Compendium of the most significant studies with reference to properties, intake, effects.
Li GX, Lee MJ, Liu AB, Yang Z, Lin Y, Shih WJ, Yang CS. δ-tocopherol is more active than α - or γ -tocopherol in inhibiting lung tumorigenesis in vivo. Cancer Prev Res (Phila). 2011 Mar;4(3):404-13. doi: 10.1158/1940-6207.CAPR-10-0130.
Abstract. 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 this 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 μmol/L for α-tocopherol, 9.7 μmol/L for γ-tocopherol, and 1.2 μmol/L 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. This study is the first in vivo assessment of δ-tocopherol in tumorigenesis and shows 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.
Xu M, Liu K, Swaroop M, Porter FD, Sidhu R, Firnkes S, Ory DS, Marugan JJ, Xiao J, Southall N, Pavan WJ, Davidson C, Walkley SU, Remaley AT, Baxa U, Sun W, McKew JC, Austin CP, Zheng W. δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem. 2012 Nov 16;287(47):39349-60. doi: 10.1074/jbc.M112.357707.
Abstract. Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca(2+) response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.
Smolarek AK, So JY, Burgess B, Kong AN, Reuhl K, Lin Y, Shih WJ, Li G, Lee MJ, Chen YK, Yang CS, Suh N. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer. Cancer Prev Res (Phila). 2012 Nov;5(11):1310-20. doi: 10.1158/1940-6207.CAPR-12-0263. Epub 2012 Sep 10.
Abstract. 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). Although 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 proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer.
Manthe RL, Rappaport JA, Long Y, Solomon M, Veluvolu V, Hildreth M, Gugutkov D, Marugan J, Zheng W, Muro S. δ-Tocopherol Effect on Endocytosis and Its Combination with Enzyme Replacement Therapy for Lysosomal Disorders: A New Type of Drug Interaction? J Pharmacol Exp Ther. 2019 Sep;370(3):823-833. doi: 10.1124/jpet.119.257345.
Abstract. Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy affects other vesicular compartments, e.g., those involved in endocytosis, is unknown. This is important both to predict side effects and to use this strategy in combination with therapies that require endocytosis for intracellular delivery, such as lysosomal enzyme replacement therapy (ERT). We investigated this using δ-tocopherol as a model previously shown to induce lysosomal exocytosis and cell models of type A Niemann-Pick disease, a LD characterized by acid sphingomyelinase (ASM) deficiency and sphingomyelin storage. δ-Tocopherol and derivative CF3-T reduced net accumulation of fluid phase, ligands, and polymer particles via phagocytic, caveolae-, clathrin-, and cell adhesion molecule (CAM)-mediated pathways, yet the latter route was less affected due to receptor overexpression. In agreement, δ-tocopherol lowered uptake of recombinant ASM by deficient cells (known to occur via the clathrin pathway) and via targeting intercellular adhesion molecule-1 (associated to the CAM pathway). However, the net enzyme activity delivered and lysosomal storage attenuation were greater via the latter route. Data suggest stimulation of exocytosis by tocopherols is not specific of lysosomes and affects endocytic cargo. However, this effect was transient and became unnoticeable several hours after tocopherol removal. Therefore, induction of exocytosis in combination with therapies requiring endocytic uptake, such as ERT, may represent a new type of drug interaction, yet this strategy could be valuable if properly timed for minimal interference.
Huang H, He Y, Cui XX, Goodin S, Wang H, Du ZY, Li D, Zhang K, Tony Kong AN, DiPaola RS, Yang CS, Conney AH, Zheng X. Potent inhibitory effect of δ-tocopherol on prostate cancer cells cultured in vitro and grown as xenograft tumors in vivo. J Agric Food Chem. 2014 Nov 5;62(44):10752-8. doi: 10.1021/jf504058f.
Abstract. In the present study, the effects of δ-tocopherol (δ-T) on growth and apoptosis of human prostate cancer cells were determined and compared with that of α-tocopherol (α-T), a commonly used form of vitamin E. Treatment of human prostate cancer cells with δ-T resulted in strong growth inhibition and apoptosis stimulation, while the effects of α-T were modest. The strong effects of δ-T on the cells were associated with suppression of androgen receptor (AR) activity and decreased level of prostate specific antigen (PSA) that is a downstream target of the AR signaling. In the in vivo study, we found that δ-T had a more potent inhibitory effect on the formation and growth of prostate xenograft tumors than that of α-T. Moreover, δ-T inhibited proliferation and stimulated apoptosis in the tumors. The present study identified δ-T as a better form of vitamin E than α-T for future clinical studies of prostate cancer prevention.
Mavon A, Raufast V, Redoulès D. Skin absorption and metabolism of a new vitamin E prodrug, delta-tocopherol-glucoside: in vitro evaluation in human skin models. J Control Release. 2004 Nov 24;100(2):221-31. doi: 10.1016/j.jconrel.2004.08.012.
Abstract. The aim of this study was to investigate the cutaneous penetration and metabolism of the new vitamin E prodrug delta-tocopherol glucoside (delta-TG), as compared to those of common vitamin E acetate, in vitro, both in reconstituted human epidermis and in viable human skin. Better diffusion was observed with alpha-tocopherol acetate (alpha-TAc) than with delta-tocopherol glucoside in both skin models, at 0.1% and 0.05% in a myritol solution; however, no metabolism was detected with alpha-tocopherol acetate. In all conditions tested (two skin models, two concentrations, three test times, and compartmental analysis) the delta-tocopherol glucoside was metabolized into free tocopherol. In the reconstituted human epidermis, after 18 h, over 90% of the delta-tocopherol glucoside was bioconverted. In the viable human skin, the extent of metabolism was about 20%, with 0.12 and 0.10 microg/cm2 of delta-tocopherol glucoside in the stratum corneum and epidermis, respectively. After topical application, the delta-tocopherol glucoside had a considerable reservoir effect, associated with gradual delivery of free tocopherol. The use of this gluco-conjugated vitamin E at a low concentration shows the capability of the skin to metabolize the prodrug in a slow and prolonged manner, making this gluco-conjugated vitamin E an excellent candidate for continuous reinforcement of antioxidants in the skin.
Mahabir S, Schendel K, Dong YQ, Barrera SL, Spitz MR, Forman MR. Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk. Int J Cancer. 2008 Sep 1;123(5):1173-80. doi: 10.1002/ijc.23649.
Abstract. Studies of vitamin E and cancer have focused on the alpha-tocopherol form of the vitamin. However, other forms of vitamin E, in particular gamma-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary alpha-tocopherol intake were 1.0, 0.63 (0.50-0.79), 0.58 (0.44-0.76) and 0.39 (0.28-0.53), respectively (p-trend < 0.0001). For dietary intake of beta-tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63-0.98), 0.59 (0.45-0.78) and 0.56 (0.42-0.74), respectively (p-trend < 0.0001). Similar results for dietary gamma-tocopherol intake were observed: 1.0, 0.84 (0.67-1.06), 0.76 (0.59-0.97) and 0.56 (0.42-0.75), respectively (p- trend = 0.0002). No significant association between delta-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary alpha-tocopherol intake remained significant; i.e., increasing intake of dietary alpha-tocopherol accounted for 34-53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (alpha-, beta-, gamma- and delta-tocohperol) on lung cancer risk. Given the limitations with case-control studies, these findings need to be confirmed in further investigations.
Delta-tocopherol 
