Skin Health

Human Studies/ Cohort Studies



Study objective/ findings

Cosmetic benefit of dietary supplements including astaxanthin and tocotrienol on human skin

Yamashita E. (2002). Food Style 21, 6(6), 112-117.

The cosmetic effect on the skin of dietary supplements containing astaxanthin and tocotrienol (EVNol 50%) was demonstrated in a double-blind clinical study. A noticeable improvement to skin condition in term of moisture and skin wrinkles was observed upon supplementation of tocotrienol and astaxanthin, despite the harsh environmental condition of winter that causing the skin of the volunteers to be particularly dry.
Clinical evaluation of photoprotective effect by a topical antioxidants combination (tocopherols and tocotrienols).

Pedrelli, V.F., (2012). J Eur Acad Dermatol Venereol.

In view of experimental evidence for the photoprotective properties of these antioxidants, we evaluated in 30 patients with photosensitivity, the prophylactic efficacy of a new topical agent, containing tocopherols 10% and tocotrienols 0.3%, compared with retinol, simple vehicle and untreated areas. The use of a new topical formulation containing significant concentrations of tocotrienols and tocopherols represents a promising strategy to reduce the photo-induced skin damage.


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

Weber, S. U., (2003). Free Radic Biol Med.

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

In-vivo / Animal Studies

Tocotrienol (unsaturated vitamin E) suppresses degranulation of mast cells and reduces allergic dermatitis in mice.

Tsuduki, T., et. al (2012). J Oleo Sci.

Tocotrienol (T3) reduces allergic dermatitis in mice and suppresses degranulation of mast cells. The effect of T3 on protein kinase C (PKC) activity was also measured, since suppression of this activity may be associated with the mechanism underlying the antidegranulation effect of T3. T3 significantly suppressed PKC activity. Therefore, we conclude that T3 suppresses degranulation of mast cells and reduces allergic dermatitis in mice through reduction of PKC activity.
Selective uptake of dietary tocotrienols into rat skin.

Ikeda, S., (2000). J Nutr Sci Vitaminol (Tokyo).

Using a vitamin E mixture extracted from palm oil, the tissue distribution of dietary tocotrienols and tocopherols was examined in rats and mice. Wistar rats (4-wk-old) were fed a diet containing 48.8mg/kg a-tocopherol, 45.8mg/kg a-tocotrienol and 71.4mg/kg γ-tocotrienol for 8 wk. Nude mice (BALB/c Sic-nu, 8-wk-old) and hairless mice (SKH1, 8-wk-old) were fed the same diet for 4 wk. α-Tocopherol was abundantly retained in the skin, liver, kidney and plasma of rats and mice. α-Tocotrienol and γ-tocotrienol were de-tected slightly in the liver, kidney and plasma, while substantial amounts of these to-cotrienols were detected in the skin of both rats and mice. The present study suggests that the skin is a unique tissue in respect to its ability to discriminate between various vitamin E analogs.
Penetration and distribution of alpha-tocopherol, alpha-, or gamma-tocotrienol applied individually onto murine skin.

Traber, M. G., (1998). Lipids.

To evaluate skin penetration of various vitamin E homologs, a 5% solution of either alpha-tocopherol, alpha-tocotrienol, or gamma-tocotrienol in polyethylene glycol was topically applied to SKH-1 hairless mice. Applied vitamin E penetrates rapidly through the skin, but the highest concentrations are found in the uppermost 5 microns.
Efficacy of topically applied tocopherols and tocotrienols in protection of murine skin from oxidative damage induced by UV-irradiation.

Weber, C., (1997). Free Radic Biol Med.

To assess the efficacy of various forms of vitamin E in protection of skin from UV-light-induced oxidative stress, vitamin E (tocotrienol-rich fraction of palm oil, TRF) was applied to mouse skin and the contents of antioxidants before and after exposure to UV-light were measured.
Ozone depletes tocopherols and tocotrienols topically applied to murine skin.

Thiele, J.J., (1997). FEBS Lett.

To evaluate ozone damage to hairless mouse skin, two parameters of oxidative damage, vitamin E depletion and malondialdehyde (MDA) production, were measured in vitamin E-enriched and in control skin from mice exposed to ozone (10 ppm). This is the first demonstration that ozone exposure causes damage to cutaneous lipids, an effect which can be attenuated by vitamin E application.

In vitro Studies

In vitro safety evaluation of palm tocotrienol-rich fraction nanoemulsion for topical application

Zafarizal et al., (2018). JOPR.

The studies on irritation potential of palm tocotrienol-rich fraction (TRF) nanoemulsion using in vitro ocular and dermal irritection assays, reconstructed human epidermis and human corneal epithelium tests were investigated. Palm TRF nanoemulsion did not exhibit any potential skin irritation in the in vitro ocular and dermal irritation assessment. The studies showed that when reconstructed human corneal epithelium and human epidermis models were treated with the tocotrienol macroemulsion and nanoemulsions, no indication of irritancy to the eyes or dermal tissues were observed giving a mean tissue viability of more than 60% and 50%, respectively.
Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol

Marzagalli et al., (2018). Scientific Reports.

For metastatic melanoma, chemotherapeutic agents, dacarbazine or temozolomide, have been considered the reference drugs; however, patients very often become resistant to these compounds, with low overall response and survival rates. On the other hand, it is now well accepted that cancer stem cells (CSCs) are deeply involved in the development of therapy resistance, thereby contributing to disease relapse after an initial positive response to therapy. This study observed that A375 cells are able to form melanospheres and show CSCs traits. The aim of this study was to identify and characterize the subpopulation of CSCs in melanoma cells and to investigate whether delta-tocotrienol might affect melanoma cell growth by targeting this aggressive subpopulation of cancer cells. Result demonstrates that delta-tocotrienol exerts its antitumor activity by targeting the CSC subpopulation of A375 melanoma cells.
Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas.

Pham. J., (2016). Drug Deliv.

 UV-irradiation of skin destroys its antioxidants: however, prior application of TRF to mouse skin results in preservation of vitamin E. The proposed hybrid nano-emulsified formulation of Tocomin® provides simple and stable delivery platform, for effective topical application against keratinocyte tumors.
Anti-melanogenic effects of δ-tocotrienol are associated with tyrosinase-related proteins and MAPK signaling pathway in B16 melanoma cells.

Ng, L.T., (2014). Phytomedicine.

 The mechanism involved in the anti-melanogenic effects of δ-tocotrienol (δT3) in B16 melanoma cells. These results suggest that δT3’s inhibitory effect against melanogenesis is mediated by the activation of ERK signaling, thereby resulting in downstream repression of melanogenesis-related proteins and the subsequent melanin production. These data provide insight to δT3’s effect and the targeting of ERK signaling for treatment against melanogenesis.
Comparable down-regulation of TYR, TYRP1 and TYRP2 genes and inhibition of melanogenesis by tyrostat, tocotrienol-rich fraction and tocopherol in human skin melanocytes improves skin pigmentation.

Makpol, S., (2014). Clin Ter.

The molecular mechanism of tyrostat, tocopherol and tocotrienol-rich fraction in inhibiting melanogenesis in human skin melanocytes. Tyrostat, tocopherol and tocotrienol-rich fraction possessed anti-melanogenic properties and might be useful in improving skin pigmentation caused by UVA exposure.
Comparative effects of biodynes, tocotrienol-rich fraction (TRF), and tocopherol in enhancing collagen synthesis and inhibiting collagen degradation in stress-induced premature senescence model of human diploid fibroblasts.

Makpol, S., (2013). Oxid Med Cell Longev

The skin aging effects of biodynes, TRF, and tocopherol on stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs) by determining the expression of collagen and MMPs at gene and protein levels. These findings indicated that biodynes, TRF, and tocopherol effectively enhanced collagen synthesis and inhibited collagen degradation and therefore may protect the skin from aging.
Tocotrienols enhance melanosome degradation through endosome docking/fusion proteins in B16F10 melanoma cells.

Choi, B., (2013). Food Funct.

To determine whether vitamin E-induced melanosome disintegration is related to the expression of endosome docking/fusion proteins in B16F10 melanoma cells, electron microscopy, reverse transcription-polymerase chain reaction (RT-PCR), and real-time PCR were used to observe the effects of tocomin (α-tocopherols and α,γ,δ-tocotrienols in palm oil) on B16F10 melanoma cells. These results indicate that the tocomin-induced degradation of melanosomes in the lysosomal compartment occurs with an increase in endosome docking/fusion proteins (syntaxin7, Vps16, Vps33, and Vps41) in cultured B16F10 melanoma cells.
Modulation of collagen synthesis and its gene expression in human skin fibroblasts by tocotrienol-rich fraction

Makpol, S., (2011). Arch Med Sci.

The molecular mechanism of tocotrienol-rich fraction (TRF) in preventing oxidative stress-induced skin aging was evaluated by determining the rate of total collagen synthesis and its gene expression in human skin fibroblasts. TRF may protect against oxidative stress-induced skin aging by modulating the expression of COL I and COL III genes with a concomitant increase in the rate of collagen synthesis. These protective effects however were only observed in the pre-treated fibroblasts.
Delta-gamma-tocotrienol mediated cell cycle arrest and apoptosis in human melanoma cells

Fernandes, N.V., (2010). AntiCancer Resarch.

The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation or dolichylation of growth-related proteins. d-δ-Tocotrienol, a post-transcriptional downregulator of HMG CoA reductase, suppresses the proliferation of murine B16 melanoma cells. Dietary d-δ- tocotrienol suppresses the growth of implanted B16 melanomas without toxicity to host mice. d-δ-Tocotrienol may have potential application in melanoma chemoprevention and/or therapy.
Effect of Delta-Tocotrienol on Melanin Content and Enzymes for Melanin Synthesis in Mouse Melanoma Cells

Akihiro, M., (2010). Biol. Pharm. Bull.

The dose-dependent effect of d-tocotrienol long term (48, 72 h) on the melanin content of cells treated with d-tocotrienol, and whether cells treated with d-tocotrienol for long a time show cytotoxicity was investigated. d-tocotrienol at up to 50 mM dose-dependently caused a reduction in melanin content by the decrease of TRP-1 and TRP-2 as well as tyrosinase, and no cytotoxicity.
Suppression of gamma-tocotrienol on UVB-induced inflammation in HaCaT keratinocytes and HR-1 hairless mice via inflammatory mediators multiple signaling.

Shibata, A. (2010). J Agric Food Chem

The anti-inflammatory effect of T3 on UVB-induced inflammatory reaction using immortalized human keratinocytes and hairless mice was evaluated. Western blot analysis revealed gamma-T3 inhibited p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase/stress-activated protein kinase activation. In HR-1 hairless mice, oral T3 suppressed UVB-induced changes in skin thickness, COX-2 protein expression, and hyperplasia, but alpha-Toc did not. These results suggest T3 has potential use to protect against UVB-induced skin inflammation.


Modulation of melanin synthesis and its gene expression in skin melanocytes by palm tocotrienol rich fraction

Makpol, S., (2009). African Journal of Biochemistry Research.

This study was to evaluate the anti-pigmentation property of palm tocotrienol rich fraction by determining melanin synthesis and expression of genes involved in its regulation in skin melanocytes. Palm tocotrienol rich fraction has an anti-pigmentation property that inhibit melanin synthesis by inhibiting tyrosinase activity and down regulating TYRP2 gene expression.
Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells

Chang, P.N., (2009). Nutr Cancer

To elucidate this anticancer property in malignant melanoma, this study aimed, first, to identify the most potent isomer for eliminating melanoma cells and second to decipher the molecular pathway responsible for its activity. Gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, synergistic effect was observed when cells were cotreated with gamma-tocotrienol and chemotherapy drugs. Together, our results demonstrated for the first time the anti-invasion and chemonsensitization effect of gamma-tocotrienol against human malignant melanoma cells.
A redox-silent analogue of tocotrienol acts as a potential cytotoxic agent against human mesothelioma cells

Kashiwagi, K, (2009). Life Sci.

The effects of tocotrienol on killing of chemoresistance mesothelioma cells (H28). Tocotrienol can be a new effective therapeutic agent against chemoresistant mesothelioma cells.

Delta-tocotrienol causes decrease of melanin content in mouse melanoma cells.

Akihiro M., (2009). J of Health Sci.

The effects of delta-tocotrienol on melanin content in mouse melanoma B12 cells.  The decrease of melanin content in cells by delta-tocotrienol was the result of the decrease of protein level of tyrosinase (tyrosinase degradation is more important than the decrease of mRNA).
Palm oil alleviates 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion response in murine skin.

Kausar, H., (2003). Cancer Lett.

In this study we therefore assessed the anti-tumor promoting potential of palm oil against TPA-mediated skin tumorigenesis in 7,12-dimethylbenz[a]anthracene-initiated Swiss albino mice. The results of the present study thus suggest that palm oil possesses anti-skin tumor promoting effects, and that the mechanism of such effects may involve the inhibition of tumor promoter-induced epidermal ODC activity, [(3)H]thymidine incorporation and cutaneous oxidative stress.