment and DNA damage. Clinical trials are required to elucidate these effects.

Barranco-Ruiz Y, Aragón-Vela J, Casals C, Martínez-Amat A, Casuso RA, Huertas JR.

Nutrition. 2017 Jan;33:278-284. doi: 10.1016/j.nut.2016.06.017. Epub 2016 Jul 28.

Abstract

Controlling antioxidant supplementation in athletes involved in studies related to oxidative stress and muscle damage is the key to ensure results. The aim of this study was to confirm through high-performance liquid chromatography (HPLC) analysis whether well-trained individuals lied during a personal interview when asked if they were taking supplements with antioxidants, and how this could affect oxidative stress, muscle damage, and antioxidant response. A total of 94 men, well trained in endurance sports, volunteered in this study. They denied taking any antioxidant supplementation at initial interview. After a HPLC analysis, abnormal α-tocopherol concentrations were detected, probably due to a hidden antioxidant supplementation. Participants were classified into two groups: no evidence of antioxidant supplementation (NS group = α-tocopherol values <80 nmol/mL; n = 75) and evidence of antioxidant supplementation (S group = α-tocopherol values >80 nmol/mL; n = 19). Lipid peroxidation, muscle damage, antioxidant enzyme activity, and nonenzymatic antioxidant content were analyzed according to this classification. Statistical comparisons were performed using Student’s t test. Data from the present study reveal that 20% of participants lied in the exclusion criteria of antioxidant supplementation in a personal interview, as they showed high plasmatic α-tocopherol concentrations after HPLC verification. Catalase activity seems to be affected by high α-tocopherol plasma levels. Therefore, we strongly recommend the HPLC analysis as a necessary tool to verify the antioxidant intake and preserve results in studies linking oxidative stress and sport.

Guitard R, Paul JF, Nardello-Rataj V, Aubry JM.

Food Chem. 2016 Dec 15;213:284-95. doi: 10.1016/j.foodchem.2016.06.038. Epub 2016 Jun 15.

Abstract

22 natural polyphenols are compared to 7 synthetic antioxidants including BHT, BHA, TBHQ and PG with regard to their ability to protect omega-3 oils from autoxidation. The antioxidant efficiency of phenols is assessed using the DPPH test and the measurement of oxygen consumption during the autoxidation of oils rich in omega-3 fatty acids. Also, the bond dissociation enthalpies (BDE) of the Ar-OH bonds are calculated and excellent correlations between thermodynamic, kinetic and oxidation data are obtained. It is shown that kinetic rates of hydrogen transfer, number of radicals scavenged per antioxidant molecule, BDE and formation of antioxidant dimers from the primary radicals play an important role regarding the antioxidant activity of phenols. Based on this, it is finally shown that myricetin, rosmarinic and carnosic acids are more efficient than α-tocopherol and synthetic antioxidants for the preservation of omega-3 oils.