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1.  Serum α-Tocopherol and γ-Tocopherol Concentrations and Prostate Cancer Risk in the PLCO Screening Trial: A Nested Case-Control Study 
PLoS ONE  2012;7(7):e40204.
Vitamin E compounds exhibit prostate cancer preventive properties experimentally, but serologic investigations of tocopherols, and randomized controlled trials of supplementation in particular, have been inconsistent. Many studies suggest protective effects among smokers and for aggressive prostate cancer, however.
We conducted a nested case-control study of serum α-tocopherol and γ-tocopherol and prostate cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, with 680 prostate cancer cases and 824 frequency-matched controls. Multivariate-adjusted, conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tocopherol quintiles.
Serum α-tocopherol and γ-tocopherol were inversely correlated (r = −0.24, p<0.0001). Higher serum α-tocopherol was associated with significantly lower prostate cancer risk (OR for the highest vs. lowest quintile = 0.63, 95% CI 0.44–0.92, p-trend 0.05). By contrast, risk was non-significantly elevated among men with higher γ-tocopherol concentrations (OR for the highest vs. lowest quintile = 1.35, 95% CI 0.92–1.97, p-trend 0.41). The inverse association between prostate cancer and α-tocopherol was restricted to current and recently former smokers, but was only slightly stronger for aggressive disease. By contrast, the increased risk for higher γ-tocopherol was more pronounced for less aggressive cancers.
Our findings indicate higher α-tocopherol status is associated with decreased risk of developing prostate cancer, particularly among smokers. Although two recent controlled trials did not substantiate an earlier finding of lower prostate cancer incidence and mortality in response to supplementation with a relatively low dose of α-tocopherol, higher α-tocopherol status may be beneficial with respect to prostate cancer risk among smokers. Determining what stage of prostate cancer development is impacted by vitamin E, the underlying mechanisms, and how smoking modifies the association, is needed for a more complete understanding of the vitamin E-prostate cancer relation.
PMCID: PMC3390343  PMID: 22792240
2.  δ-Tocopherol Is More Active than α- or γ-Tocopherol in Inhibiting Lung Tumorigenesis In Vivo 
In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol–rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed the present study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol—up to 45 µM for α-tocopherol, 9.7 µM for γ-tocopherol, and 1.2 µM for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain–degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. The present study is the first in vivo assessment of δ-tocopherol in tumorigenesis and demonstrates that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results.
PMCID: PMC3071153  PMID: 21372040
Tocopherols; lung cancer cells; xenograft; tocopherol metabolites
3.  Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study 
Vitamin E includes several tocopherol isoforms which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women’s Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline, and also reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared to the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace (HR=0.53 (0.29-0.97), p-trend = 0.04). In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female non-smokers, however supplements may increase lung adenocarcinoma risk and requires further investigation.
PMCID: PMC4232456  PMID: 24916784
diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women
4.  Prediagnostic serum tocopherol levels and the risk of Non-Hodgkin Lymphoma: The Multiethnic Cohort 
Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology.
This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high pressure liquid chromatography/photodiode-array detection with NHL risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).
We observed U-shaped associations with NHL for total and α-tocopherols (Ptrend<0.01 for polynomial terms [3 df]). The ORs (95% CI) for total tocopherols, which consisted primarily of α-tocopherol, were 0.41 (0.25–0.68), 0.52 (0.32–0.85), 0.39 (0.23–0.65), and 0.78 (0.47–1.29) for the 2nd-5th quintiles as compared to the 1st. The risk estimates were similar for α-tocopherol but non-significant for β- and γ-tocopherol combined and for δ-tocopherol. Adjustment for serum lipids strengthened the non-linear associations for total and α-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than non-users (21.32±9.04 vs 17.72±7.43 μg/mL; P <0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype.
Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial.
The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL.
PMCID: PMC3819232  PMID: 24045922
non-Hodgkin lymphoma; tocopherols; ethnicity; prospective cohort; nested case-control study
5.  Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen-receptor positive, but not HER-2 breast cancer 
Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ- or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). While administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (p<0.01) and 7.1 ± 0.7 g (p<0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (p<0.001) and 32% (p<0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of pro-apoptotic markers (BAX, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP) were increased, while anti-apoptotic markers (Bcl2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKC α), survival (PPARγ, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, appear to be promising agents for the prevention of hormone-dependent breast cancer.
PMCID: PMC3491089  PMID: 22964476
Breast Cancer; Tocopherols; Apoptosis; Cell Cycle; PPARγ
6.  Tocotrienols-induced inhibition of platelet thrombus formation and platelet aggregation in stenosed canine coronary arteries 
Dietary supplementation with tocotrienols has been shown to decrease the risk of coronary artery disease. Tocotrienols are plant-derived forms of vitamin E, which have potent anti-inflammatory, antioxidant, anticancer, hypocholesterolemic, and neuroprotective properties. Our objective in this study was to determine the extent to which tocotrienols inhibit platelet aggregation and reduce coronary thrombosis, a major risk factor for stroke in humans. The present study was carried out to determine the comparative effects of α-tocopherol, α-tocotrienol, or tocotrienol rich fraction (TRF; a mixture of α- + γ- + δ-tocotrienols) on in vivo platelet thrombosis and ex vivo platelet aggregation (PA) after intravenous injection in anesthetized dogs, by using a mechanically stenosed circumflex coronary artery model (Folts' cyclic flow model).
Collagen-induced platelet aggregation (PA) in platelet rich plasma (PRP) was decreased markedly after treatment with α-tocotrienol (59%; P < 0.001) and TRF (92%; P < 0.001). α-Tocopherol treatment was less effective, producing only a 22% (P < 0.05) decrease in PA. Adenosine diphosphate-induced (ADP) PA was also decreased after treatment with α-tocotrienol (34%; P < 0.05) and TRF (42%; P < 0.025). These results also indicate that intravenously administered tocotrienols were significantly better than tocopherols in inhibiting cyclic flow reductions (CFRs), a measure of the acute platelet-mediated thrombus formation. Tocotrienols (TRF) given intravenously (10 mg/kg), abolished CFRs after a mean of 68 min (range 22 -130 min), and this abolition of CFRs was sustained throughout the monitoring period (50 - 160 min).
Next, pharmacokinetic studies were carried out and tocol levels in canine plasma and platelets were measured. As expected, α-Tocopherol treatment increased levels of total tocopherols in post- vs pre-treatment specimens (57 vs 18 μg/mL in plasma, and 42 vs 10 μg/mL in platelets). However, treatment with α-tocopherol resulted in slightly decreased levels of tocotrienols in post- vs pre-treatment samples (1.4 vs 2.9 μg/mL in plasma and 2.3 vs 2.8 μg/mL in platelets). α-Tocotrienol treatment increased levels of both tocopherols and tocotrienols in post- vs pre-treatment samples (tocopherols, 45 vs 10 μg/mL in plasma and 28 vs 5 μg/mL in platelets; tocotrienols, 2.8 vs 0.9 μg/mL in plasma and 1.28 vs 1.02 μg/mL in platelets). Treatment with tocotrienols (TRF) also increased levels of tocopherols and tocotrienols in post- vs pre-treatment samples (tocopherols, 68 vs 20 μg/mL in plasma and 31.4 vs 7.9 μg/mL in platelets; tocotrienols, 8.6 vs 1.7 μg/mL in plasma and 3.8 vs 3.9 μg/mL in platelets).
The present results indicate that intravenously administered tocotrienols inhibited acute platelet-mediated thrombus formation, and collagen and ADP-induced platelet aggregation. α-Tocotrienols treatment induced increases in α-tocopherol levels of 4-fold and 6-fold in plasma and platelets, respectively. Interestingly, tocotrienols (TRF) treatment induced a less pronounced increase in the levels of tocotrienols in plasma and platelets, suggesting that intravenously administered tocotrienols may be converted to tocopherols. Tocotrienols, given intravenously, could potentially prevent pathological platelet thrombus formation and thus provide a therapeutic benefit in conditions such as stroke and myocardial infarction.
PMCID: PMC3096575  PMID: 21489303
7.  Blood α-Tocopherol, γ-Tocopherol Levels and Risk of Prostate Cancer: A Meta-Analysis of Prospective Studies 
PLoS ONE  2014;9(3):e93044.
Epidemiological studies that have examined the association of blood α-tocopherol and γ-tocopherol (the principal bioactive form of vitamin E) levels with the risk of prostate cancer have yielded inconsistent results. In addition, a quantitative assessment of published studies is not available.
Methods and Findings
In this meta-analysis, relevant studies were sought by a search of the PubMed and Embase databases for articles published up to October 2013, with no restrictions. Bibliographies from retrieved articles also were scoured to find further eligible studies. Prospective studies that reported adjusted relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between blood tocopherol levels and the risk of prostate cancer were included. Nine nested case–control studies involving approximately 370,000 participants from several countries were eligible. The pooled RRs of prostate cancer for the highest versus lowest category of blood α-tocopherol levels were 0.79 (95% CI: 0.68–0.91), and those for γ-tocopherol levels were 0.89 (95% CI: 0.71–1.12), respectively. Significant heterogeneity was present among the studies in terms of blood γ-tocopherol levels (p = 0.008) but not in terms of blood α-tocopherol levels (p = 0.33). The risk of prostate cancer decreased by 21% for every 25-mg/L increase in blood α-tocopherol levels (RR: 0.79; 95% CI: 0.69–0.91).
Blood α-tocopherol levels, but not γ-tocopherol levels, were inversely associated with the risk of prostate cancer in this meta-analysis.
PMCID: PMC3965522  PMID: 24667740
8.  Vitamin E intake and Risk of Esophageal and Gastric Cancers in the NIH-AARP Diet and Health Study 
We investigated the association of dietary α-tocopherol, γ-tocopherol, and supplemental vitamin E intake with the risk of esophageal squamous cell carcinoma (ESCC; n = 158), esophageal adenocarcinoma (EAC; n = 382), gastric cardia adenocarcinoma (GCA; n = 320), and gastric noncardia adenocarcinoma (GNCA; n = 327) in the NIH-AARP Diet and Health Study, a cohort of approximately 500,000 people. Data on dietary and supplemental vitamin E intake were collected using a validated questionnaire at baseline and were analyzed using Cox regression models. Intakes were analyzed as continuous variables and as quartiles.
For dietary α-tocopherol, we found some evidence of association with decreased ESCC and increased EAC risk in the continuous analyses, with adjusted hazard ratios (HR) and 95% confidence intervals (CI) of 0.90 (0.81 – 0.99) and 1.05 (1.00 – 1.11), respectively, per 1.17 mg (half the interquartile range) increased intake. However, in quartile analyses, the p-value for trend was non-significant for both of these cancers. There was no association between dietary α-tocopherol and GCA or GNCA. We observed no statistically significant associations with γ-tocopherol. For supplemental vitamin E, the results were mainly null, except for a significantly lower risk of GNCA with higher doses of supplemental vitamin E. An increase of 71 mg/day (half the interquartile range) in supplemental vitamin E had an HR (95% CI) of 0.92 (0.85–1.00) and the p-value for trend in the quartile analyses was 0.015.
PMCID: PMC2686122  PMID: 19326432
9.  The uptake of tocopherols by RAW 264.7 macrophages 
Nutrition Journal  2002;1:2.
Alpha-Tocopherol and gamma-tocopherol are the two major forms of vitamin E in human plasma and the primary lipid soluble antioxidants. The dietary intake of gamma-tocopherol is generally higher than that of alpha-tocopherol. However, alpha-tocopherol plasma levels are about four fold higher than those of gamma-tocopherol. Among other factors, a preferential cellular uptake of gamma-tocopherol over alpha-tocopherol could contribute to the observed higher plasma alpha-tocopherol levels. In this investigation, we studied the uptake and depletion of both alpha-tocopherol and gamma-tocopherol (separately and together) in cultured RAW 264.7 macrophages. Similar studies were performed with alpha-tocopheryl quinone and gamma-tocopheryl quinone, which are oxidation products of tocopherols.
RAW 264.7 macrophages showed a greater uptake of gamma-tocopherol compared to alpha-tocopherol (with uptake being defined as the net difference between tocopherol transported into the cells and loss due to catabolism and/or in vitro oxidation). Surprisingly, we also found that the presence of gamma-tocopherol promoted the cellular uptake of alpha-tocopherol. Mass balance considerations suggest that products other than quinone were formed during the incubation of tocopherols with macrophages.
Our data suggests that gamma-tocopherol could play a significant role in modulating intracellular antioxidant defence mechanisms. Moreover, we found the presence of gamma-tocopherol dramatically influenced the cellular accumulation of alpha-tocopherol, i.e., gamma-tocopherol promoted the accumulation of alpha-tocopherol. If these results could be extrapolated to in vivo conditions they suggest that gamma-tocopherol is selectively taken up by cells and removed from plasma more rapidly than alpha-tocopherol. This could, in part, contribute to the selective maintenance of alpha-tocopherol in plasma compared to gamma-tocopherol.
PMCID: PMC139959  PMID: 12537596
10.  Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines 
BMC Cancer  2006;6:13.
Mediterranean societies, with diets rich in vitamin E isoforms, have a lower risk for colon cancer than those of northern Europe and the Americas. Vitamin E rich diets may neutralize free radicals generated by fecal bacteria in the gut and prevent DNA damage, but signal transduction activities can occur independent of the antioxidant function. The term vitamin E represents eight structurally related compounds, each differing in their potency and mechanisms of chemoprevention. The RRR-γ-tocopherol isoform is found primarily in the US diet, while RRR-α-tocopherol is highest in the plasma.
The effectiveness of RRR-α- and RRR-γ-tocopherol at inhibiting cell growth and inducing apoptosis in colon cancer cell lines with varying molecular characteristics (SW480, HCT-15, HCT-116 and HT-29) and primary colon cells (CCD-112CoN, nontransformed normal phenotype) was studied. Colon cells were treated with and without RRR-α- or RRR-γ-tocopherol using varying tocopherol concentrations and time intervals. Cell proliferation and apoptosis were measured using the trypan blue assay, annexin V staining, DNA laddering and caspase activation.
Treatment with RRR-γ-tocopherol resulted in significant cell death for all cancer cell lines tested, while RRR-α-tocopherol did not. Further, RRR-γ-tocopherol treatment showed no cytotoxicity to normal colon cells CCD-112CoN at the highest concentration and time point tested. RRR-γ-tocopherol treatment resulted in cleavage of PARP, caspase 3, 7, and 8, but not caspase 9. Differences in the percentage cell death and apoptosis were observed in different cell lines suggesting that molecular differences in these cell lines may influence the ability of RRR-γ-tocopherol to induce cell death.
This is the first study to demonstrate that multiple colon cancer cell lines containing varying genetic alterations will under go growth reduction and apoptosis in the presence of RRR-γ-tocopherol without damage to normal colon cells. The amount growth reduction was dependent upon the molecular signatures of the cell lines. Since RRR-γ-tocopherol is effective at inhibition of cell proliferation at both physiological and pharmacological concentrations dietary RRR-γ-tocopherol may be chemopreventive, while pharmacological concentrations of RRR-γ-tocopherol may aid chemotherapy without toxic effects to normal cells demonstrated by most chemotherapeutic agents.
PMCID: PMC1379650  PMID: 16417629
11.  Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (γ) expression in SW 480 human colon cancer cell lines 
BMC Cancer  2003;3:25.
Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of γ-tocopherol is higher than α-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used α-tocopherol. Recent epidemiological, experimental and molecular studies suggest that γ-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied α-tocopherol. γ-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor γ (PPARγ) is a promising molecular target for colon cancer prevention. Upregulation of PPARγ activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARγ ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both α and γ tocopherol on the expression of PPARγ mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines.
We have discovered that the α and γ isoforms of vitamin E upregulate PPARγ mRNA and protein expression in the SW480 colon cancer cell lines. γ-Tocopherol is a better modulator of PPARγ expression than α-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, γ-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of α-tocopherol.
Our data suggest that both α and γ tocopherol can upregulate the expression of PPARγ which is considered an important molecular target for colon cancer chemoprevention. We show that the expression of PPARγ mRNA and protein are increased and these effects are more pronounced with γ-tocopherol. γ-Tocopherol's ability to upregulate PPARγ expression and achieve higher intracellular concentrations in the colonic tissue may be relevant to colon cancer prevention. We also show that the intracellular concentrations of γ-tocopherol are several fold higher than α-tocopherol. Further work on other colon cancer cell lines are required to quantitate differences in the ability of these forms of vitamin E to induce apoptosis, suppress cell proliferation and act as PPAR ligands as well as determine their effects in conjunction with other chemopreventive agents. Upregulation of PPARγ by the tocopherols and in particular by γ-tocopherol may have relevance not only to cancer prevention but also to the management of inflammatory and cardiovascular disorders.
PMCID: PMC222914  PMID: 14521714
Approximately 40% of Americans take dietary supplements, including vitamin E (α-tocopherol). Unlike other fat-soluble vitamins, α-tocopherol is not accumulated to toxic levels. Rather tissue levels are tightly regulated, in part via increased hepatic metabolism and excretion that could, theoretically, alter metabolism of drugs, environmental toxins and other nutrients. To date, in vivo subcellular location(s) of α-tocopherol metabolism have not been identified. The proposed pathway of α-tocopherol metabolism proceeds via ω-hydroxylation to 13′-OH-α-tocopherol, followed by successive rounds of β-oxidation to form α-CEHC. To test the hypothesis that α-tocopherol ω-hydroxylation occurs in microsomes while β-oxidation occurs in peroxisomes, rats received daily injections of vehicle, 10 mg α-tocopherol or 10 mg trolox/100 g body wt for 3 days, then microsomes, mitochondria and peroxisomes were isolated from liver homogenates. Homogenate α-tocopherol levels increased 16-fold in α-tocopherol-injected rats, while remaining unchanged in trolox- or vehicle-injected rats. Total α-tocopherol recovered in the three subcellular fractions represented 93 ± 4% of homogenate α-tocopherol levels. In α-tocopherol-injected rats, microsome α-tocopherol levels increased 28-fold, while mitochondria and peroxisome levels increased 8- and 3-fold, respectively, indicating greater partitioning of α-tocopherol to the microsomes with increasing liver α-tocopherol. In α-tocopherol-injected rats, microsome 13′-OH-α-tocopherol levels increased 24-fold compared to controls, and were 7-fold greater than 13′-OH-α-tocopherol levels in peroxisome and mitochondrial fractions of α-tocopherol-injected rats. An unexpected finding was that α-CEHC, the end product of α-tocopherol metabolism, was found almost exclusively in mitochondria. These data are the first to indicate a mitochondrial role in α-tocopherol metabolism.
PMCID: PMC2818260  PMID: 19819327
vitamin E; cytochrome P450; xenobiotic metabolism; mitochondria; peroxisome; β-oxidation; ω-oxidation; CYP
13.  The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study 
Respiratory Research  2014;15(1):31.
Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.
To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.
In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV1 and FVC at ages 21–55 years.
Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.
PMCID: PMC4003816  PMID: 24629024
α-tocopherol; γ-tocopherol; FEV1; FVC; Human
14.  Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-γ 
Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis.
Experimental Design
Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells.
Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer.
The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer.
PMCID: PMC2753525  PMID: 19509159
breast cancer; γ-tocopherol; δ-tocopherol; estrogen receptor; PPAR-γ
15.  Plasma and dietary carotenoid, retinol and tocopherol levels and the risk of gastric adenocarcinomas in the European prospective investigation into cancer and nutrition 
British Journal of Cancer  2006;95(3):406-415.
Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. Its aetiology may involve dietary antioxidant micronutrients such as carotenoids and tocopherols. The objective of this study was to determine the association of plasma levels of seven common carotenoids, their total plasma concentration, retinol and α- and γ-tocopherol, with the risk of gastric adenocarcinoma in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 countries. A secondary objective was to determine the association of total sum of carotenoids, retinol and α-tocopherol on GCs by anatomical subsite (cardia/noncardia) and histological subtype (diffuse/intestinal). Analytes were measured by high-performance liquid chromatography in prediagnostic plasma from 244 GC cases and 645 controls matched by age, gender, study centre and date of blood donation. Conditional logistic regression models adjusted by body mass index, total energy intake, smoking and Helicobacter pylori infection status were used to estimate relative cancer risks. After an average 3.2 years of follow-up, a negative association with GC risk was observed in the highest vs the lowest quartiles of plasma β-cryptoxanthin (odds ratio (OR)=0.53, 95% confidence intervals (CI)=0.30–0.94, Ptrend=0.006), zeaxanthin (OR=0.39, 95% CI=0.22–0.69, Ptrend=0.005), retinol (OR=0.55, 95% CI=0.33–0.93, Ptrend=0.005) and lipid-unadjusted α-tocopherol (OR=0.59, 95% CI=0.37–0.94, Ptrend=0.022). For all analytes, no heterogeneity of risk estimates or significant associations were observed by anatomical subsite. In the diffuse histological subtype, an inverse association was observed with the highest vs lowest quartile of lipid-unadjusted α-tocopherol (OR=0.26, 95% CI=0.11–0.65, Ptrend=0.003). These results show that higher plasma concentrations of some carotenoids, retinol and α-tocopherol are associated with reduced risk of GC.
PMCID: PMC2360629  PMID: 16832408
carotenoids; tocopherol; retinol; gastric cancer; diet; EPIC
16.  Vitamin E: maternal concentrations are associated with fetal growth2 
Few data exist on the effects of the 2 most abundant isomers of vitamin E (α- and γ-tocopherols) on fetal growth.
We measured maternal plasma concentrations of α- and γ-tocopherols and examined their relation with measures of fetal growth. We also examined the relation, controlled for associated maternal factors, of diet and supplement use to tocopherol concentrations at week 28 of gestation.
A cohort of 1231 gravid women from Camden, NJ, was studied from entry to care (16.0 ± 0.15 wk gestation); plasma tocopherol concentrations were measured at entry and at week 28.
Plasma concentrations of α-tocopherol at entry and at week 28 were positively related to increased fetal growth (birth weight for gestation), a decreased risk of small-for-gestational-age births, and an increased risk of large-for-gestational-age births. Concentration of α-tocopherol at week 28 was positively related to use of prenatal multivitamins and dietary intake of vitamin E; concentration of γ-tocopherol was related positively to dietary fat intake and negatively to multivitamin use.
Early and late circulating concentrations of α-tocopherol are positively associated with fetal growth.
PMCID: PMC1876684  PMID: 17158428
Birth weight; fetal growth; small for gestational age; large for gestational age; vitamin E; antioxidants; γ-tocopherol; α-tocopherol; multivitamins; maternal nutrition; pregnancy
17.  Association of Serum α-Tocopherol with Sex Steroid Hormones and Interactions with Smoking: Implications for Prostate Cancer Risk 
Cancer causes & control : CCC  2011;22(6):827-836.
Vitamin E may protect against prostate cancer, possibly only in smokers and, we hypothesize, through altered sex steroid hormones. A controlled trial in smokers showed that sex hormone levels were inversely associated with baseline serum α-tocopherol and decreased in response to vitamin E supplementation. The vitamin E-hormone relation is understudied in non-smokers.
Serum sex steroid hormones and α-tocopherol were measured for 1,457 men in NHANES III. Multivariable-adjusted geometric mean hormone concentrations by α-tocopherol quintile were estimated.
We observed lower mean testosterone, estradiol, and SHBG concentrations with increasing serum α-tocopherol (Q1=5.5 and Q5=4.6 ng/mL, p-trend=0.0007; Q1=37.8 and Q5=33.1 pg/mL, p-trend=0.02; Q1=38.8 and Q5=30.6 pg/mL, p-trend=0.05, respectively). Interactions between serum α-tocopherol and exposure to cigarette smoke for total testosterone, total estradiol, and SHBG were found with the inverse relation observed only among smokers.
Results from this nationally representative, cross-sectional study indicate an inverse association between serum α-tocopherol and circulating testosterone, estradiol, and SHBG, but only in men who smoked. Our findings support vitamin E selectively influencing sex hormones in smokers, and afford possible mechanisms through which vitamin E may impact prostate cancer risk.
PMCID: PMC3499970  PMID: 21424597
Gonadal Steroid Hormones; alpha-Tocopherol; Smoking; Prostatic Neoplasms; Cross-Sectional Studies
18.  Vitamin E Serum Levels and Controlled Supplementation and Risk of Amyotrophic Lateral Sclerosis 
There are no observational studies or controlled trials of amyotrophic lateral sclerosis (ALS) and circulating α-tocopherol (vitamin E) for prevention of ALS. This study addresses that gap.
The study population comprised 29,127 Finnish male smokers, aged 50–69 years, who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which is both a prospective cohort and a randomized, double-blind, placebo-controlled trial of α-tocopherol (50 mg/day) and β-carotene (20 mg/day). Serum α-tocopherol and β-carotene was assayed at baseline (1985–1988). Follow-up (median 16.7 years) continued through 2004. ALS cases were identified through the national Hospital Discharge Register with diagnostic verification by hospital records and death certificates.
During 407,260 person-years of follow-up, 50 men were identified with ALS. For men with serum α-tocopherol concentration above the median (≥11.6 mg/l), the age-adjusted relative risk (RR) compared to α-tocopherol below the median, was 0.56 (95% confidence interval= 0.32–0.99), p=0.046. The RR among α-tocopherol supplement recipients was 0.75 (95% CI=0.32–1.79), p=0.52. Neither serum β-carotene level nor β-carotene supplementation was associated with ALS.
The results are consistent with a hypothesized protective effect of α-tocopherol on ALS risk. However, pooled analyses of cohorts with serum and controlled trials are needed to clarify the role of α-tocopherol in ALS risk.
PMCID: PMC3673294  PMID: 23286756
Amyotrophic lateral sclerosis; vitamin E; cohort studies; risk factors in epidemiology
19.  Supplemental and highly-elevated tocopherol doses differentially regulate allergic inflammation: reversibility of α-tocopherol and γ-tocopherol's effects 
We have reported that supplemental doses of the α- and γ-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with antigen and supplemental tocopherols in a first phase of treatment followed by a 4 week clearance phase and then the mice received a second phase of antigen and tocopherol treatments. The pro-inflammatory effects of supplemental levels of γ-tocopherol in phase 1 were only partially reversed by supplemental α-tocopherol in phase 2 but were completely reversed by raising α-tocopherol levels 10-fold in phase 2. When γ-tocopherol levels were increased 10-fold (highly-elevated tocopherol) so that the lung tissue γ-tocopherol levels were equal to the lung tissue levels of supplemental α-tocopherol, γ-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly-elevated levels of γ-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly-elevated tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of antigen challenge without tocopherols. In summary, the pro-inflammatory effects of supplemental γ-tocopherol on lung inflammation were partially reversed by supplemental levels of α-tocopherol but were completely reversed by highly-elevated-levels of α-tocopherol. Also, highly-elevated levels of γ-tocopherol were inhibitory and reversible in lung lavage but, importantly, were pro-inflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a new context in which to review vitamin E studies in the literature.
PMCID: PMC3271805  PMID: 21317387
inflammation; tocopherol; vitamin E; endothelial cell; leukocyte recruitment
20.  Prospective analysis of serum carotenoids, vitamin A and tocopherols in adults with short bowel syndrome undergoing intestinal rehabilitation 1 
Carotenoids, vitamin A and tocopherols serve important roles in many key body functions. However, availability of these compounds may be decreased in patients with short bowel syndrome (SBS) due to decreased oral intake of fruits and vegetables and/or decreased intestinal absorption. Little information is available on serum concentrations of carotenoids, vitamin A and tocopherols during chronic parenteral nutrition (PN) or during PN weaning. The aim of this study was to prospectively examine serum concentrations of a wide variety of carotenoids, vitamin A and tocopherols in SBS patients undergoing an intensive 12-week intestinal rehabilitation program. Twenty-one PN-dependent adult SBS patients were enrolled in a 12-week intestinal rehabilitation program, which included individualized dietary modification, multivitamin supplementation, and randomization to receive either s.c. placebo (n=9) or human growth hormone (GH, 0.1 mg/kg/day). PN weaning was initiated after week 4 and advanced as tolerated. Serum concentrations of carotenoids, vitamin A and tocopherols were determined at baseline and at weeks 4 and 12. Results showed that a significant % of subjects exhibited low serum concentrations for carotenoids and α-tocopherol at study entry, while a few subjects had low concentrations of retinol (5%). Serum α-tocopherol concentration was negatively associated with PN lipid dose (r = - 0.34, p < 0.008). We conclude that SBS patients are depleted in diet-derived carotenoids despite oral and intravenous multivitamin supplementation and dietary adjustment during intestinal rehabilitation and PN weaning. Reduction of PN lipid infusion may improve serum α-tocopherol concentrations.
PMCID: PMC2670964  PMID: 19081706
short bowel syndrome; carotenoids; vitamin A; tocopherols; parenteral nutrition
21.  Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: The Multiethnic Cohort Study 
While smoking is the primary risk factor for lung cancer, there is evidence to suggest that fruit and vegetable intake are important co-factors. The present case-control study, nested within the Multiethnic Cohort Study, examined the associations of biomarkers of fruit and vegetable intake (individual plasma micronutrient levels), serum selenium and a urinary biomarker for total lipid peroxidation with lung cancer risk. 207 incident cases were matched to 414 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection and hours of fasting. We measured prediagnositic circulating levels of individual tocopherols and carotenoids, retinol, and serum selenium, and urinary 15-isoprostane F2t. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). For men, strong reductions in risk were seen with increasing tertiles of each plasma carotenoid, with the ORs for the third tertile, compared to the first tertile, ranging from 0.24 to 0.45 (p for trends: 0.002-0.04). No associations were found among women for carotenoids or among either sex for tocopherols, selenium and retinol. A doubling in risk was seen for men in the second and third tertiles, compared to the first tertile of urinary 15-isoprostane F2t (OR=2.31, 95% CI: 1.02-5.25 and OR=2.16, 95% CI: 0.98-4.78). This study supports the previously observed association between circulating carotenoids and lung cancer risk in men, and adds to the limited literature regarding urinary 15-isoprostane F2t as a marker of cancer risk. Future research examining the possible relationship between isoprostanes and lung cancer is warranted.
PMCID: PMC2755047  PMID: 19531680
antioxidant; biomarkers; tocopherol; carotenoid; selenium; retinol; isoprostane; lipid peroxidation; lung cancer
22.  Association of variants in two vitamin E transport genes with circulating vitamin E concentrations and prostate cancer risk 
Cancer research  2009;69(4):1429-1438.
Significant reductions in prostate cancer incidence and mortality were observed in men randomized to receive 50 mg supplemental vitamin E (α-tocopherol) per day in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We hypothesized that variation in key vitamin E transport genes might directly affect prostate cancer risk or modify the effects of vitamin E supplementation. Associations between prostate cancer risk and 13 polymorphisms in two genes – TTPA and SEC14L2 – were examined in 982 incident prostate cancer cases and 851 controls drawn from the ATBC Study. There was no association between the genetic variants and prostate cancer risk. Significant interactions were observed, however, between two variants in SEC14L2 (IVS11+931A>G and IVS11−896A>T) and the trial α-tocopherol supplement such that vitamin E supplementation reduced prostate cancer risk among men who were homozygous for either common allele [odds ratios (OR) and 95% confidence intervals (CI) = 0.52 (0.30−0.90) and 0.64 (0.46−0.88), respectively] and nonsignificantly increased risk among those who carried one or two copies of either variant allele [ORs = 1.27 (0.90−1.79) and 1.21 (0.96−1.52), respectively] (both p for interaction < 0.05). Genotype-phenotype analyses revealed significant but modest differences in baseline circulating concentrations of α-tocopherol and serum responses to the vitamin E supplementation for several polymorphisms. This study demonstrates that genetic variation in TTPA and SEC14L2 is associated with serum α-tocopherol but does not have a direct impact on prostate cancer. Our results do, however, suggest that polymorphisms in SEC14L2 may modify the effect of vitamin supplementation regimens on prostate cancer risk.
PMCID: PMC2644342  PMID: 19190344
genetic variants; prostate cancer; SNP; vitamin E
23.  Relation of Serum α- and γ-Tocopherol Levels to Cardiovascular Disease-Related Mortality Among Japanese Men and Women 
Journal of Epidemiology  2012;22(5):402-410.
There is limited evidence regarding the relationship between serum tocopherol levels and cardiovascular disease.
We conducted a nested case-control study as part of the Japan Collaborative Cohort Study for evaluation of cancer risk (JACC Study). Baseline serum samples were collected from 39 242 participants (age range, 40–79 years) between 1988 and 1990. During the 13-year follow-up, there were 530 stroke deaths (302 ischemic strokes and 210 hemorrhagic strokes) and 211 deaths from coronary heart disease. Controls were matched for sex, age, and area of residence.
Serum α-tocopherol level was not associated with any type of cardiovascular death in men; however, in women, it was inversely associated with total stroke mortality and hemorrhagic stroke mortality. The multivariate odds ratio (95% CI) for the highest versus the lowest quintile of serum α-tocopherol levels among women was 0.35 (0.16–0.77; P for trend = 0.009) for total stroke and 0.26 (0.07–0.97; P for trend = 0.048) for hemorrhagic stroke. Serum γ-tocopherol was inversely associated with ischemic stroke mortality in men but positively associated with hemorrhagic stroke mortality in women. The respective multivariate odds ratios (95% CI) for the highest versus the lowest quintile and for a 1-standard deviation increment in γ-tocopherol level were 0.48 (0.22–1.06; P for trend = 0.07) and 0.77 (0.58–1.02), respectively, for ischemic stroke in men and 3.10 (0.95–10.12; P for trend = 0.052) and 1.49 (1.04–2.13) for hemorrhagic stroke in women.
Among women, hemorrhagic stroke mortality was inversely associated with serum α-tocopherol and positively associated with serum γ-tocopherol. These findings are due in part to the antioxidative and antithrombotic activities of these tocopherols.
PMCID: PMC3798634  PMID: 22672959
α-tocopherol; γ-tocopherol; vitamin E; prospective study; stroke; cardiovascular disease; nested case-control study
24.  No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma 
Previous epidemiologic studies that have examined the relationship between renal cell carcinoma (RCC) risk and intakes of plant foods and antioxidant nutrients have yielded inconsistent results. We therefore examined the associations between intakes of fruit, vegetables, carotenoids, flavonoids, vitamin E, and vitamin C and RCC risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. At baseline, 27,062 male Finnish smokers aged 50–69 years completed a 276-item dietary questionnaire that included questions on frequency of consumption and portion size. During up to 19 years of follow-up, 255 men developed RCC. Cox proportional hazards models were utilized to estimate relative risks (RR) and 95% confidence intervals (CI). Despite a large range in intake, no association was observed between fruit, vegetables, or antioxidant nutrients and RCC risk. For example, multivariate RRs and 95% CIs for the highest versus the lowest quartile of intake were 0.79 (0.55–1.14), 1.23 (0.85–1.79), 1.09 (0.74–1.60), 0.83 (0.57–1.21), 1.09 (0.73–1.64), and 0.99 (0.67–1.46) for fruit, vegetables, total carotenoids, total flavonoids, total vitamin E, and vitamin C, respectively (all p-values for trend > 0.05). Our results indicate that diet may not play a large role in the etiology of RCC in male smokers, although further examination of these associations in nonsmokers, women, and diverse racial populations is warranted.
PMCID: PMC2811212  PMID: 19685494
antioxidants; cohort study; diet; fruit; renal cell cancer; vegetables
25.  Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. 
The independent and joint associations of serum selenium and vitamin A (retinol) and E (alpha tocopherol) concentrations with the risk of death from cancer were studied in 51 case-control pairs--that is, 51 patients with cancer, each paired with a control matched for age, sex, and smoking. Case-control pairs came from a random sample of some 12000 people aged 30-64 years resident in two provinces of eastern Finland who were followed up for four years. Patients who died of cancer during the follow up period had a 12% lower mean serum selenium concentration (p = 0.015) than the controls. The difference persisted when deaths from cancer in the first follow up year were excluded. The adjusted risk of fatal cancer was 5.8-fold (95% confidence interval 1.2-29.0) among subjects in the lowest tertile of selenium concentrations compared with those with higher values. Subjects with both low selenium and low alpha tocopherol concentrations in serum had an 11.4-fold adjusted risk. Among smoking men with cancer serum retinol concentrations were 26% lower than in smoking controls (p = 0.002). These data suggest that dietary selenium deficiency is associated with an increased risk of fatal cancer, that low vitamin E intake may enhance this effect, and that decreased vitamin or provitamin A intake contributes to the risk of lung cancer among smoking men with a low selenium intake.
PMCID: PMC1417771  PMID: 3918611

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