Disease relevance of zeta1-Tocopherol

• Induction of cytotoxicity in human lung adenocarcinoma cells by 6-O-carboxypropyl-alpha-tocotrienol, a redox-silent derivative of alpha-tocotrienol [1].
• Contrary to alpha-tocopheryl succinate, 50 microM or repeatedly 20 microM of alpha-tocotrienol significantly inhibited proliferation without causing cellular toxicity (maximal effect: 46.8%) [2].
• Female Sprague-Dawley rats were divided into 4 groups: 1) normal rat chow (RC), 2) vitamin E deficiency (VED), vitamin E deficient rats supplemented with 3) 60 mg/kg alpha-tocotrienol (ATT) and 4) 60 mg/kg (alpha-tocopherol (ATF) [3].

High impact information on zeta1-Tocopherol

• In silico docking studies indicated that alpha-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site [4].
• Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase [5].
• Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains [5].
• To determine the mechanism underlying this response, human umbilical vein endothelial cells (HUVECs) were assessed for their ability to accumulate vitamin E analogs. alpha-Tocotrienol accumulated in HUVECs to levels approximately 10-fold greater than that of alpha-tocopherol [6].
• Both alpha-tocopherol and alpha-tocotrienol suppressed VCAM-1 expression and adhesion of THP-1 cells to HUVECs in a concentration-dependent manner [6].

Chemical compound and disease context of zeta1-Tocopherol

• Recently, we have observed that alpha-tocotrienol is multi-fold more potent than alpha-tocopherol in protecting HT4 and primary neuronal cells against toxicity induced by glutamate as well as by a number of other toxins [7].

Biological context of zeta1-Tocopherol

• The data suggest that alpha-tocotrienol supplementation counteracts the lipid peroxidation but not the barrier perturbation in the SC induced by 10% BPO [8].
• Inhibition of THP-1 cell adhesion to endothelial cells by alpha-tocopherol and alpha-tocotrienol is dependent on intracellular concentration of the antioxidants [6].
• In the present study, we found that pre-treatment with vitamin E analogs including alphaT (alpha-tocopherol), alphaT3 (alpha -tocotrienol), gammaT, and gammaT3 for 24 h prevented the cultured cortical neurons from cell death in oxidative stress stimulated by H2O2, while Trolox, a cell-permeable analog of alphaT, did not [9].
• Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively [10].
• Of the three tocotrienols, alpha-tocotrienol had the highest oral bioavailability, at about 27.7+/-9.2%, compared with gamma- and delta-tocotrienols, which had values of 9.1+/-2.4% and 8.5+/-3.5%, respectively [11].

Anatomical context of zeta1-Tocopherol

• Furthermore, Triton WR1339 injection tended to elevate the serum gamma-tocopherol (P = 0.071) and alpha-tocotrienol (P = 0.053) concentrations and lowered them (P < 0.05) in the liver and adrenal gland of rats administered gamma-tocopherol or alpha-tocotrienol [12].
• Irrespective of the prooxidant used, the order of effectiveness was:delta-tocotrienol > gamma-tocotrienol = alpha-tocotrienol in both isolated membranes and intact cells [13].
• The accumulation of alpha-tocopherol in the yolk sac membrane (YSM) started after day 20 of development and at hatching the alpha-tocopherol concentration in the YSM was twice that of beta- + gamma-tocopherols and 15 times greater than that of alpha-tocotrienol [14].
• METHODS: Using human Tenon's capsule fibroblast cultures, the antiproliferative and cytotoxic effects of the different vitamin E forms alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl succinate and alpha-tocotrienol were compared with those of mitomycin C [2].
• Protective effect of alpha-tocotrienol against free radical-induced impairment of erythrocyte deformability [15].

Associations of zeta1-Tocopherol with other chemical compounds

• TRF treatment (n = 19 mice) increased mouse skin alpha-tocopherol 28 +/- 16-fold, alpha-tocotrienol 80 +/- 50-fold, gamma-tocopherol 130 +/- 108-fold, and gamma-tocotrienol 51 +/- 36-fold [16].
• The observation that micromolar, but not nanomolar, alpha-tocotrienol functions as an antioxidant was verified in a model involving linoleic acid-induced oxidative stress and cell death [17].
• In addition, alpha-tocotrienol, but not gamma- or delta-tocotrienol, prevented oxidative stress-independent apoptotic cell death, DNA cleavage and nuclear morphological changes induced by a non-specific protein kinase inhibitor, staurosporine [18].
• The maximal alpha-tocotrienol concentrations in supplemented individuals averaged approximately 3 microM in blood plasma, 1.7 microM in LDL, 0.9 microM in triglyceride-rich lipoprotein, and 0.5 microM in HDL [19].

Gene context of zeta1-Tocopherol

• Western blot analysis also showed that alpha-tocotrienol did not induce FasL or FADD translocation from the cytosolic to membrane fraction in these cells [20].
• Treatment with cytotoxic doses of alpha-tocotrienol (20 microM) resulted in a time-dependent increase in caspase-8 and caspase-3 activity [20].
• In contrast, alpha-tocotrienol treatment had no effect on caspase-9 activation, and combined treatment with a specific caspase-9 inhibitor did not block alpha-tocotrienol-induced apoptosis in (+)SA cells [20].
• This suggests that the antioxidant potency of alpha-tocotrienol requires the membrane environment [21].
• To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox-silent analogue of alpha-tocotrienol (T3), 6-O-carboxypropyl-alpha-tocotrienol (T3E) [1].

Analytical, diagnostic and therapeutic context of zeta1-Tocopherol

• Synthetic alpha-tocotrienol was separated into four geometrical E/Z side chain isomers by preparative HPLC (permethylated beta-cyclodextrin phase) [22].

References