Vitamin E is a mixture of eight compounds alpha, beta, gamma, delta- tocopherols and alpha, beta, gamma, delta- tocotrienols. Their individual role in cellular transport as antioxidants and in metabolic pathways has been highlighted in the present work. All the eight compounds have been docked with the respective metabolizing enzymes (alpha-tocopherol transfer protein (ATTP), alpha-tocopherol associated protein (TAP), P-glycoprotein (P-gly) and human serum albumin (HSA)) to understand molecular interactions for pharmacokinetics. These have been structurally aligned against the four human phospholipids in order to reveal their individual role in chylomicron formation and hence the mechanism of cellular transport. The study of their binding with their metabolizing enzymes provides insight to the comparative antioxidant activity of each of these isomers.
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Delta-tocotrienol causes decrease of melanin content in mouse melanoma cells
Akihiro Michihara, Sachiyo Morita, Yae Hirokawa, Saya Ago, Kenji Akasaki and Hiroshi Tsuji
Journal of Health Science, 55(2) 314-318 (2009)
We examined the effect of –tocotrienol on melanin content in mouse melanoma B16 cells. Melanin content was significantly reduced in cells reated with 50 and 100µM δ–tocotrienol, but not 10µM δ–tocotrienol. The activity and amount of tyrosinase also significantly decreased in cells treated with 10, 50 and 100µM δ –tocotrienol. Furthermore, the mRNA level of tyrosinase as measured using real-time PCR was significantly decreased compared to controls in cells treated with 100µM δ–tocotrienol, but not 10 or 50µM δ–tocotrienol. These results indicated that at first δ-tocotrienol caused tyrosinase degradation, and then caused further decrease in the tyrosinase protein level via both tyrosinase degradation and a decrease in the mRNA level of tyrosinase. We conclude that the decrease of melanin content in the cells by δ–tocotrienol was the result of the decrease of the protein level of tyrosinase (tyrosinase degradation is more important than the decrease of mRNA).
Vitamin E is divided into two subgroups; tocopherols and tocotrienols. Both have protective roles in biological systems. The present study was conducted to compare the effect of short-term supplementation at 200 mg/d of either alpha-tocopherol or a tocotrienol-rich fraction (TRF) from palm oil on immune modulation and plasma vitamin E levels in normal healthy Asian volunteers. In a randomised, double-blind placebo-controlled trial conducted, fifty-three healthy volunteers aged 20-50 years were recruited based on the study’s inclusion and exclusion criteria. They were randomly assigned into three groups, i.e. two experimental groups that received daily supplementation at 200 mg of either alpha-tocopherol or the TRF, and the control group that received a placebo. Blood was drawn on days 0, 28 and 56 for several laboratory analyses. Differences in the production of IL-4 or interferon-gamma by concanavalin A-stimulated lymphocytes isolated from these volunteers were not significant (P>0.05). There were no significant differences observed in immune parameters between the healthy volunteers who received daily supplementation with either alpha-tocopherol or the TRF. As these observations were made in the absence of any immunogenic challenge, we feel it would be of benefit to study if there would be any differences observed when an immunogenic challenge such as vaccination were introduced.
Vitamin E is an important lipophilic antioxidant. The term refers to eight essential naturally occurring fat-soluble nutrients called tocopherols or tocotrienols. Among these isomers, _-tocopherol has the highest biologically active form and is found in all lipoprotein fractions. Vitamin E deficiency during pregnancy may cause miscarriage, preterm birth, preeclampsia, and intrauterine growth restriction. This review highlights recent findings that have led to a better understanding of vitamin E absorption, transport, bioavailability, and its role in pregnancy, and that underline the need for re-evaluation of the potential benefits of vitamin E supplementation in pregnant women.
Hexane extracts obtained from Hordeum vulgare L. (barley), Avena sativa L. (oat), Triticum spelta Schrank and Triticum dicoccum Schrank ex Schübler (spelt or emmer) whole grains, were examined for their tocochromanol (tocopherol and tocotrienol) content. The analyses were carried out on fatty extracts by means of HPLC coupled with a coulometric array electrochemical detector (ECD). Due to the specific high selectivity of the detector, the sample can be directly injected without any preliminary treatment (e.g., saponification). Eight tocochromanol isomers have been detected in barley grains. Different barley cultivars examined showed a tocochromanol content ranging from 1620 to 1852 ng/g caryopses. Oat grains contained ca. 45 ng/g caryopses and Triticum species ca.1070 ng/g caryopses. The results are considered in view of a potential use of vitamin E derivatives as human health enhancer and as sources of antioxidants for food lipid preservation.
Vitamin E is an essential nutrient of still increasing economic importance. Vitamin E derivatives include many nonracemic chiral compounds whose chirooptical characterization is scarcely described in the literature. We report the CD spectra of delta-tocopherol and its unsaturated analog delta-tocotrienol. TDDFT calculations demonstrate that the weak CD of delta-tocopherol is determined by the helicity of dihydropyrane ring. In addition, the moderate CD of delta-tocotrienol is due to the exciton interaction between the aromatic ring and the closest alkene group. Direct exciton-coupled CD calculations on structures generated by two different conformational sampling approaches reveal that, although such exciton coupling is expected to be weak, it is sufficient to explain the spectral differences between tocopherol and tocotrienol.
This study was conducted to determine the effectiveness of three forms of vitamin E supplements following nicotine treatment on bone histomorphometric parameters in an adult male rat model. Rats were divided into seven groups: baseline (B, killed without treatment), control (C, normal saline for 4 months), nicotine (N, nicotine for 2 months), nicotine cessation (NC), tocotrienol-enhanced fraction (TEF), gamma-tocotrienol(GTT), and alpha-tocopherol (ATF). Treatments for the NC, TEF, GTT, and ATF groups were performed in two phases. For the first 2 months they were given nicotine (7 mg/kg), and for the following 2 months nicotine administration was stopped and treatments with respective vitamin E preparations (60 mg/kg) were commenced except for the NC group, which was allowed to recover without treatment. Rats in the N and NC groups had lower trabecular bone volume, mineral appositional rate (MAR), and bone formation rate (BFR/BS) and higher single labeled surface and osteoclast surface compared to the C group. Vitamin E treatment reversed these nicotine effects. Both the TEF and GTT groups, but not the ATF group, had a significantly higher trabecular thickness but lower eroded surface (ES/BS) than the C group. The tocotrienol-treated groups had lower ES/BS than the ATF group. The GTT group showed a significantly higher MAR and BFR/BS than the TEF and ATF groups. In conclusion, nicotine induced significant bone loss, while vitamin E supplements not only reversed the effects but also stimulated bone formation significantly above baseline values. Tocotrienol was shown to be slightly superior compared to tocopherol. Thus, vitamin E, especially GTT, may have therapeutic potential to repair bone damage caused by chronic smoking.
Vitamin E delta-tocotrienol levels in tumor and pancreatic tissue of mice after oral administration
Husain K, Francois RA, Hutchinson SZ, Neuger AM, Lush R, Coppola D, Sebti S, Malafa MP. Source
Pharmacology. 2009;83(3):157-63. Epub 2009 Jan 13.
Tocotrienols are natural vitamin E compounds that are known to have a neuroprotective effect at nanomolar concentration and anti-carcinogenic effect at micromolar concentration. In this report, we investigated the pharmacokinetics, tumor and pancreatic tissue levels, and toxicity of delta-tocotrienol in mice because of its anti-tumor activity against pancreatic cancer. Following a single oral administration of delta-tocotrienol at 100 mg/kg, the peak plasma concentration (C(max)) was 57 +/- 5 micromol/l, the time required to reach peak plasma concentration (T(max)) was 2 h and plasma half-life (t(1/2)) was 3.5 h. The delta-tocotrienol was cleared from plasma and liver within 24 h, but delayed from the pancreas. When mice were fed delta-tocotrienol for 6 weeks, the concentration in tumor tissue was 41 +/- 3.5 nmol/g. This concentration was observed with the oral dose (100 mg/kg) of delta-tocotrienol which inhibited tumor growth by 80% in our previous studies. Interestingly, delta-tocotrienol was 10-fold more concentrated in the pancreas than in the tumor. We observed no toxicity due to delta-tocotrienol as mice gained normal weight with no histopathological changes in tissues. Our data suggest that bioactive levels of delta-tocotrienol can be achieved in the pancreas following oral administration and supports its clinical investigation in pancreatic cancer.
In vivo studies show that alpha-tocotrienol and gamma-tocotrienol accumulate in adipose tissue. Furthermore, a recent study reports that the oral administration of gamma-tocotrienol from a tocotrienol-rich fraction from palm oil (TRF) decreases body fat levels in rats. The objective of this study was to evaluate the effect of TRF and its components on adipocyte differentiation in 3T3-L1 preadipocytes, which differentiated into adipocytes in the presence of 1.8 micromol/L insulin. TRF suppressed the insulin-induced mRNA expression of adipocyte-specific genes such as PPARgamma, adipocyte fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha) compared with the differentiation of 3T3-L1 preadipocytes into adipocytes only in the presence of insulin. To confirm the suppressive effect of TRF, the major components of TRF, such as alpha-tocotrienol, gamma-tocotrienol, and alpha-tocopherol, were investigated. Alpha-tocotrienol and gamma-tocotrienol decreased the insulin-induced PPARgamma mRNA expression by 55 and 90%, respectively, compared with insulin, whereas alpha-tocopherol increased the mRNA expression. In addition, gamma-tocotrienol suppressed the insulin-induced aP2 and C/EBPalpha mRNA expression, triglyceride accumulation, and PPARgamma protein levels compared with insulin. The current results also revealed that gamma-tocotrienol inhibited the insulin-stimulated phosphorylation of Akt but not extracellular signal-regulated kinase (ERK)1/2 in the insulin signaling pathway of 3T3-L1 preadipocytes. Thus, the antiadipogenic effect of TRF depends on alpha-tocotrienol and gamma-tocotrienol, and gamma-tocotrienol may be a more potent inhibitor of adipogenesis than alpha-tocotrienol. Therefore, the results of this study suggest that tocotrienol suppresses insulin-induced differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. Furthermore, tocotrienol could act as an antiadipogenic vitamin in the nutrient-mediated regulation of body fat through its effects on differentiation.
Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases
Jiang Q, Yin X, Lill MA, Danielson ML, Freiser H, Huang J.
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20464-9. Epub 2008 Dec 11.
Cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoid formation plays a key role in inflammation-associated diseases. Natural forms of vitamin E are recently shown to be metabolized to long-chain carboxychromanols and their sulfated counterparts. Here we find that vitamin E forms differentially inhibit COX-2-catalyzed prostaglandin E(2) in IL-1beta-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of gamma-tocotrienol approximately delta-tocopherol > gamma-tocopherol >> alpha- or beta-tocopherol. The cellular inhibition is partially diminished by sesamin, which blocks the metabolism of vitamin E, suggesting that their metabolites may be inhibitory. Consistently, conditioned media enriched with long-chain carboxychromanols, but not their sulfated counterparts or vitamin E, reduce COX-2 activity in COX-preinduced cells with 5 microM arachidonic acid as substrate. Under this condition, 9′- or 13′-carboxychromanol, the vitamin E metabolites that contain a chromanol linked with a 9- or 13-carbon-length carboxylated side chain, inhibits COX-2 with an IC(50) of 6 or 4 microM, respectively. But 13′-carboxychromanol inhibits purified COX-1 and COX-2 much more potently than shorter side-chain analogs or vitamin E forms by competitively inhibiting their cyclooxygenase activity with K(i) of 3.9 and 10.7 microM, respectively, without affecting the peroxidase activity. Computer simulation consistently indicates that 13′-carboxychromanol binds more strongly than 9′-carboxychromanol to the substrate-binding site of COX-1. Therefore, long-chain carboxychromanols, including 13′-carboxychromanol, are novel cyclooxygenase inhibitors, may serve as anti-inflammation and anticancer agents, and may contribute to the beneficial effects of certain forms of vitamin E.