Synthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics.

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, ß-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E's biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.

γ-Tocopherol Is Metabolized Faster than α-Tocopherol in Young Japanese Women.

To elucidate the characteristics of γ-tocopherol metabolism, serum concentrations of α- and γ-tocopherol, and urinary excretion of their metabolites after ingestion of α- or γ-tocopherol, major isoforms in our diet, were compared. Six healthy Japanese women (age 22.7±1.7 y old, BMI 21.4±0.9) ingested 134 mg of α- or γ-tocopherol, and blood and urine were collected until 72 h later. After α-tocopherol intake, the serum concentration of α-tocopherol increased at 12-24 h, and urinary excretion of 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (α-CEHC), an α-tocopherol metabolite, increased at 12-36 h. However, after γ-tocopherol intake, the serum concentration of γ-tocopherol increased at 6-12 h, and excretion of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (γ-CEHC), a γ-tocopherol metabolite, increased at 3-12 h. The area under the curve from 0 to 72 h and serum maximal concentration of γ-tocopherol were lower than those of α-tocopherol. The time to maximal concentration of γ-tocopherol was faster than that of α-tocopherol. The ratio of urinary excretion of carboxyethyl-hydroxychroman to tocopherol intake was 2.9% for α-CEHC and 7.7% for γ-CEHC. These results revealed that γ-tocopherol is metabolized faster than α-tocopherol in healthy young women.

The long chain α-tocopherol 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.

SCOPE: Members of the vitamin E family or their metabolites may induce the xenobiotic transporter P-glycoprotein (P-gp), which can limit the bioavailability of drugs and phytochemicals. This study aimed to investigate if α- and γ-tocopherol, α- and γ-tocotrienol, the long chain metabolite α-tocopherol-13'-COOH, the short chain metabolites α- and γ-carboxyethylhydroxychromanol and plastochromanol-8 activate the pregnane X receptor (PXR) and thereby modulate P-gp expression and/or activity. METHODS AND RESULTS: P-gp protein expression and activity were studied in LS 180 cells incubated with the respective test compound for 48 h. Furthermore, we determined if the compounds activate PXR in LS 180 cells, as PXR regulates P-gp expression. Neither P-gp protein expression and activity, nor PXR activity were influenced by α-tocopherol, γ-tocopherol and plastochromanol-8. α-Tocotrienol activated PXR in the reporter gene assay but did not induce protein expression or activity of P-gp. γ-Tocotrienol and α-13'-COOH activated PXR and induced protein expression and transporter activity of P-gp. CONCLUSION: Because the induction of P-gp in the intestine may limit the systemic bioavailability of its substrates, the concurrent intake of drugs and γ-tocotrienol and, if ever applicable, α-13'-COOH should be avoided.

Cluster-determinant 36 (CD36) impacts on vitamin E postprandial response.

SCOPE: A single nucleotide polymorphism in the cluster determinant 36 (CD36) gene has recently been associated with plasma α-tocopherol concentration, suggesting a possible role of this protein in vitamin E intestinal absorption or tissue uptake. METHODS AND RESULTS: To investigate the involvement of CD36 in vitamin E transport, we first evaluated the effect of CD36 on α- and γ-tocopherol transmembrane uptake and efflux using transfected HEK cells. γ-Tocopherol postprandial response was then assessed in CD36-deficient mice compared with wild-type mice, after the mice had been fully characterized for their α-tocopherol, vitamin A and lipid plasma, and tissue contents. Both α- and γ-tocopherol uptake was significantly increased in cells overexpressing CD36 compared with control cells. Compared with wild-type mice, CD36-deficient mice displayed a significantly decreased cholesterol hepatic concentration, and males exhibited significantly higher triacylglycerol contents in liver, brain, heart, and muscle. Although tissue α-tocopherol concentration after adjustment for lipid content was not modified, γ-tocopherol postprandial response was significantly increased in CD36-deficient mice compared with controls, likely reflecting the postprandial hypertriglyceridemia observed in these mice. CONCLUSION: Our findings show for the first time that CD36 participates-directly or indirectly-in vitamin E uptake, and that CD36 effect on postprandial lipid metabolism in turn modifies vitamin E postprandial response.

Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice.

Inflammation can promote colon cancer. Mechanistic studies indicate that γ-tocopherol (γT), a major form of vitamin E in diets, has anti-inflammatory and anticancer properties. Here we investigated the effectiveness of γT and a mixture of tocopherols against colitis and colitis-promoted colon tumorigenesis in male BALB/c mice. γT or mixed tocopherols (at 0.1% diet) did not show any effect on colon tumorigenesis induced by azoxymethane (AOM, 10mg/kg) with three cycles of dextran sodium sulfate (DSS at 1.5-2.5%). γT failed to exhibit protection of severe colitis caused by three cycles of DSS at 2.5%. In contrast, when AOM-initiated carcinogenesis was promoted by relatively mild colitis induced by one-cycle DSS (1.5%), γT, but not mixed tocopherols, suppressed total multiplicity of macroscopic adenomas (P=0.06) and large adenomatous polyps (>2mm(2), P<0.05) by 60 and 85%, respectively. γT also significantly decreased tumor multiplicity (>2mm(2)) induced by AOM with two cycles of 1.5% DSS even when dietary supplementation was started after AOM injection. Consistently, γT but not mixed tocopherols attenuated DSS (1.5%)-induced colon inflammation and damage as well as formation of atypical glandular hyperplasia. Mice supplemented with tocopherols had high fecal excretion of 13'-carboxychromanol, a long-chain vitamin E metabolite shown to have potent anti-inflammatory activities. Our study demonstrates that γT is able to alleviate moderate but not severe colitis and its promoted tumorigenesis, and indicates that inflammation severity should be considered in evaluating anticancer effectiveness of chemoprevention agents.

Safety and pharmacokinetic studies of liposomal antioxidant formulations containing N-acetylcysteine, α-tocopherol or γ-tocopherol in beagle dogs.

The safety and pharmacokinetic profile of liposomal formulations containing combinations of the antioxidants α-tocopherol, γ-tocopherol or N-acetylcysteine in beagle dogs was examined. Each group consisted of beagle dogs of both genders with a control group receiving empty dipalmitoylphosphatidylcholine (DPPC) liposomes (330 mg/kg DPPC, EL), and test groups receiving liposomes prepared from DPPC lipids with (i) N-acetylcysteine (NAC) (60 mg/kg NAC [L-NAC]); (ii) NAC and α-tocopherol (αT) (60 mg/kg NAC and 25 mg/kg α-tocopherol [L-αT-NAC]) and (iii) NAC and γ-tocopherol (60 mg/kg NAC and 25 mg/kg γ-tocopherol (γT) [L-γT-NAC]). The dogs in the control group (EL) and three test groups exhibited no signs of toxicity during the dosing period or day 15 post treatment. Weight gain, feed consumption and clinical pathology findings (hematology, coagulation, clinical chemistry, urinalysis) were unremarkable in all dogs and in all groups. Results from the pharmacokinetic study revealed that the inclusion of tocopherols in the liposomal formulation significantly increased the area under the curve (AUC) and ß-half life for NAC; the tocopherols had greater impact on the clearance of NAC, where reductions of central compartment clearance (CL) ranged from 56% to 60% and reductions of tissue clearance (CL2) ranged from 73% to 77%. In conclusion, there was no treatment-related toxicity in dogs at the maximum feasible dose level by a single bolus intravenous administration while the addition of tocopherols to the liposomal formulation prolonged the circulation of NAC in plasma largely due to a decreased clearance of NAC.

Comparison of the intestinal absorption and bioavailability of γ-tocotrienol and α-tocopherol: in vitro, in situ and in vivo studies.

The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of γ-tocotrienol (γ-T3) and α-tocopherol (α-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of γ-T3 or α-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of γ-T3 in the aqueous phase, the oral bioavailability of α-Tph (36%) was significantly higher than γ-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for α-Tph compared with γ-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for α-Tph compared with γ-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of α-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of γ-T3, suggesting that enhancing its permeability would increase its oral bioavailability.

Tissue distribution of α- and γ-tocotrienol and γ-tocopherol in rats and interference with their accumulation by α-tocopherol.

The aim of this study was to evaluate tissue distribution of vitamin E isoforms such as α- and γ-tocotrienol and γ-tocopherol and interference with their tissue accumulation by α-tocopherol. Rats were fed a diet containing a tocotrienol mixture or γ-tocopherol with or without α-tocopherol, or were administered by gavage an emulsion containing tocotrienol mixture or γ-tocopherol with or without α-tocopherol. There were high levels of α-tocotrienol in the adipose tissue and adrenal gland, γ-tocotrienol in the adipose tissue, and γ-tocopherol in the adrenal gland of rats fed tocotrienol mixture or γ-tocopherol for 7 weeks. Dietary α-tocopherol decreased the α-tocotrienol and γ-tocopherol but not γ-tocotrienol concentrations in tissues. In the oral administration study, both tocopherol and tocotrienol quickly accumulated in the adrenal gland; however, their accumulation in adipose tissue was slow. In contrast to the dietary intake, α-tocopherol, which has the highest affinity for α-tocopherol transfer protein (αTTP), inhibited uptake of γ-tocotrienol to tissues including adipose tissue after oral administration, suggesting that the affinities of tocopherol and tocotrienol for αTTP in the liver were the critical determinants of their uptake to peripheral tissues. Vitamin E deficiency for 4 weeks depleted tocopherol and tocotrienol stores in the liver but not in adipose tissue. These results indicate that dietary vitamin E slowly accumulates in adipose tissue but the levels are kept without degradation. The property of adipose tissue as vitamin E store causes adipose tissue-specific accumulation of dietary tocotrienol.

Serum vitamin E concentrations and recovery of physical function during the year after hip fracture.

BACKGROUND: Poor nutritional status after hip fracture is common and may contribute to physical function decline. Low serum concentrations of vitamin E have been associated with decline in physical function among older adults, but the role of vitamin E in physical recovery from hip fracture has never been explored. METHODS: Serum concentrations of α- and γ-tocopherol, the two major forms of vitamin E, were measured in female hip fracture patients from the Baltimore Hip Studies cohort 4 at baseline and at 2-, 6-, and 12-month postfracture follow-up visits. Four physical function measures-Six-Minute Walk Distance, Lower Extremity Gain Scale, Short Form-36 Physical Functioning Domain, and Yale Physical Activity Survey-were assessed at 2, 6, and 12 months postfracture. Generalized estimating equations modeled the relationship between baseline and time-varying serum tocopherol concentrations and physical function after hip fracture. RESULTS: A total of 148 women aged 65 years and older were studied. After adjusting for covariates, baseline vitamin E concentrations were positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, and Yale Physical Activity Survey scores (p < .1) and faster improvement in Lower Extremity Gain Scale and Yale Physical Activity Survey scores (p < .008). Time-varying vitamin E was also positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, Yale Physical Activity Survey, and Short Form-36 Physical Functioning Domain (p < .03) and faster improvement in Six-Minute Walk Distance and Short Form-36 Physical Functioning Domain (p < .07). CONCLUSIONS: Serum concentrations of both α- and γ-tocopherol were associated with better physical function after hip fracture. Vitamin E may represent a potentially modifiable factor related to recovery of postfracture physical function.

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.

The metabolism of gamma-tocotrienol (gamma-TE) and gamma-tocopherol (gamma-T) was investigated in human A549 cells and in rats. Similar to gamma-T, A549 cells metabolized gamma-TE to sulfated 9'-, 11'-, and 13'-carboxychromanol and their unconjugated counterparts. After 72-h incubation with the cells, 90% of long-chain carboxychromanols in the culture media from gamma-TE, but <45% from gamma-T, were in the sulfated form. The formation of these metabolites was further investigated in rats gavaged by gamma-TE at 10 or 50 mg/kg, gamma-T at 10 mg/kg, or tocopherol-stripped corn oil in controls. Six hours after a single dosing, the supplemented rats had increased plasma concentrations of 13'-carboxychromanol and sulfated 9'-, 11'-, 13'-carboxychromanol, whereas none of these metabolites were detectable in the controls. Sulfated 11'-carboxychromanol was the most abundant long-chain metabolite in gamma-TE-supplemented rats. Sulfatase/glucuronidase hydrolysis revealed for the first time that >88% 2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), the terminal beta-oxidation metabolite, was in the conjugated form in the plasma. In all groups, conjugated gamma-CEHC accounted for >75% of total metabolites, whereas free CEHC was a minor metabolite. At 10 mg/kg, the plasma concentrations of total metabolites from gamma-TE-supplemented rats were higher (P < 0.05) than those from gamma-T-fed rats. These results demonstrate that in rats, conjugation such as sulfation occurs parallel to beta-oxidation in the liver and is quantitatively important to vitamin E metabolism. Conjugated long-chain carboxychromanols may be novel excreted metabolites during supplementation. Our data also provide in vivo evidence that gamma-TE is more extensively metabolized than gamma-T.

Nanoemulsions of an anti-oxidant synergy formulation containing gamma tocopherol have enhanced bioavailability and anti-inflammatory properties.

The present study investigated whether MicroFluidizer Processor-based nanoemulsions of an antioxidant synergy formulation (ASF), containing delta, alpha and gamma tocopherol influenced inflammation and bioavailability in CD-1 mice. Croton oil was applied to all animals' right ear lobe to induce inflammation. Auricular thickness was measured after 2 and 6h after the various treatments. The animal plasma and ear lobes were collected and frozen for bioavailability and cytokine analyses. The ASF nanoemulsions of alpha, delta, or gamma tocopherol significantly reduced auricular thickness compared to control (57, -57, and -71%, respectively) and blank nanoemulsion (-50, -50, -67%, respectively). Relative to the suspensions of ASF, only the nanoemulsion of ASF containing gamma tocopherol significantly reduced auricular thickness (-60%), whereas the 40% reduction with nanoemulsions of delta tocopherol compared to suspension was not statistically significant. Auricular concentrations of cytokines TNF-alpha and IL-1 alpha were significantly reduced in mice treated only with ASF nanoemulsions of gamma tocopherol compared to control (-53, -46%, respectively) and blank nanoemulsion (-52, -46%, respectively). Auricular thickness was significantly associated with tissue TNF-alpha (r=0.539, p<0.001) and IL-1 alpha concentrations (r=0.404, p=0.01). Bioavailability for gamma and delta was dramatically enhanced (2.2- and 2.4-folds) with the nanoemulsion compared to suspensions. Only the plasma gamma tocopherol concentration was significantly associated with auricular thickness (r=-0.643, P=0.001). In conclusion, nanoemulsions of ASF containing gamma, alpha, and delta tocopherol, have enhanced anti-inflammatory properties and increased bioavailability, with gamma tocopherol, in particular compared to their suspensions.

A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis.

BACKGROUND: Pancreatic insufficiency and a diminished bile acid pool cause malabsorption of important essential nutrients and other dietary components in cystic fibrosis (CF). Of particular significance is the malabsorption of fat-soluble antioxidants such as carotenoids, tocopherols and coenzyme Q(10) (CoQ(10)). Despite supplementation, CF patients are often deficient in these compounds, resulting in increased oxidative stress, which may contribute to adverse health effects. This pilot study was designed to evaluate the safety of a novel micellar formulation (CF-1) of fat-soluble nutrients and antioxidants and to determine its efficacy in improving plasma levels of these compounds and reducing inflammatory markers in induced sputum. METHODS: Ten CF subjects, ages 8 to 45 years old, were given orally 10 ml of the CF-1 formulation daily for 56 days after a 21-day washout period in which subjects stopped supplemental vitamin use except for a standard multivitamin. Plasma obtained at -3, 0 (baseline), 1, 2, 4, and 8 weeks was assayed for beta-carotene, gamma-tocopherol, retinol, and CoQ(10) as well as for safety parameters (comprehensive metabolic panel and complete blood count). In addition, pulmonary function was measured and induced sputum was assayed for markers of inflammation and quantitative bacterial counts both prior and during dosing. RESULTS: No serious adverse effects, laboratory abnormalities or elevated nutrient levels (above normal) were identified as related to CF-1. Supplementation with CF-1 significantly increased beta-carotene levels at all dosing time points when compared to screening and baseline. In addition, gamma-tocopherol and CoQ(10) significantly increased from baseline in all subjects. Induced sputum myeloperoxidase significantly decreased and there was a trend toward decreases in PMN elastase and total cell counts with CF-1. There was a significant inverse correlation between the antioxidant levels and induced sputum changes in IL-8 and total neutrophils. Lung function and sputum bacterial counts were unchanged. CONCLUSION: The novel CF-1 formulation safely and effectively increased plasma levels of important fat-soluble nutrients and antioxidants. In addition, improvements in antioxidant plasma levels were associated with reductions in airway inflammation in CF patients.

Bioavailability of a novel, water-soluble vitamin E formulation in malabsorbing patients.

In cystic fibrosis (CF), pancreatic insufficiency and a diminished bile acid pool cause malabsorption of important nutrients and dietary components leading to deficiency, poor nutritional status, and oxidative stress. Of particular significance is the malabsorption of fat-soluble nutrients and antioxidants, which are important for normal immune and neurologic function. Patients with CF often are deficient in these compounds despite supplementation with the current standard of care therapy. The objective was to compare the pharmacokinetic profile of this water-soluble vitamin E formulation (Aqua-E) with an oil-based softgel formulation in a malabsorbing patient population. Patients with CF who had documented malabsorption were recruited for participation in this pharmacokinetic study. Patients who met inclusion and exclusion criteria discontinued vitamin E supplementation, except for that in a multivitamin, for 7 to 21 days before the day of dosing. Patients were randomized to a single dose of 20 ml of Aqua-E or three oil-based softgels, which contained equivalent amounts of tocopherols. Blood was drawn from patients at time 0, 2, 4, 8, 24, 48, and 168 hr and analyzed for tocopherols. Eight patients were enrolled in the study and randomized to Aqua-E or softgels. The primary outcome, the absorption of gamma-tocopherol in Aqua-E (AUC=115 micro g/ml(*)hr), was significantly greater than that of oil-based softgels (AUC=25.3 micro g/ml(*)hr; P=0.013). Total-tocopherols (alpha+gamma+delta) in Aqua-E (AUC=294 micro g/ml(*)hr) showed a strong trend toward increased absorption compared with that of oil-based softgels (AUC=117 micro g/ml(*)hr; P=0.09). In conclusion, this novel, water-soluble formulation showed a marked and statistically significant increase in absorption of gamma-tocopherol in malabsorbing patients with CF compared with an oil-based formulation.

How an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopherol.

alpha-Tocopherol is the only form of vitamin E in vitamin supplements, whereas gamma-tocopherol is the predominant form of vitamin E in the US diet. gamma-Tocopherol has beneficial properties as an anti-inflammatory and possibly anti-atherogenic and anticancer agent. Excess a-tocopherol taken in supplements causes a reduction of gamma-tocopherol concentration in plasma. The biochemical mechanism of this effect, which is important to human nutrition, has recently been elucidated.

Vitamin E attenuates acute lung injury in sheep with burn and smoke inhalation injury.

INTRODUCTION: A decrease in alpha-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (alpha-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury. MATERIALS AND METHODS: Under deep anesthesia, sheep (33 +/- 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40 degrees C). Half of the injured group received alpha-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH2O; tidal volume = 15 ml/kg) for 48 h. RESULTS: Plasma alpha-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 +/- 6.2 ml/min, compared with 27.3 +/- 6.0 ml/min, respectively), increased the PaO2/FiO2 ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine. CONCLUSIONS: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.

Failure of vitamin E in clinical trials: is gamma-tocopherol the answer?

Oxidative stress and inflammation play a crucial role in atherosclerosis. However, prospective clinical trials of dietary antioxidants with anti-inflammatory properties, such as alpha-tocopherol (AT), have not yielded positive results. AT supplementation decreases gamma-tocopherol (GT) levels. GT is an antioxidant with potent anti-inflammatory activity, and plasma GT levels are inversely associated with cardiovascular diseases. Thus, studies using pure GT, alone or in conjunction with AT, will elucidate its utility in cardiovascular disease prevention.

The effect of gamma-tocopherol administration on alpha-tocopherol levels and metabolism in humans.

BACKGROUND: The bioavailability of gamma-tocopherol and metabolites of vitamin E after gamma-tocopherol administration is not well understood. We investigated the effect of gamma-tocopherol administration on the levels and metabolism of alpha- and gamma-tocopherol in healthy volunteers. METHODS: We measured two metabolites of vitamin E (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC)) in plasma and urine by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) during administration of gamma-tocopherol. Two groups of volunteers were enrolled. The gamma-tocopherol group received two gamma-tocopherol capsules (each containing 186.4 mg of gamma-tocopherol and 5 mg of alpha-tocopherol) for 28 days, while the control group received d-alpha-tocopherol at 5 mg/day, which was the same dose as that given to the gamma-tocopherol group. Blood and urine samples were obtained on days 0, 14, 28, 35, 42, and 56 after the initiation of gamma-tocopherol administration. RESULTS: The plasma gamma-tocopherol concentration increased markedly during administration of gamma-tocopherol and the plasma gamma-CEHC concentration increased along with that of gamma-tocopherol. The plasma alpha-tocopherol concentration decreased significantly during gamma-tocopherol administration. The plasma concentration of alpha-CEHC decreased significantly and urinary excretion of alpha-CEHC tended to increase in the gamma-tocopherol group. Urinary sodium secretion was significantly increased at 1 week after the cessation of gamma-tocopherol administration, but there was no significant difference of urine volume between the two groups. CONCLUSION: Metabolism of alpha-tocopherol is accelerated and the plasma alpha-tocopherol concentration is decreased during gamma-tocopherol administration.

Gamma-tocopherol--an underestimated vitamin?

The main research activities of the last decades on tocopherols were mainly focused on alpha-tocopherol, in particular when considering the biological activities. However, recent studies have increased the knowledge on gamma-tocopherol, which is the major form of vitamin E in the diet in the USA, but not in Europe. gamma-Tocopherol provides different antioxidant activities in food and in-vitro studies and showed higher activity in trapping lipophilic electrophiles and reactive nitrogen and oxygen species. The lower plasma levels of gamma- compared to alpha-tocopherol might be discussed in the light of different bioavailability, but also in a potential transformation from gamma- into alpha-tocopherol. From the metabolism end product, only that of gamma-tocopherol (2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman), but not that of alpha-tocopherol, was identified to provide natriuretic activity. Studies also indicate that only the gamma-tocopherol plasma level served as biomarker for cancer and cardiovascular risk. Therefore, this paper provides a comprehensive review on gamma-tocopherol with emphasis on its chemistry, biosynthesis, occurrence in food, different intake linking to different plasma levels in USA and Europe, absorption and metabolism, biological activities, and possible role in human health.

Cereal alkylresorcinols elevate gamma-tocopherol levels in rats and inhibit gamma-tocopherol metabolism in vitro.

Alkylresorcinols (AR) are a class of amphiphilic phenolic lipids present in high amounts in wheat and rye bran. They have been reported to be both growth retarding and innocuous when fed to rats, and to have a broad range of bioactivities in vitro, suggested to be related to their ability to bind to proteins and modify membranes. This study was designed to test the effects of AR (purified from rye bran) on growth, tocopherol levels, and cholesterol levels in rats. Rats were fed 1 of 4 different levels of AR for 4 wk: 0 (control), 1, 2, and 4 g/kg diet. AR did not affect final body, liver, or lung weights. The AR diets increased the levels of gamma-tocopherol in liver and lungs (P < 0.05). To investigate whether AR could have increased gamma-tocopherol levels via inhibition of tocopherol-omega-hydroxylase, HepG2 cells were incubated with AR and the metabolism of gamma-tocopherol measured. AR significantly inhibited the conversion of gamma-tocopherol to its water-soluble hydroxychroman metabolite in vitro, indicating that AR may increase gamma-tocopherol levels via inhibition of tocopherol metabolism in vivo. The 4 g AR/kg diet decreased liver cholesterol (P < 0.001), but did not affect plasma lipids. AR were detected in the perirenal adipose tissue samples of rats fed AR, indicating that they can accumulate in the fatty tissues of rats. High levels of dietary AR moderately affect gamma-tocopherol, possibly via inhibition of tocopherol metabolism, and decrease liver cholesterol in rats.