Topical alpha-tocotrienol supplementation inhibits lipid peroxidation but fails to mitigate increased transepidermal water loss after benzoyl peroxide treatment of human skin

Weber SU, Thiele JJ, Han N, Luu C, Valacchi G, Weber S, Packer L.

Free Radic Biol Med. 2003 Jan 15;34(2):170-6.

Benzoyl peroxide (BPO) is a commonly used drug in the treatment of acne vulgaris, but it induces unwanted side effects related to stratum corneum (SC) function. Since it has been recently shown to oxidize SC antioxidants, it was hypothesized that antioxidant supplementation may mitigate the BPO-induced SC changes. To test this, 11 subjects were selected to be topically supplemented with alpha-tocotrienol (5% w/vol) for 7 d on defined regions of the upper back, while the contralateral region was used for vehicle-only controls. Starting on day 8, all test sites were also treated with BPO (10%) for 7 d; the alpha-tocotrienol supplementation was continued throughout the study. A single dose of BPO depleted 93.2% of the total vitamin E. While continuing the BPO exposure for 7 d further depleted vitamin E in both vehicle-only and alpha-tocotrienol-treated sites, significantly more vitamin E remained in the alpha-tocotrienol-treated areas. Seven BPO applications increased lipid peroxidation. Alpha-tocotrienol supplementation significantly mitigated the BPO-induced lipid peroxidation. The transepidermal water loss was increased 1.9-fold by seven BPO applications, while there was no difference between alpha-tocotrienol treatment and controls. The data suggest that alpha-tocotrienol supplementation counteracts the lipid peroxidation but not the barrier perturbation in the SC induced by 10% BPO.

Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice

Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M.

Neurosci Lett. 2003 Jan 30;337(1):56-60.

Alpha-tocopherol and its derivatives have been shown to be effective in reducing cerebral ischemia-induced brain damage. However, the effects of other vitamin E isoforms have not been characterized. In the present study, we investigated the effects of six different isoforms of vitamin E on the ischemic brain damage in the mice middle cerebral artery (MCA) occlusion model. All vitamin E isoforms were injected i.v., twice, immediately before and 3 h after the occlusion. Alpha-tocopherol (2 mM), alpha-tocotrienol (0.2 and 2 mM) and gamma-tocopherol (0.2 and 2 mM) significantly decreased the size of the cerebral infarcts 1 day after the MCA occlusion, while gamma-tocotrienol, delta-tocopherol and delta-tocotrienol showed no effect on the cerebral infarcts. These results suggest that alpha-tocotrienol and gamma-tocopherol are potent and effective agents for preventing cerebral infarction induced by MCA occlusion.

Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia

Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ.

Am J Clin Nutr. 2002 Dec;76(6):1237-43.

Background: Tocotrienols have been reported to lower LDL-cholesterol and fasting glucose concentrations and to have potent antioxidant effects, but the results are contradictory.

Objective: The objective was to study the relative effect of tocotrienol supplements of different compositions (mixed alpha- plus gamma-, high gamma-, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F(2alpha), a measure of oxidative stress, in healthy hypercholesterolemic men and women.

Design: This was a double-blind, randomized, parallel-design study in which subjects (n = 67 men and women) consumed 1 of 3 commercially available tocotrienol supplements or a safflower oil placebo for 28 d. Blood and urine samples were obtained before and after the 28-d supplementation phase for analysis of fasting blood lipids, glucose, tocotrienols and tocopherols, and 8-iso-prostaglandin F(2alpha).

Results: Overall, serum tocotrienols were increased in subjects who consumed tocotrienols, which showed that the putatively active components were absorbed. No significant differences in mean lipid or glucose concentrations were observed among the 4 treatment groups at the end of the 28-d supplementation phase. However, when the values were expressed as a percentage change from the concentrations during the presupplementation run-in phase, LDL cholesterol increased slightly (7 +/- 2%) but significantly (P < 0.05) in the group consuming the mixed alpha- plus gamma-tocotrienol supplement when compared with LDL cholesterol in the group consuming the P25-complex tocotrienol. Neither mean concentrations nor the percentage change in 8-iso-prostaglandin F(2alpha) differed significantly among treatments.

Conclusion: Supplementation with 200 mg tocotrienols/d from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.

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Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats

Wan Nazaimoon WM, Khalid BA.

Malays J Pathol. 2002 Dec;24(2):77-82.

This study determined the effects of palm vitamin E (TRF) diet on the levels of blood glucose, glycated hemoglobin (gHb), serum advanced glycosylation end-products (AGE) and malondialdehyde (MDA) of diabetic Sprague-Dawley rats. The rats received either control (normal rat chow), TRF diet (normal chow fortified with TRF at 1 g/kg) or Vitamin C diet (vitamin E-deficient but contained vitamin C at 45 g/kg). The animals were maintained on the respective diet for 4 weeks, made diabetic with streptozotocin (STZ), then followed-up for a further 8 weeks. At week-4, mean serum AGE levels of rats given TRF diet (0.7 +/- 0.3 units/ml) were significantly lower than those of control or Vitamin C diet rats (p pounds 0.03). The levels increased after STZ and became comparable to the other groups. At week 12, blood glucose (20.9 +/- 6.9 mM) and gHb (10.0 +/- 1.6%) of rats on TRF diet remained significantly low compared to that of control or Vitamin C diet rats (p pounds 0.03). MDA however, was not affected and remained comparable between groups throughout the study. This study showed that TRF may be a useful antioxidant; effectively prevented increase in AGE in normal rats, and caused decrease in blood glucose and gHb in diabetic rats. Further studies are needed to elucidate the mechanisms of action of TRF.

Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters

Raederstorff D, Elste V, Aebischer C, Weber P.

Ann Nutr Metab. 2002;46(1):17-23.

Background/Aims: Tocotrienols has been shown to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity; however, the published animal and human studies yield conflicting results. We investigated the effects of a 4-week dietary supplement of either gamma-tocotrienol (86% gamma-T3) or a mixture of tocotrienols (29.5% alpha-T3, 3.3% beta-T3, 41.4% gamma-T3, 0.1% delta-T3: mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet.

Methods: The hamsters were randomized into 7 groups: no treatment, 16 mg/day/kg BW simvastatin, 23, 58, 263 mg/day/kg BW gamma-tocotrienol, and 39 or 263 mg/day/kg BW for the mixture of tocotrienols. Plasma lipid levels were measured after 2 and 4 weeks of treatment.

Results: In all groups treated with tocotrienol total cholesterol levels were decreased, ranging from 7 to 23% after 2 weeks of treatment and from 7 to 15% after 4 weeks. Low-density lipoprotein plasma levels changed accordingly: a decline of 6-37% after 2 weeks and of 12-32% at the end of the study was observed. After 4 weeks of treatment, total cholesterol and low-density lipoprotein plasma levels were significantly reduced in the 263 mg/day/kg BW mixed tocotrienols and the 58 mg/day/kg BW and 263 mg/day/kg BW gamma-tocotrienol groups when compared to the no treatment group. Plasma triglycerides and high-density lipoprotein levels did not change significantly.

Conclusion: This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.

Role of GTP-binding proteins in reversing the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells

Sylvester PW, Nachnani A, Shah S, Briski KP.

Asia Pac J Clin Nutr. 2002;11 Suppl 7:S452-9.

Tocotrienols are a subclass of vitamin E compounds that display potent anticancer activity. Determining the anticancer mechanism of action oftocotrienols will provide essential information necessary for understanding the potential health benefits of these compounds in reducing the risk of breast cancer in women. Epidermal growth factor (EGF) is a potent mitogen for normal and neoplastic mammary epithelial cells. Initial events in EGF-receptor (EGF-R) mitogenic-signalling are G-protein activation, stimulation of adenylyl cyclase and cyclic AMP (cAMP) production. Studies were conducted to determine if the antiproliferative effects of tocotrienols are associated with reduced EGF-induced G-protein and cAMP-dependent mitogenic signalling. Preneoplastic CL-S1 mouse mammary epithelial cells were grown in culture and maintained on serum-free media containing 0-25 micro mol/L tocotrienol-rich fraction of palm oil and/or different doses of pharmacological agents that alter intracellular cAMP levels. Tocotrienol-induced effects on EGF-receptor levels of tyrosine kinase activity, as well as EGF-dependent mitogen-activated pathway kinase (MAPK) and Akt activation, were determined by western blot analysis. Results demonstrate that the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells do not reflect a reduction in EGF-receptor mitogenic responsiveness, but rather, result from an inhibition in early post-receptor events involved in cAMP production upstream from EGF-dependent MAPK and phosphoinositide 3-kinase/Akt mitogenic signalling. In summary, these data further characterise the mechanism of action of tocotrienols in suppressing preneoplastic mammary epithelial cell proliferation, and advance the current understanding of the potential health benefits of these compounds in reducing the risk of breast cancer in women.

Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans

Qureshi, A. A.,Sami, S. A.,Salser, W. A.,Khan, F. A.

Atherosclerosis, 2002. 161(1): 199-207.

Tocotrienols are effective in lowering serum total and LDL-cholesterol levels by inhibiting the hepatic enzymic activity of beta-hydroxy-beta-methylglutaryl coenzymeA (HMG-CoA) reductase through the post-transcriptional mechanism. alpha-Tocopherol, however, has an opposite effect (induces) on this enzyme activity. Since tocotrienols are also converted to tocopherols in vivo, it is necessary not to exceed a certain dose, as this would be counter-productive. The present study demonstrates the effects of various doses of a tocotrienol-rich fraction (TRF25) of stabilized and heated rice bran in hypercholesterolemic human subjects on serum lipid parameters. Ninety (18/group) hypercholesterolemic human subjects participated in this study, which comprised three phases of 35 days each. The subjects were initially placed on the American Heart Association (AHA) Step-1 diet and the effects noted. They were then administered 25, 50, 100, and 200 mg/day of TRF25 while on the restricted (AHA) diet. The results show that a dose of 100 mg/day of TRF25 produce maximum decreases of 20, 25, 14 (P<0.05) and 12%, respectively, in serum total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides compared with the baseline values, suggesting that a dose of 100 mg/day TRF25 plus AHA Step-1 diet may be the optimal dose for controlling the risk of coronary heart disease in hypercholesterolemic human subjects.

Vitamin E sensitive genes in the developing rat fetal brain: A high-density oligonucleotide microarray analysis

Roy S, Lado BH, Khanna S, Sen CK.

FEBS Lett. 2002 Oct 23;530(1-3):17-23.

Vitamin E (tocopherols and tocotrienols) is essential for normal neurological function. Recently we have reported that the neuroprotective properties oftocotrienols are much more potent than that of the widely studied tocopherols (Sen, C.K., Khanna, S., Roy, S. and Parker, L. (2000) J. Biol. Chem. 275, 13049-13055). The objective of this study was to evaluate whether (i) oral supplementation of tocotrienols during pregnancy is bioavailable to fetal and mother brains; (ii) short-term change in dietary vitamin E levels of pregnant rats influences gene expression profile of developing fetal brains. We report that dietary tocotrienol is bioavailable to both mother and fetal brains. The enrichment is more in fetal brain tissue. Using a GeneChip microarray expression profiling approach we have identified a specific set of vitamin E sensitive genes in the developing rat fetal brain.

Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells

Birringer M, Pfluger P, Kluth D, Landes N, Brigelius-Flohé R.

J Nutr. 2002 Oct;132(10):3113-8.

The metabolism of alpha- and gamma-tocotrienol was investigated in HepG2 cells. Metabolites were identified by HPLC and gas chromatography/mass spectrometry. gamma-Tocotrienol was degraded to gamma-CEHC (carboxyethyl hydroxychroman), gamma-CMBHC (carboxymethylbutyl hydroxychroman), gamma-CMHenHC (carboxymethylhexenyl hydroxychroman), gamma-CDMOenHC (carboxydimethyloctenyl hydroxychroman) and gamma-CDMD(en)(2)HC (carboxydimethyldecadienyl hydroxychroman). alpha-Tocotrienol yielded alpha-CEHC, alpha-CMBHC, alpha-CMHenHC and alpha-CDMOenHC, whereas alpha-CDMD(en)(2)HC could not be detected. These findings demonstrate that the trienols are metabolized essentially like tocopherols, i.e., by omega-oxidation followed by beta-oxidation of the side chain. The failure to detect CMBHC with the original double bond in the side chain reveals that auxiliary enzymes are involved, as in the metabolism of unsaturated fatty acids. CMBHC were the most abundant metabolites obtained from the tocotrienols as well as from alpha-tocopherol. Quantitatively, the tocotrienols were degraded to a larger extent than their counterparts with saturated side chains. The pronounced quantitative differences in the metabolism between individual tocopherols as well as between tocotrienols and tocopherols in vitro suggest a corresponding lack of equivalence in vivo.

Effects on the human serum lipoprotein profile of beta-glucan, soy protein and isoflavones, plant sterols and stanols, garlic and tocotrienols

Kerckhoffs DA, Brouns F, Hornstra G, Mensink RP.

J Nutr. 2002 Sep;132(9):2494-505

The effects of beta-glucan, soy protein, isoflavones, plant sterols and stanols, garlic and tocotrienols on serum lipoproteins have been of great interest the last decade. From a critical review of the literature, it appeared that recent studies found positive as well as no effects of beta-glucan from oats on serum LDL cholesterol concentrations. These conflicting results may suggest that the cholesterol-lowering activity of products rich in oat beta-glucan depends on factors, such as its viscosity in the gastrointestinal tract, the food matrix and/or food processing. The effects of beta-glucan from barley or yeast on the lipoprotein profile are promising, but more human trials are needed to further substantiate these effects. It is still not clear whether the claimed hypocholesterolemic effects of soy can be attributed solely to the isoflavones. Several studies found no changes in serum LDL cholesterol concentrations after consumption of isolated soy isoflavones (without soy protein), indicating that a combination of soy protein and isoflavones may be needed for eliciting a cholesterol-lowering effect of soy. Therefore, the exact (combination of) active ingredients in soy products need to be identified. The daily consumption of 2-3 g of plant sterols or stanols reduces LDL cholesterol concentrations by 9-14%. It has been demonstrated that functional foods enriched with plant sterols and stanols are effective in various population groups, and in combination with cholesterol-lowering diets or drugs. Whether garlic or garlic preparations can be used as a lipid-lowering agent is still uncertain. It is important to characterize the active components in garlic and their bioavailability after ingestion. It is not very likely that tocotrienols from palm oil or rice bran oil have favorable effects on the human serum lipoprotein profile.

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