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Life Extension Magazine March 2012

Vitamin E

Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.

BACKGROUND: Selenium and alpha-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of gamma-tocopherol, a major component of vitamin E in the US diet and the second most common tocopherol in human serum. A nested case-control study was conducted to examine the associations of alpha-tocopherol, gamma-tocopherol, and selenium with incident prostate cancer. METHODS: In 1989, a total of 10,456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, alpha-tocopherol, and gamma-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: The risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol (odds ratio (highest versus lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32; P(trend) =.28). For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (P:(trend) =.002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (P(trend) =.27). Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high. CONCLUSIONS: The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium.

J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23

Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms.

We found that gamma-tocopherol, the predominant vitamin E form in diets, but not alpha-tocopherol, which is the exclusive form of vitamin E in most supplements, exhibited antiproliferation effect on prostate (PC-3, LNCaP) and lung (A549) cancer cells. gamma-Tocopherol induced apoptosis in androgen-sensitive LNCaP but not androgen-resistant PC-3 cells. Consequently, gamma-tocopherol treatment caused cytochrome c release and caspase-9, -3 and -7 activation. However, the apoptosis could not be completely reversed by an irreversible pancaspase inhibitor, indicating that an alternative caspase-independent pathway may also be involved. Our study suggests that gamma-tocopherol may be valuable in the prevention and therapy for certain types of cancer.

Ann N Y Acad Sci. 2004 Dec;1031:399-400

Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice.

Gamma-tocopherol (gamma-T) alone or in combination with alpha-tocopherol has been shown to suppress biomarkers of oxidative stress in asthamatics and human subjects with metabolic syndrome. Oxidative stress has been implicated as a key event in prostate carcinogenesis. Hence, the purpose of this study was to examine the effects of gamma-tocopherol-enriched mixed tocopherol diet on prostate carcinogenesis in a murine prostate cancer model (TRAMP). 8 week old TRAMP males were fed 0.1% gamma-T-enriched mixed tocopherol diet that contained 20-fold higher levels of gamma-tocopherol, and roughly 3-fold higher levels of alpha-tocopherol. The effect of such diet on tumor and PIN development was observed. The expression of phase II detoxifying, antioxidant enzymes and Nrf2 mRNA and protein were determined by RT-PCR, immunohistochemistry and western blotting techniques. Treatment with gamma-T-enriched mixed tocopherols significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development without affecting the expression of the transgene (SV-40). Tumor progression occurred with a significant suppression of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, heme-oxygenase-1 and phase II detoxifying enzymes. Treatment with gamma-T-enriched mixed tocopherol diet upregulated the expression of most detoxifying and antioxidant enzymes. Nrf2-a redox sensitive transcription factor known to mediate the expression of phase II detoxifying enzymes, was also significantly upregulated following treatment with gamma-T-enriched mixed tocopherol diet. Gamma-T-enriched mixed tocopherols significantly up-regulated the expression of Nrf2 and its related detoxifying and antioxidant enzymes thereby suppressing PIN and tumor development.

Int J Cancer. 2009 Apr 1;124(7):1693-9

RRR-gamma-tocopherol induces human breast cancer cells to undergo apoptosis via death receptor 5 (DR5)-mediated apoptotic signaling.

Goal of this study was to investigate the pro-apoptotic properties of RRR-gamma-tocopherol (gammaT) in human breast cancer cells. gammaT was shown to induce cancer cells but not normal cells to undergo apoptosis, sensitize cancer cells to Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis, and increase death receptor 5 (DR5) mRNA, protein and cell surface expression. Knockdown of DR5 attenuated gammaT-induced apoptosis. Investigations of post-receptor signaling showed: caspase-8, Bid and Bax activation, increases in mitochondria permeability, cytochrome c release and caspase-9 activation. Thus, gammaT is a potent pro-apoptotic agent for human breast cancer cells inducing apoptosis via activation of DR5-mediated apoptotic pathway.

Cancer Lett. 2008 Feb 8;259(2):165-76

Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol.

In the vitamin E group, alpha-tocopherol is generally considered to be the most potent antioxidant with the highest vitamin bioactivity, yet gamma-tocopherol is produced in greater amounts by many plants and is the principal tocopherol in the United States diet. This report describes a fundamental difference in the chemical reactivities of alpha-tocopherol and gamma-tocopherol with nitrogen dioxide (NO2), which leads to the formation of a nitrosating agent from alpha-tocopherol, but not from gamma-tocopherol. Nitric oxide (NO) is a major product of the reaction of gamma-tocopherol with NO2, while alpha-tocopherol reacts with NO2 to form an intermediate tocopheroxide analogue. The biological significance of gamma-tocopherol is suggested by limited epidemiological data as well as the observation that it is a more potent inhibitor than alpha-tocopherol of neoplastic transformation during the postinitiation phase in 3-methylcholanthrene-treated C3H/10T1/2 murine fibroblasts. This latter property suggests the superiority of gamma-tocopherol in a mammalian biological assay and a role for endogenous NO production in promotion of neoplastic transformation.

Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1771-5

gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications.

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of .NO and O2.- during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the .NO and O2.- generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximately 50% and approximately 75%, respectively, was not affected by the presence of alphaT. These results suggest that despite alphaT’s action as an antioxidant gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.

Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3217-22

Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. OBJECTIVE: To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8,752 to receive selenium; 8,737, vitamin E; 8,702, both agents, and 8,696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. INTERVENTIONS: Oral selenium (200 µg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-a-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer incidence. RESULTS: This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. CONCLUSION: Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.

JAMA. 2011 Oct 12;306(14):1549-56

Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE: To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS: Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS: As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.

JAMA. 2009 Jan 7;301(1):39-51

Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.

Nutr Cancer. 2009;61(5):649-62

Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome.

Metabolic syndrome (MetS) is associated with increased incidence of diabetes and cardiovascular disease (CVD). Prospective clinical trials with alpha-tocopherol (AT) have not yielded positive results. Because AT supplementation decreases circulating gamma-tocopherol (GT), we evaluated supplementation with GT (800 mg/day), AT (800 mg/day), the combination or placebo for 6 weeks alone AT and GT concentrations, biomarkers of oxidative stress, and inflammation in subjects with MetS (n=20/group). Plasma AT and GT levels increased following supplementation with AT alone or GT alone or in combination. AT supplementation significantly decreased GT levels. Urinary alpha- and gamma-CEHC, metabolites of the respective Ts, also increased correspondingly, i.e., alpha-CEHC with AT and gamma-CEHC with GT supplementation, compared to placebo. HsCRP levels significantly decreased in the combined AT+GT group. LPS-activated whole blood release of IL-1 and IL-6 did not change. There was a significant decrease in TNF with AT alone or in combination with GT. Plasma MDA/HNE and lipid peroxides were significantly decreased with AT, GT, or in combination. Nitrotyrosine levels were significantly decreased only with GT or GT+AT but not with AT compared to placebo. Thus, the combination of AT and GT supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials to elucidate its utility in CVD prevention.

Free Radic Biol Med. 2008 Mar 15;44(6):1203-8

Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus.

INTRODUCTION: The aim of this study was to evaluate the effects of high-dose vitamin E supplementation (1,200 mg/day) on reducing both microalbuminuria (MA) and oxidative stress in patients with type 1 diabetes mellitus (T1DM) and persistent MA. METHODS: We performed a 12-month, randomized, placebo-controlled, double-blind cross-over trial in ten Caucasian young adults (7m/3f; mean age 18.87 +/- 2.91 years) with T1DM and persistent MA. At baseline and at end of the treatment period, determination of albumin excretion rate (AER) and HbA(1c) and evaluation of the oxidant/antioxidant status were performed. RESULTS: At the beginning of the study, AER and HbA(1c) were not significantly different between the vitamin E and placebo group. No differences in terms of oxidant and antioxidant status were found between the two groups. This was associated with no significantly different urinary VEGF and TGF-beta levels. After 6 months, no significant differences in AER were observed between the two groups (p = 0.59). However, plasma and LDL-vitamin E content were significantly higher in the vitamin E group compared to the placebo group (p = 0.0001 and p = 0.004, respectively). This was associated with a significantly longer lag phase (p = 0.002) and lower MDA (p = 0.049). However, no statistically significant differences were detected in terms of VEGF and TGF-beta urinary levels. CONCLUSION: These data demonstrate that high-dose vitamin E supplementation reduces markers of oxidative stress and improves antioxidant defence in young patients with T1DM. However, although it positively affects the oxidant/antioxidant status, vitamin E supplementation does not reduce AER in patients with T1DM and persistent MA.

Diabetes Metab Res Rev. 2007 Oct;23(7):539-46

g-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men.

Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant g-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3±1.0 years; 29.3±2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in g-tocopherol (500 mg/day). g-Tocopherol supplementation increased (P<.0001) plasma g-tocopherol from 2.22±0.32 to 7.06±0.71 µmol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by g-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental g-tocopherol (P<.05), but not following g-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of g-tocopherol than without (area under the curve (0-180 min), -778±1010 vs. 2277±705). Plasma concentrations of g-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma g-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of g-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk.

J Nutr Biochem. 2011 May 2

Anti-inflammatory properties of alpha- and gamma-tocopherol.

Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.

Mol Aspects Med. 2007 Oct-Dec;28(5-6):668-91

Effects of gamma-tocopherol supplementation on thrombotic risk factors.

OBJECTIVE: The antioxidant activity of vitamin E is derived primarily from alpha-tocopherol (alpha-T) and gamma-tocopherol (gamma-T). Results of epidemiological studies have demonstrated an inverse relationship between vitamin E intake and coronary disease. However, the results of clinical trials using alpha-T are equivocal. We determined the effect of 5 weeks of 100 mg/d or 200 mg/d gamma-T supplementation on thrombotic markers such as platelet reactivity, lipid profile and the inflammation marker C-reactive protein (CRP). METHODS AND RESULTS: Fourteen healthy subjects consumed 100 mg/day while 13 consumed 200 mg/d of gamma-T and 12 received placebo (soybean capsules with less than 5 mg/d gamma-T) in a double-blinded parallel study design. Fasting pre and post dose blood samples were analysed. Blood gamma-T concentrations increased significantly (p<0.05) relative to dose during the intervention period. Both groups receiving active ingredients showed significantly lower platelet activation after supplementation (p<0.05). Subjects consuming 100 mg/d gamma-T had significantly decreased LDL cholesterol, platelet aggregation and mean platelet volume (MPV) (p<0.05). Little effect of gamma-T was observed on other parameters. CONCLUSIONS: These data suggest that gamma-T supplementation may have a permissive role in decreasing the risk of thrombotic events by improving lipid profile and reducing platelet activity.

Asia Pac J Clin Nutr. 2007;16(3):422-8

Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma.

BACKGROUND: Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that gamma-tocopherol (gammaT), the primary form of dietary vitamin E, is more effective than alpha-tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non-immunogenic stimuli. OBJECTIVE: We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with gammaT would protect from adverse nasal and pulmonary responses to airway allergen provocation. METHODS: Ovalbumin (OVA)-sensitized Brown Norway rats were treated orally with gammaT before intranasal provocation with OVA. Twenty-four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma. RESULTS: We found that acute dosing for 4 days with gammaT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with gammaT. Pulmonary production of soluble mediators PGE(2), LTB(4) and cysteinyl leukotrienes, and nasal expression of IL-4, -5, -13 and IFN-gamma were also inhibited by gammaT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with gammaT. CONCLUSIONS: Acute treatment with gammaT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with gammaT may be a novel complementary therapy for allergic airways disease.

Clin Exp Allergy. 2008 Mar;38(3):501-11